Current Psychiatry

Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

More on T. gondii

We reviewed the article by Dr. Torrey on Toxoplasma gondii (T. gondii) and schizophrenia (“Cats, toxoplasmosis, and psychosis: Understanding the risks,” Current Psychiatry, May 2022, p. 14-19) with interest. Understanding infections in utero, during the perinatal period, and at other critical developmental stages may offer ways to prevent neurodevelopmental disorders. There appear to be good reasons to explore infectious and immune disruption of normal brain development. In a meta-analysis of 7 studies, Nayeri et al¹ found evidence to suggest T. gondii is a risk factor for autism spectrum disorder (ASD). Given the enormous loss of human potential and suffering resulting from schizophrenia and ASD, further exploration of toxoplasmosis and other infections may be valuable as we try to reduce the severe impact of these diseases.

The natural history of toxoplasmosis is an extraordinary example of nature’s complexity. The life cycle of this parasite uses the nervous system of the mouse to increase its transmission. Behavior changes ranging from reduced cat urine avoidance and increased risk-taking are observed in mice infected with T. gondii.² Chronic toxoplasmosis may also affect human behavior.³

Cats are fascinating, complex creatures. Of note, they produce a protein structurally like the secretion of the slow loris.⁴ The loris uses this brachial gland protein secretion as part of a defense strategy.⁵ Consideration of a possible toxic, neuroimmune role of these small mammal proteins in psychiatric disorders may open other avenues to explore.⁶

Our relationship to domesticated animals has been connected to serious diseases throughout human history.⁷ Severe acute respiratory syndrome and COVID-19 appear to be linked to animal reservoirs, mammals of the small animal trade, and the fur industry.^8,9 The rapid development of vaccines for COVID-19 is commendable. In conditions with multifactorial causation, managing an infectious component is worthy of consideration.

With mounting evidence suggesting a link between T. gondii and schizophrenia, ASD, and other diseases, further epidemiological studies and pilot interventions offer value. Interventions, including encouraging keeping cats indoors only, cat immunization, and human treatment, could be implemented in high-risk families. Efficacy requires data collection. While not easy, collaborative work by psychiatrists, developmental pediatricians, veterinarians, and epidemiologists is encouraged.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Michelle Douglass, PA-S2
Duke University Physician Assistant Program
Durham, North Carolina

References

1. Nayeri T, Sarvi S, Moosazadeh M, et al. Relationship between toxoplasmosis and autism: a systematic review and meta-analysis. Microb Pathog. 2020;147:104434. doi:10.1016/j.micpath.2020.104434
2. Kochanowsky JA, Koshy AA. Toxoplasma gondii. Curr Biol. 2018;28(14):R770-R771. doi:10.1016/j.cub.2018.05.035
3. Letcher S. Parasite mind control: how a single celled parasite carried in the cat intestine may be quietly tweaking our behavior. Scientific Kenyon: The Neuroscience Edition. 2018;22(1):4-11.
4. Scheib H, Nekaris KA, Rode-Margono J, et al. The toxicological intersection between allergen and toxin: a structural comparison of the cat dander allergenic protein Fel d1 and the slow loris brachial gland secretion protein. Toxins (Basel). 2020;12(2):86. doi:10.3390/toxins12020086
5. Nekaris KA, Moore RS, Rode EJ, et al. Mad, bad and dangerous to know: the biochemistry, ecology and evolution of slow loris venom. J Venom Anim Toxins Incl Trop Dis. 2013;19(1):21. doi:10.1186/1678-9199-19-21
6. Ligabue-Braun R. Hello, kitty: could cat allergy be a form of intoxication? J Venom Anim Toxins Incl Trop Dis. 2020;26:e20200051. doi:10.1590/1678-9199-JVATITD-2020-0051
7. Pearce-Duvet JM. The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease. Biol Rev Camb Philos Soc. 2006;81(3):369-382. doi:10.1017/S1464793106007020
8. Jo WK, de Oliveira-Filho EF, Rasche A, et al. Potential zoonotic sources of SARS-CoV-2 infections. Transbound Emerg Dis. 2021;68(4):1824-1834. doi:10.1111/tbed.13872
9. Bell D, Roberton S, Hunter PR. Animal origins of SARS coronavirus: possible links with the international trade in small carnivores. Philos Trans R Soc Lond B Biol Sci. 2004;359(1447):1107-1114. doi:10.1098/rstb.2004.1492

