User login
Opioid use remits, depression remains
Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opioid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].1 He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.
Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertraline, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublingual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.2 Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a complete routine laboratory workup rule out an organic cause for his deteriorating cognition.
How would you diagnose Mr. B’s condition at this point?
a) treatment-resistant MDD
b) cognitive disorder not otherwise specified
c) opioid use disorder
d) a and c
The authors' observations
Relapse is a core feature of substance use disorders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treatment estimated at more than 60%,3 SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.
To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to consider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recognizing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.
History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe without psychotic features. Trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.
At age 40, he entered a methadone program, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.
We considered electroconvulsive therapy (ECT) at the time, but switching the antidepressant or starting ECT would address only the persistent depression; buprenorphine/naloxone would target opioid craving. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafaxine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.4,5 he reported no anergia and said he felt more motivated and productive.
Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychiatrist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone initiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.
How would you treat Mr. B’s depression at this point?
a) switch to a daytime antidepressant
b) adjust the dosage of buprenorphine/ naloxone
c) try ECT
d) try mindfulness-based cognitive therapy
The authors’ observations
Mindfulness meditation (MM) is a meditation practice that cultivates awareness. While learning MM, the practitioner intentionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being conscious of what the practitioner is doing while he is doing it is the core of mindfulness practice.6
Mindfulness-based interventions. We recommended the following forms of MBI to treat Mr. B:
• Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on cultivating mindfulness.7
• Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.6
Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.8
A study to evaluate effects of mindfulness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neuroendocrine response to interpersonal stress.9 Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and function.10 Meta-analysis of studies of animal models and humans described how specific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.11 This work concluded that, by taking responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain promoted could produce lasting beneficial consequences for social and emotional behavior.11
What could be perpetuating Mr. B’s depression?
a) psychosocial stressors
b) over-expression of CRF gene due to psychosocial stressors
c) a and b
Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anxiety, depression, or cognitive distortions.
We consider MBI for Mr. B, which was developed by Segal et al7 to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.12 Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.7 He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute session, we instruct Mr. B to independently practice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.
We score Mr. B’s day-to-day level of mindfulness experience, depression, and anxiety symptoms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.13 The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, including awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typical item on MAAS is “I find myself doing things without paying attention.”
Depression and anxiety symptoms are measured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).
There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.14 PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the severity of Mr. B’s subjective anxiety.15 He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.
Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI techniques for 45 minutes every morning between 5 AM and 6 AM.6
After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and concentration and anxiety symptoms.
The treating psychiatrist reassures Mr. B and provides support to restart MBI. He manages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI consistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.
The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depressive and anxiety symptoms, thereby helping to prevent relapse of depression and substance abuse. He benefited from MBI practices in several areas of his life, which can be described with the acronym FACES.10
Flexible. Mr. B became more cognitively flexible. He started to realize that “thoughts are not facts.”7 This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of practicing MBI.
Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.
Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.
Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.
Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.
As we hypothesized, for Mr. B, practicing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.
Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.
Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.
Drug Brand Names
Aripiprazole • Abilify Mirtazapine • Remeron
Buprenorphine/naloxone • Quetiapine • Seroquel
Suboxone
Bupropion • Wellbutrin Sertraline • Zoloft
Duloxetine • Cymbalta Trazodone • Desyrel
Methadone • Dolophine Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta
Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case report at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.
Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.
1. Tan EM, Eiger RI, Roth JD. A life of drugs and ‘downtime.’ Current Psychiatry. 2007;6(8):98-103.
2. Diagnostic and statistical manual of mental disorders, 4th edition, text revision. Washington, DC, American Psychiatric Association; 2000.
3. McLellan AT, Lewis DC, O’Brien CP, et al. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689-1695.
4. Schreiber S, Bleich A, Pick CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects—a possible opioid involvement in severe depression? J Mol Neurosci. 2002; 18(1-2):143-149.
5. Sikka P, Kaushik S, Kumar G, et al. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice. J Pharm Bioallied Sci. 2011;3(3):412-416.
6. Kabat-Zinn J. Full catastrophe living. 15th ed. New York, NY: Bantam Books; 1990.
7. Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression: a new approach for preventing relapse. New York, NY: Guilford Press; 2002.
8. Koob GF. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 2010;1314:3-14.
9. Laurent H, Laurent S, Hertz R, et al. Sex-specific effects of mindfulness on romantic partners’ cortisol responses to conflict and relations with psychological adjustment. Psychoneuroendocrinology. 2013;38(12):2905-2913.
10. Siegel DJ. The mindful brain: reflection and attunement in the cultivation of well-being. New York, NY: W.W. Norton & Company; 2007.
11. Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15(5):689-695.
12. Bowen S, Chawla N, Collins SE, et al. Mindfulness-based prevention for substance use disorders: a pilot efficacy trial. Subst Abus. 2009;30(4):295-305.
13. Grossman P. Defining mindfulness by how poorly I think I pay attention during everyday awareness and other intractable problems for psychology’s (re)invention of mindfulness: comment on Brown et al. (2001). Psychol Assess. 2011;23(4):1034-1040; discussion 1041-1046.
14. Koola MM, Fawcett JA, Kelly DL. Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care. J Nerv Ment Dis. 2011;199(12):989-990.
15. Nock MK, Hwang I, Sampson N, et al. Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS Med. 2009;6(8):e1000123. doi: 10.1371/journal.pmed.1000123.
Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opioid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].1 He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.
Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertraline, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublingual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.2 Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a complete routine laboratory workup rule out an organic cause for his deteriorating cognition.
How would you diagnose Mr. B’s condition at this point?
a) treatment-resistant MDD
b) cognitive disorder not otherwise specified
c) opioid use disorder
d) a and c
The authors' observations
Relapse is a core feature of substance use disorders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treatment estimated at more than 60%,3 SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.
To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to consider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recognizing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.
History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe without psychotic features. Trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.
At age 40, he entered a methadone program, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.
We considered electroconvulsive therapy (ECT) at the time, but switching the antidepressant or starting ECT would address only the persistent depression; buprenorphine/naloxone would target opioid craving. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafaxine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.4,5 he reported no anergia and said he felt more motivated and productive.
Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychiatrist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone initiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.
How would you treat Mr. B’s depression at this point?
a) switch to a daytime antidepressant
b) adjust the dosage of buprenorphine/ naloxone
c) try ECT
d) try mindfulness-based cognitive therapy
The authors’ observations
Mindfulness meditation (MM) is a meditation practice that cultivates awareness. While learning MM, the practitioner intentionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being conscious of what the practitioner is doing while he is doing it is the core of mindfulness practice.6
Mindfulness-based interventions. We recommended the following forms of MBI to treat Mr. B:
• Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on cultivating mindfulness.7
• Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.6
Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.8
A study to evaluate effects of mindfulness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neuroendocrine response to interpersonal stress.9 Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and function.10 Meta-analysis of studies of animal models and humans described how specific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.11 This work concluded that, by taking responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain promoted could produce lasting beneficial consequences for social and emotional behavior.11
What could be perpetuating Mr. B’s depression?
a) psychosocial stressors
b) over-expression of CRF gene due to psychosocial stressors
c) a and b
Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anxiety, depression, or cognitive distortions.
We consider MBI for Mr. B, which was developed by Segal et al7 to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.12 Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.7 He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute session, we instruct Mr. B to independently practice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.
We score Mr. B’s day-to-day level of mindfulness experience, depression, and anxiety symptoms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.13 The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, including awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typical item on MAAS is “I find myself doing things without paying attention.”
Depression and anxiety symptoms are measured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).
There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.14 PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the severity of Mr. B’s subjective anxiety.15 He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.
Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI techniques for 45 minutes every morning between 5 AM and 6 AM.6
After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and concentration and anxiety symptoms.
The treating psychiatrist reassures Mr. B and provides support to restart MBI. He manages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI consistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.
The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depressive and anxiety symptoms, thereby helping to prevent relapse of depression and substance abuse. He benefited from MBI practices in several areas of his life, which can be described with the acronym FACES.10
Flexible. Mr. B became more cognitively flexible. He started to realize that “thoughts are not facts.”7 This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of practicing MBI.
Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.
Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.
Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.
Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.
As we hypothesized, for Mr. B, practicing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.
Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.
Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.
Drug Brand Names
Aripiprazole • Abilify Mirtazapine • Remeron
Buprenorphine/naloxone • Quetiapine • Seroquel
Suboxone
Bupropion • Wellbutrin Sertraline • Zoloft
Duloxetine • Cymbalta Trazodone • Desyrel
Methadone • Dolophine Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta
Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case report at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.
Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.
Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opioid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].1 He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.
Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertraline, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublingual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.2 Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a complete routine laboratory workup rule out an organic cause for his deteriorating cognition.
How would you diagnose Mr. B’s condition at this point?
a) treatment-resistant MDD
b) cognitive disorder not otherwise specified
c) opioid use disorder
d) a and c
The authors' observations
Relapse is a core feature of substance use disorders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treatment estimated at more than 60%,3 SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.
To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to consider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recognizing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.
History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe without psychotic features. Trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.
At age 40, he entered a methadone program, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.
We considered electroconvulsive therapy (ECT) at the time, but switching the antidepressant or starting ECT would address only the persistent depression; buprenorphine/naloxone would target opioid craving. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafaxine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.4,5 he reported no anergia and said he felt more motivated and productive.
Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychiatrist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone initiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.
How would you treat Mr. B’s depression at this point?
a) switch to a daytime antidepressant
b) adjust the dosage of buprenorphine/ naloxone
c) try ECT
d) try mindfulness-based cognitive therapy
The authors’ observations
Mindfulness meditation (MM) is a meditation practice that cultivates awareness. While learning MM, the practitioner intentionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being conscious of what the practitioner is doing while he is doing it is the core of mindfulness practice.6
Mindfulness-based interventions. We recommended the following forms of MBI to treat Mr. B:
• Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on cultivating mindfulness.7
• Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.6
Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.8
A study to evaluate effects of mindfulness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neuroendocrine response to interpersonal stress.9 Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and function.10 Meta-analysis of studies of animal models and humans described how specific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.11 This work concluded that, by taking responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain promoted could produce lasting beneficial consequences for social and emotional behavior.11
What could be perpetuating Mr. B’s depression?
a) psychosocial stressors
b) over-expression of CRF gene due to psychosocial stressors
c) a and b
Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anxiety, depression, or cognitive distortions.
We consider MBI for Mr. B, which was developed by Segal et al7 to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.12 Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.7 He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute session, we instruct Mr. B to independently practice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.
We score Mr. B’s day-to-day level of mindfulness experience, depression, and anxiety symptoms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.13 The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, including awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typical item on MAAS is “I find myself doing things without paying attention.”
Depression and anxiety symptoms are measured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).
There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.14 PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the severity of Mr. B’s subjective anxiety.15 He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.
Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI techniques for 45 minutes every morning between 5 AM and 6 AM.6
After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and concentration and anxiety symptoms.
The treating psychiatrist reassures Mr. B and provides support to restart MBI. He manages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI consistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.
The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depressive and anxiety symptoms, thereby helping to prevent relapse of depression and substance abuse. He benefited from MBI practices in several areas of his life, which can be described with the acronym FACES.10
Flexible. Mr. B became more cognitively flexible. He started to realize that “thoughts are not facts.”7 This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of practicing MBI.
Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.
Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.
Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.
Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.
As we hypothesized, for Mr. B, practicing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.
Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.
Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.
Drug Brand Names
Aripiprazole • Abilify Mirtazapine • Remeron
Buprenorphine/naloxone • Quetiapine • Seroquel
Suboxone
Bupropion • Wellbutrin Sertraline • Zoloft
Duloxetine • Cymbalta Trazodone • Desyrel
Methadone • Dolophine Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta
Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case report at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.
Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.
1. Tan EM, Eiger RI, Roth JD. A life of drugs and ‘downtime.’ Current Psychiatry. 2007;6(8):98-103.
2. Diagnostic and statistical manual of mental disorders, 4th edition, text revision. Washington, DC, American Psychiatric Association; 2000.
3. McLellan AT, Lewis DC, O’Brien CP, et al. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689-1695.
4. Schreiber S, Bleich A, Pick CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects—a possible opioid involvement in severe depression? J Mol Neurosci. 2002; 18(1-2):143-149.
5. Sikka P, Kaushik S, Kumar G, et al. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice. J Pharm Bioallied Sci. 2011;3(3):412-416.
6. Kabat-Zinn J. Full catastrophe living. 15th ed. New York, NY: Bantam Books; 1990.
7. Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression: a new approach for preventing relapse. New York, NY: Guilford Press; 2002.
8. Koob GF. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 2010;1314:3-14.
9. Laurent H, Laurent S, Hertz R, et al. Sex-specific effects of mindfulness on romantic partners’ cortisol responses to conflict and relations with psychological adjustment. Psychoneuroendocrinology. 2013;38(12):2905-2913.