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

Continue to: Pramipexole for MDD

I appreciate Dr. Espejo’s recommendations for treating patients who experience limited response from initial antidepressant therapy (“Treating major depressive disorder after limited response to an initial agent,” Current Psychiatry, October 2021, p. 51-53). I would like to add that pramipexole, a dopamine receptor agonist, can also alleviate depression. A meta-analysis concluded that patients receiving monotherapy or augmentation with pramipexole (mean maximum dose 1.62 mg/d) achieved response or remission of depression.¹ In an observational study of 116 patients with unipolar or bipolar depression, nearly 75% experienced response and 66% achieved remission with pramipexole augmentation (median maximum dose 1.05 mg/d).² Pramipexole is usually well-tolerated, although patients may experience nausea, somnolence, headache, and constipation, and they should be cautioned about the risk for compulsive behaviors and psychosis.

Jonathan R. Scarff, MD
Lexington VA Health Care System
Lexington, Kentucky

References

1. Tundo A, de Filippis R, De Crescenzo F. Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis. Acta Psychiatr Scand. 2019;140(2):116-125.
2. Tundo A, Betrò S, Iommi M, et al. Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study. Prog Neuropsychopharmacol Biol Psychiatry. 2022;112:110425. doi:10.1016/j.pnpbp.2021.110425

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on T. gondii

We reviewed the article by Dr. Torrey on Toxoplasma gondii (T. gondii) and schizophrenia (“Cats, toxoplasmosis, and psychosis: Understanding the risks,” Current Psychiatry, May 2022, p. 14-19) with interest. Understanding infections in utero, during the perinatal period, and at other critical developmental stages may offer ways to prevent neurodevelopmental disorders. There appear to be good reasons to explore infectious and immune disruption of normal brain development. In a meta-analysis of 7 studies, Nayeri et al¹ found evidence to suggest T. gondii is a risk factor for autism spectrum disorder (ASD). Given the enormous loss of human potential and suffering resulting from schizophrenia and ASD, further exploration of toxoplasmosis and other infections may be valuable as we try to reduce the severe impact of these diseases.

The natural history of toxoplasmosis is an extraordinary example of nature’s complexity. The life cycle of this parasite uses the nervous system of the mouse to increase its transmission. Behavior changes ranging from reduced cat urine avoidance and increased risk-taking are observed in mice infected with T. gondii.² Chronic toxoplasmosis may also affect human behavior.³

Cats are fascinating, complex creatures. Of note, they produce a protein structurally like the secretion of the slow loris.⁴ The loris uses this brachial gland protein secretion as part of a defense strategy.⁵ Consideration of a possible toxic, neuroimmune role of these small mammal proteins in psychiatric disorders may open other avenues to explore.⁶

Our relationship to domesticated animals has been connected to serious diseases throughout human history.⁷ Severe acute respiratory syndrome and COVID-19 appear to be linked to animal reservoirs, mammals of the small animal trade, and the fur industry.^8,9 The rapid development of vaccines for COVID-19 is commendable. In conditions with multifactorial causation, managing an infectious component is worthy of consideration.

With mounting evidence suggesting a link between T. gondii and schizophrenia, ASD, and other diseases, further epidemiological studies and pilot interventions offer value. Interventions, including encouraging keeping cats indoors only, cat immunization, and human treatment, could be implemented in high-risk families. Efficacy requires data collection. While not easy, collaborative work by psychiatrists, developmental pediatricians, veterinarians, and epidemiologists is encouraged.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Michelle Douglass, PA-S2
Duke University Physician Assistant Program
Durham, North Carolina