10. Siegel DJ. The mindful brain: reflection and attunement in the cultivation of well-being. New York, NY: W.W. Norton & Company; 2007.
11. Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15(5):689-695.
12. Bowen S, Chawla N, Collins SE, et al. Mindfulness-based prevention for substance use disorders: a pilot efficacy trial. Subst Abus. 2009;30(4):295-305.
13. Grossman P. Defining mindfulness by how poorly I think I pay attention during everyday awareness and other intractable problems for psychology’s (re)invention of mindfulness: comment on Brown et al. (2001). Psychol Assess. 2011;23(4):1034-1040; discussion 1041-1046.
14. Koola MM, Fawcett JA, Kelly DL. Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care. J Nerv Ment Dis. 2011;199(12):989-990.
15. Nock MK, Hwang I, Sampson N, et al. Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS Med. 2009;6(8):e1000123. doi: 10.1371/journal.pmed.1000123.
1. Tan EM, Eiger RI, Roth JD. A life of drugs and ‘downtime.’ Current Psychiatry. 2007;6(8):98-103.
2. Diagnostic and statistical manual of mental disorders, 4th edition, text revision. Washington, DC, American Psychiatric Association; 2000.
3. McLellan AT, Lewis DC, O’Brien CP, et al. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689-1695.
4. Schreiber S, Bleich A, Pick CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects—a possible opioid involvement in severe depression? J Mol Neurosci. 2002; 18(1-2):143-149.
5. Sikka P, Kaushik S, Kumar G, et al. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice. J Pharm Bioallied Sci. 2011;3(3):412-416.
6. Kabat-Zinn J. Full catastrophe living. 15th ed. New York, NY: Bantam Books; 1990.
7. Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression: a new approach for preventing relapse. New York, NY: Guilford Press; 2002.
8. Koob GF. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 2010;1314:3-14.
9. Laurent H, Laurent S, Hertz R, et al. Sex-specific effects of mindfulness on romantic partners’ cortisol responses to conflict and relations with psychological adjustment. Psychoneuroendocrinology. 2013;38(12):2905-2913.
10. Siegel DJ. The mindful brain: reflection and attunement in the cultivation of well-being. New York, NY: W.W. Norton & Company; 2007.
11. Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15(5):689-695.
12. Bowen S, Chawla N, Collins SE, et al. Mindfulness-based prevention for substance use disorders: a pilot efficacy trial. Subst Abus. 2009;30(4):295-305.
13. Grossman P. Defining mindfulness by how poorly I think I pay attention during everyday awareness and other intractable problems for psychology’s (re)invention of mindfulness: comment on Brown et al. (2001). Psychol Assess. 2011;23(4):1034-1040; discussion 1041-1046.
14. Koola MM, Fawcett JA, Kelly DL. Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care. J Nerv Ment Dis. 2011;199(12):989-990.
15. Nock MK, Hwang I, Sampson N, et al. Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS Med. 2009;6(8):e1000123. doi: 10.1371/journal.pmed.1000123.
A life of drugs and ‘downtime’
CASE: Near-fatal combination
Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.
Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.
Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.
Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.
HISTORY: Depression and drugs
Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.
Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.
Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.
At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.
HISTORY: Family problems
Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.
The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.
The authors’ observations
Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.
Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.1 Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.2 According to Gold et al,3 long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.
Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.
As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.4 “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.
Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.
TREATMENT: Medication change
We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.
Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.
After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.
The authors’ observations
Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:
- work with the mesolimbic dopaminergic system to mediate pleasure and reward
- modulate the mesolimbic system
- or have the same attenuating effect on both psychic and physical pain.
Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.11 Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.
Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.
The authors’ observations
Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.
Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.
Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.
The Drug Enforcement Administration (DEA) requires physicians to obtain a waiver to use buprenorphine to treat opioid dependence in outpatients. This waiver exempts outpatient practitioners from the DEA requirement that only specially licensed opioid treatment programs—such as methadone clinics—can dispense opioid medications.
To obtain the waiver, a physician must:
- show competency to use buprenorphine—usually by completing an 8-hour training course
- certify that he/she can conveniently refer patients for psychosocial treatment.
To receive DEA-approved buprenorphine training, in person or online, contact:
- American Society of Addiction Medicine. (888) 362-6784, www.asam.org/BuprenorphineCME.html
- American Academy of Addiction Psychiatry. (401) 524-3076, www.aaap.org/buprenorphine/buprenorphine.htm
- American Psychiatric Association. (703) 907-7300, www.psych.org/edu/bup_training.cfm
- American Osteopathic Academy of Addiction Medicine. (800) 621-1773, ext. 8163, www.aoaam.org.
For information on obtaining the waiver, visit www.buprenorphine.samhsa.gov.
Buprenorphine risks
Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.
Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.
Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.
When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.
TREATMENT: An opioid option
After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.
We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.
Remember these 8 steps
- Address depression and substance abuse concurrently
- Communicate regularly with other providers about progress on depression and substance abuse issues
- Recommend and support involvement in 12-step programs such as AA
- Use medications for both depression—such as antidepressants—and relapse prevention—such as naltrexone, acamprosate, or buprenorphine/naloxone
- Explore family history of addiction and how this affected the patient developmentally. Find out if depression and substance abuse had common causes; this helps the patient realize that he/she did not become depressed or addicted by choice
- Ask about and discuss multiple addictions that were not initially reported
- Help the patient express, tolerate, and experience difficult feelings rather than avoid them
- Empathize with the patient; express understanding that factors out of the patient’s control caused depression and addiction
The authors’ observations
Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.
Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.
Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.2,12
FOLLOW-UP: ‘Bup’ stigma
Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”
Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.
During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.
The authors’ observations
Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.
Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.
Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.
Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.
Related resources
- U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
- Acamprosate • Campral
- Alprazolam • Xanax
- Aripiprazole • Abilify
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Bupropion • Wellbutrin
- Diphenoxylate/atropine • Lomotil
- Methadone • Dolophine
- Methylphenidate • Ritalin, Concerta
- Mirtazapine • Remeron
- Naltrexone • ReVia, Vivitrol
- Quetiapine • Seroquel
- Sertraline • Zoloft
- Trazodone • Desyrel
- Venlafaxine • Effexor
Dr. Roth is a speaker for Reckitt Benckiser.
Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry 2004;56:793-802.
2. Graham AW, Schultz TK, Mayo-Smith MF, et al, eds. Principles of addiction medicine. 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine; 2003.
3. Gold MS, Pottash AL, Extein I, et al. Evidence for an endorphin dysfunction in methadone addicts: lack of ACTH response to naloxone. Drug Alcohol Depend 1981;8:257-62.
4. Carnes PJ, Murray RE, Charpentier L. Addiction interaction disorder. In: Coombs RH, ed. Handbook of addictive disorders: a practical guide to diagnosis and treatment. Hoboken, NJ: John Wiley & Sons 2004:31-59.
5. Kosten TR, Morgan C, Kosten TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7:51-4.
6. Dean AJ, Bell J, Christie MJ, Mattick RP. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomized, controlled trial in opioid dependence. Eur Psychiatry. 2004;19:510-13.
7. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49-57.
8. Jaffe JH, Jaffe AB. Neurobiology of opioids. In: Galanter M, Kleber HD, eds. Textbook of substance abuse treatment.. 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:17-30.
9. Jones HE. Practical considerations for the clinical use of buprenorphine. NIDA Sci Pract Perspectives. 2004;2:4-20.
10. Geppert CM, Toney GB, Siracusano D, Thorius M. Outpatient buprenorphine treatment for opioid dependence. Fed Practitioner. 2005;22:9-40.
11. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305:323-30.
12. Van Geffen EC, Hugtenburg JG, Heerdink ER, et al. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt continuation. Eur J Clin Pharmacol. 2005;61:303-7.
CASE: Near-fatal combination
Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.
Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.
Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.
Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.
HISTORY: Depression and drugs
Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.
Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.
Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.
At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.
HISTORY: Family problems
Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.
The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.
The authors’ observations
Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.
Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.1 Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.2 According to Gold et al,3 long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.
Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.
As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.4 “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.
Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.
TREATMENT: Medication change
We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.
Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.
After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.
The authors’ observations
Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:
- work with the mesolimbic dopaminergic system to mediate pleasure and reward
- modulate the mesolimbic system
- or have the same attenuating effect on both psychic and physical pain.
Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.11 Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.
Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.
The authors’ observations
Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.
Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.
Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.
The Drug Enforcement Administration (DEA) requires physicians to obtain a waiver to use buprenorphine to treat opioid dependence in outpatients. This waiver exempts outpatient practitioners from the DEA requirement that only specially licensed opioid treatment programs—such as methadone clinics—can dispense opioid medications.
To obtain the waiver, a physician must:
- show competency to use buprenorphine—usually by completing an 8-hour training course
- certify that he/she can conveniently refer patients for psychosocial treatment.
To receive DEA-approved buprenorphine training, in person or online, contact:
- American Society of Addiction Medicine. (888) 362-6784, www.asam.org/BuprenorphineCME.html
- American Academy of Addiction Psychiatry. (401) 524-3076, www.aaap.org/buprenorphine/buprenorphine.htm
- American Psychiatric Association. (703) 907-7300, www.psych.org/edu/bup_training.cfm
- American Osteopathic Academy of Addiction Medicine. (800) 621-1773, ext. 8163, www.aoaam.org.
For information on obtaining the waiver, visit www.buprenorphine.samhsa.gov.
Buprenorphine risks
Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.
Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.
Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.
When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.
TREATMENT: An opioid option
After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.
We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.
Remember these 8 steps
- Address depression and substance abuse concurrently
- Communicate regularly with other providers about progress on depression and substance abuse issues
- Recommend and support involvement in 12-step programs such as AA
- Use medications for both depression—such as antidepressants—and relapse prevention—such as naltrexone, acamprosate, or buprenorphine/naloxone
- Explore family history of addiction and how this affected the patient developmentally. Find out if depression and substance abuse had common causes; this helps the patient realize that he/she did not become depressed or addicted by choice
- Ask about and discuss multiple addictions that were not initially reported
- Help the patient express, tolerate, and experience difficult feelings rather than avoid them
- Empathize with the patient; express understanding that factors out of the patient’s control caused depression and addiction
The authors’ observations
Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.
Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.
Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.2,12
FOLLOW-UP: ‘Bup’ stigma
Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”
Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.
During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.
The authors’ observations
Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.
Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.
Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.
Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.
Related resources
- U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
- Acamprosate • Campral
- Alprazolam • Xanax
- Aripiprazole • Abilify
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Bupropion • Wellbutrin
- Diphenoxylate/atropine • Lomotil
- Methadone • Dolophine
- Methylphenidate • Ritalin, Concerta
- Mirtazapine • Remeron
- Naltrexone • ReVia, Vivitrol
- Quetiapine • Seroquel
- Sertraline • Zoloft
- Trazodone • Desyrel
- Venlafaxine • Effexor
Dr. Roth is a speaker for Reckitt Benckiser.
Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
CASE: Near-fatal combination
Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.
Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.
Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.
Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.
By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.
HISTORY: Depression and drugs
Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.
Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.
Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.
At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.
HISTORY: Family problems
Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.
The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.
The authors’ observations
Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.
Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.1 Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.2 According to Gold et al,3 long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.
Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.
As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.4 “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.
Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.
TREATMENT: Medication change
We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.
Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.
After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.
The authors’ observations
Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:
- work with the mesolimbic dopaminergic system to mediate pleasure and reward
- modulate the mesolimbic system
- or have the same attenuating effect on both psychic and physical pain.
Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.11 Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.
Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.
The authors’ observations
Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.
Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.
Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.
The Drug Enforcement Administration (DEA) requires physicians to obtain a waiver to use buprenorphine to treat opioid dependence in outpatients. This waiver exempts outpatient practitioners from the DEA requirement that only specially licensed opioid treatment programs—such as methadone clinics—can dispense opioid medications.
To obtain the waiver, a physician must:
- show competency to use buprenorphine—usually by completing an 8-hour training course
- certify that he/she can conveniently refer patients for psychosocial treatment.
To receive DEA-approved buprenorphine training, in person or online, contact:
- American Society of Addiction Medicine. (888) 362-6784, www.asam.org/BuprenorphineCME.html
- American Academy of Addiction Psychiatry. (401) 524-3076, www.aaap.org/buprenorphine/buprenorphine.htm
- American Psychiatric Association. (703) 907-7300, www.psych.org/edu/bup_training.cfm
- American Osteopathic Academy of Addiction Medicine. (800) 621-1773, ext. 8163, www.aoaam.org.
For information on obtaining the waiver, visit www.buprenorphine.samhsa.gov.
Buprenorphine risks
Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.
Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.
Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.
When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.
TREATMENT: An opioid option
After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.
We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.