References

1. Nayeri T, Sarvi S, Moosazadeh M, et al. Relationship between toxoplasmosis and autism: a systematic review and meta-analysis. Microb Pathog. 2020;147:104434. doi:10.1016/j.micpath.2020.104434
2. Kochanowsky JA, Koshy AA. Toxoplasma gondii. Curr Biol. 2018;28(14):R770-R771. doi:10.1016/j.cub.2018.05.035
3. Letcher S. Parasite mind control: how a single celled parasite carried in the cat intestine may be quietly tweaking our behavior. Scientific Kenyon: The Neuroscience Edition. 2018;22(1):4-11.
4. Scheib H, Nekaris KA, Rode-Margono J, et al. The toxicological intersection between allergen and toxin: a structural comparison of the cat dander allergenic protein Fel d1 and the slow loris brachial gland secretion protein. Toxins (Basel). 2020;12(2):86. doi:10.3390/toxins12020086
5. Nekaris KA, Moore RS, Rode EJ, et al. Mad, bad and dangerous to know: the biochemistry, ecology and evolution of slow loris venom. J Venom Anim Toxins Incl Trop Dis. 2013;19(1):21. doi:10.1186/1678-9199-19-21
6. Ligabue-Braun R. Hello, kitty: could cat allergy be a form of intoxication? J Venom Anim Toxins Incl Trop Dis. 2020;26:e20200051. doi:10.1590/1678-9199-JVATITD-2020-0051
7. Pearce-Duvet JM. The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease. Biol Rev Camb Philos Soc. 2006;81(3):369-382. doi:10.1017/S1464793106007020
8. Jo WK, de Oliveira-Filho EF, Rasche A, et al. Potential zoonotic sources of SARS-CoV-2 infections. Transbound Emerg Dis. 2021;68(4):1824-1834. doi:10.1111/tbed.13872
9. Bell D, Roberton S, Hunter PR. Animal origins of SARS coronavirus: possible links with the international trade in small carnivores. Philos Trans R Soc Lond B Biol Sci. 2004;359(1447):1107-1114. doi:10.1098/rstb.2004.1492

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

Continue to: Pramipexole for MDD

I appreciate Dr. Espejo’s recommendations for treating patients who experience limited response from initial antidepressant therapy (“Treating major depressive disorder after limited response to an initial agent,” Current Psychiatry, October 2021, p. 51-53). I would like to add that pramipexole, a dopamine receptor agonist, can also alleviate depression. A meta-analysis concluded that patients receiving monotherapy or augmentation with pramipexole (mean maximum dose 1.62 mg/d) achieved response or remission of depression.¹ In an observational study of 116 patients with unipolar or bipolar depression, nearly 75% experienced response and 66% achieved remission with pramipexole augmentation (median maximum dose 1.05 mg/d).² Pramipexole is usually well-tolerated, although patients may experience nausea, somnolence, headache, and constipation, and they should be cautioned about the risk for compulsive behaviors and psychosis.

Jonathan R. Scarff, MD
Lexington VA Health Care System
Lexington, Kentucky

References

1. Tundo A, de Filippis R, De Crescenzo F. Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis. Acta Psychiatr Scand. 2019;140(2):116-125.
2. Tundo A, Betrò S, Iommi M, et al. Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study. Prog Neuropsychopharmacol Biol Psychiatry. 2022;112:110425. doi:10.1016/j.pnpbp.2021.110425

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on T. gondii

We reviewed the article by Dr. Torrey on Toxoplasma gondii (T. gondii) and schizophrenia (“Cats, toxoplasmosis, and psychosis: Understanding the risks,” Current Psychiatry, May 2022, p. 14-19) with interest. Understanding infections in utero, during the perinatal period, and at other critical developmental stages may offer ways to prevent neurodevelopmental disorders. There appear to be good reasons to explore infectious and immune disruption of normal brain development. In a meta-analysis of 7 studies, Nayeri et al¹ found evidence to suggest T. gondii is a risk factor for autism spectrum disorder (ASD). Given the enormous loss of human potential and suffering resulting from schizophrenia and ASD, further exploration of toxoplasmosis and other infections may be valuable as we try to reduce the severe impact of these diseases.

The natural history of toxoplasmosis is an extraordinary example of nature’s complexity. The life cycle of this parasite uses the nervous system of the mouse to increase its transmission. Behavior changes ranging from reduced cat urine avoidance and increased risk-taking are observed in mice infected with T. gondii.² Chronic toxoplasmosis may also affect human behavior.³

Cats are fascinating, complex creatures. Of note, they produce a protein structurally like the secretion of the slow loris.⁴ The loris uses this brachial gland protein secretion as part of a defense strategy.⁵ Consideration of a possible toxic, neuroimmune role of these small mammal proteins in psychiatric disorders may open other avenues to explore.⁶

Our relationship to domesticated animals has been connected to serious diseases throughout human history.⁷ Severe acute respiratory syndrome and COVID-19 appear to be linked to animal reservoirs, mammals of the small animal trade, and the fur industry.^8,9 The rapid development of vaccines for COVID-19 is commendable. In conditions with multifactorial causation, managing an infectious component is worthy of consideration.