Remember these 8 steps
- Address depression and substance abuse concurrently
- Communicate regularly with other providers about progress on depression and substance abuse issues
- Recommend and support involvement in 12-step programs such as AA
- Use medications for both depression—such as antidepressants—and relapse prevention—such as naltrexone, acamprosate, or buprenorphine/naloxone
- Explore family history of addiction and how this affected the patient developmentally. Find out if depression and substance abuse had common causes; this helps the patient realize that he/she did not become depressed or addicted by choice
- Ask about and discuss multiple addictions that were not initially reported
- Help the patient express, tolerate, and experience difficult feelings rather than avoid them
- Empathize with the patient; express understanding that factors out of the patient’s control caused depression and addiction
The authors’ observations
Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.
Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.
Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.2,12
FOLLOW-UP: ‘Bup’ stigma
Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”
Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.
During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.
The authors’ observations
Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.
Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.
Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.
Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.
Related resources
- U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
- Acamprosate • Campral
- Alprazolam • Xanax
- Aripiprazole • Abilify
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Bupropion • Wellbutrin
- Diphenoxylate/atropine • Lomotil
- Methadone • Dolophine
- Methylphenidate • Ritalin, Concerta
- Mirtazapine • Remeron
- Naltrexone • ReVia, Vivitrol
- Quetiapine • Seroquel
- Sertraline • Zoloft
- Trazodone • Desyrel
- Venlafaxine • Effexor
Dr. Roth is a speaker for Reckitt Benckiser.
Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry 2004;56:793-802.
2. Graham AW, Schultz TK, Mayo-Smith MF, et al, eds. Principles of addiction medicine. 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine; 2003.
3. Gold MS, Pottash AL, Extein I, et al. Evidence for an endorphin dysfunction in methadone addicts: lack of ACTH response to naloxone. Drug Alcohol Depend 1981;8:257-62.
4. Carnes PJ, Murray RE, Charpentier L. Addiction interaction disorder. In: Coombs RH, ed. Handbook of addictive disorders: a practical guide to diagnosis and treatment. Hoboken, NJ: John Wiley & Sons 2004:31-59.
5. Kosten TR, Morgan C, Kosten TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7:51-4.
6. Dean AJ, Bell J, Christie MJ, Mattick RP. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomized, controlled trial in opioid dependence. Eur Psychiatry. 2004;19:510-13.
7. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49-57.
8. Jaffe JH, Jaffe AB. Neurobiology of opioids. In: Galanter M, Kleber HD, eds. Textbook of substance abuse treatment.. 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:17-30.
9. Jones HE. Practical considerations for the clinical use of buprenorphine. NIDA Sci Pract Perspectives. 2004;2:4-20.
10. Geppert CM, Toney GB, Siracusano D, Thorius M. Outpatient buprenorphine treatment for opioid dependence. Fed Practitioner. 2005;22:9-40.
11. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305:323-30.
12. Van Geffen EC, Hugtenburg JG, Heerdink ER, et al. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt continuation. Eur J Clin Pharmacol. 2005;61:303-7.
1. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry 2004;56:793-802.
2. Graham AW, Schultz TK, Mayo-Smith MF, et al, eds. Principles of addiction medicine. 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine; 2003.
3. Gold MS, Pottash AL, Extein I, et al. Evidence for an endorphin dysfunction in methadone addicts: lack of ACTH response to naloxone. Drug Alcohol Depend 1981;8:257-62.
4. Carnes PJ, Murray RE, Charpentier L. Addiction interaction disorder. In: Coombs RH, ed. Handbook of addictive disorders: a practical guide to diagnosis and treatment. Hoboken, NJ: John Wiley & Sons 2004:31-59.
5. Kosten TR, Morgan C, Kosten TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7:51-4.
6. Dean AJ, Bell J, Christie MJ, Mattick RP. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomized, controlled trial in opioid dependence. Eur Psychiatry. 2004;19:510-13.
7. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49-57.
8. Jaffe JH, Jaffe AB. Neurobiology of opioids. In: Galanter M, Kleber HD, eds. Textbook of substance abuse treatment.. 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:17-30.
9. Jones HE. Practical considerations for the clinical use of buprenorphine. NIDA Sci Pract Perspectives. 2004;2:4-20.
10. Geppert CM, Toney GB, Siracusano D, Thorius M. Outpatient buprenorphine treatment for opioid dependence. Fed Practitioner. 2005;22:9-40.
11. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305:323-30.
12. Van Geffen EC, Hugtenburg JG, Heerdink ER, et al. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt continuation. Eur J Clin Pharmacol. 2005;61:303-7.