With mounting evidence suggesting a link between T. gondii and schizophrenia, ASD, and other diseases, further epidemiological studies and pilot interventions offer value. Interventions, including encouraging keeping cats indoors only, cat immunization, and human treatment, could be implemented in high-risk families. Efficacy requires data collection. While not easy, collaborative work by psychiatrists, developmental pediatricians, veterinarians, and epidemiologists is encouraged.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Michelle Douglass, PA-S2
Duke University Physician Assistant Program
Durham, North Carolina

References

1. Nayeri T, Sarvi S, Moosazadeh M, et al. Relationship between toxoplasmosis and autism: a systematic review and meta-analysis. Microb Pathog. 2020;147:104434. doi:10.1016/j.micpath.2020.104434
2. Kochanowsky JA, Koshy AA. Toxoplasma gondii. Curr Biol. 2018;28(14):R770-R771. doi:10.1016/j.cub.2018.05.035
3. Letcher S. Parasite mind control: how a single celled parasite carried in the cat intestine may be quietly tweaking our behavior. Scientific Kenyon: The Neuroscience Edition. 2018;22(1):4-11.
4. Scheib H, Nekaris KA, Rode-Margono J, et al. The toxicological intersection between allergen and toxin: a structural comparison of the cat dander allergenic protein Fel d1 and the slow loris brachial gland secretion protein. Toxins (Basel). 2020;12(2):86. doi:10.3390/toxins12020086
5. Nekaris KA, Moore RS, Rode EJ, et al. Mad, bad and dangerous to know: the biochemistry, ecology and evolution of slow loris venom. J Venom Anim Toxins Incl Trop Dis. 2013;19(1):21. doi:10.1186/1678-9199-19-21
6. Ligabue-Braun R. Hello, kitty: could cat allergy be a form of intoxication? J Venom Anim Toxins Incl Trop Dis. 2020;26:e20200051. doi:10.1590/1678-9199-JVATITD-2020-0051
7. Pearce-Duvet JM. The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease. Biol Rev Camb Philos Soc. 2006;81(3):369-382. doi:10.1017/S1464793106007020
8. Jo WK, de Oliveira-Filho EF, Rasche A, et al. Potential zoonotic sources of SARS-CoV-2 infections. Transbound Emerg Dis. 2021;68(4):1824-1834. doi:10.1111/tbed.13872
9. Bell D, Roberton S, Hunter PR. Animal origins of SARS coronavirus: possible links with the international trade in small carnivores. Philos Trans R Soc Lond B Biol Sci. 2004;359(1447):1107-1114. doi:10.1098/rstb.2004.1492

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

Continue to: Pramipexole for MDD

I appreciate Dr. Espejo’s recommendations for treating patients who experience limited response from initial antidepressant therapy (“Treating major depressive disorder after limited response to an initial agent,” Current Psychiatry, October 2021, p. 51-53). I would like to add that pramipexole, a dopamine receptor agonist, can also alleviate depression. A meta-analysis concluded that patients receiving monotherapy or augmentation with pramipexole (mean maximum dose 1.62 mg/d) achieved response or remission of depression.¹ In an observational study of 116 patients with unipolar or bipolar depression, nearly 75% experienced response and 66% achieved remission with pramipexole augmentation (median maximum dose 1.05 mg/d).² Pramipexole is usually well-tolerated, although patients may experience nausea, somnolence, headache, and constipation, and they should be cautioned about the risk for compulsive behaviors and psychosis.

Jonathan R. Scarff, MD
Lexington VA Health Care System
Lexington, Kentucky

References

1. Tundo A, de Filippis R, De Crescenzo F. Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis. Acta Psychiatr Scand. 2019;140(2):116-125.
2. Tundo A, Betrò S, Iommi M, et al. Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study. Prog Neuropsychopharmacol Biol Psychiatry. 2022;112:110425. doi:10.1016/j.pnpbp.2021.110425

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron