Henry A. Nasrallah, MD

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

Consider stroke. Guidelines for acute treatment, access, intervention, pre­vention of post-hospitalization relapse, and rehabilitation are extensively spelled out and implemented.¹ (The Box outlines Mayo Clinic guidelines for stroke management, as a demonstration of the comprehensive­ness of the approach.)

Schizophrenia and related severe mental illnesses (SMI) need a similar all-inclusive system that seamlessly provides the myriad components of care needed for this vulnerable population. I propose the term “therapeutic placenta” to describe what people with a dis­abling SMI brain disorder deserve, just as stroke patients do.

Closing asylums: Psychosocial abruptio placentae
In a past Editorial,² I described the appalling consequences of eliminat­ing the asylum, an entity that I believe must be a key component of the SMI therapeutic placenta. The asylum is to schizophrenia as the skilled nurs­ing home is to stroke. SMI patients suffered extensively when asylums were shut down; they lost a medical refuge with psychiatric and primary care, nursing and social work sup­port, occupational and recreational therapies, and work therapy (farming, carpentry shop, cafeteria, laundry, etc.). For SMI, these services are the psychosocial counterpart of various physical rehabilitation therapies for stroke patients that no one would ever dare to eliminate.

Persons with schizophrenia and other SMI have suffered tragically with rupture of the main compo­nents of the therapeutic placenta that existed for decades before the advent of medications. The massive home­lessness, widespread incarceration, persistent poverty, rampant access to alcohol and drugs of abuse, early death due to lack of primary care, and absence of meaningful opportu­nities for vocational rehabilitation are all consequences of a neglectful soci­ety that refuses to fund a therapeutic placenta for the SMI population.

The public mental health system in charge of SMI patients is broken, disconnected, and failing to provide the necessary components of a therapeutic placenta. It should not be surprising to witness the terribly stressful life and premature mortality of SMI patients, who are modern-day les misérables.

The Table lists what I consider to be the necessary spectrum of health care services through the life of an SMI patient that an optimal therapeutic pla­centa must provide until an effective pre­vention or a cure for SMI is discovered.

Reasons to be hopeful
Admittedly, encouraging steps are being made toward establishing a therapeutic placenta for SMI:

The RAISE Study³and Navigate Program⁴ demonstrate that implement­ing a comprehensive program of acute treatment and psychosocial interven­tions and rehabilitation yields better outcomes in SMI.

The Institute of Medicine released a landmark report on psychosocial interventions for mental illness and substance abuse disorders. It outlines a new model for establishing the effec­tiveness of intervention and the imple­mentation of psychosocial strategies in clinical practice.⁵

The 21st Century Cures Act, if passed by Congress and signed by the President, will increase funding for the National Institutes of Health, which in turn will bolster the budgets of the National Institute of Mental Health, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism and enhance the chances of discovering better treatments and prevention of SMI. 

The Helping Families in Mental Health Crisis Act, more directly relevant to men­tal health and psychiatry, proposes, if passed, to:
   • enhance evidence-based and sci­entifically validated interventions in the public sector
   • raise the profile of mental health within the federal government by creat­ing a position of Assistant Secretary for Mental Health in the U.S. Department of Health and Human Services, who will have oversight of both research and mental health care within the fed­eral government.

Unacceptable disparity must be remedied
Planning an effective therapeutic pla­centa is imperative if health care for SMI patients is to approach the comprehen­sive spectrum of treatment, rehabilita­tion, and prevention available to stroke patients. Although stroke is regarded as a sensory-motor brain disorder, it is also associated with mental symp­toms, just as schizophrenia is associ­ated with sensory-motor symptoms. Both are disabling brain disorders: one, physically and cognitively; the other, mentally and socially. Both require a therapeutic placenta: Stroke is sup­ported by one; schizophrenia is not. This is an unacceptable disparity that must be addressed—soon.

Consider stroke. Guidelines for acute treatment, access, intervention, pre­vention of post-hospitalization relapse, and rehabilitation are extensively spelled out and implemented.¹ (The Box outlines Mayo Clinic guidelines for stroke management, as a demonstration of the comprehensive­ness of the approach.)

Schizophrenia and related severe mental illnesses (SMI) need a similar all-inclusive system that seamlessly provides the myriad components of care needed for this vulnerable population. I propose the term “therapeutic placenta” to describe what people with a dis­abling SMI brain disorder deserve, just as stroke patients do.

Closing asylums: Psychosocial abruptio placentae
In a past Editorial,² I described the appalling consequences of eliminat­ing the asylum, an entity that I believe must be a key component of the SMI therapeutic placenta. The asylum is to schizophrenia as the skilled nurs­ing home is to stroke. SMI patients suffered extensively when asylums were shut down; they lost a medical refuge with psychiatric and primary care, nursing and social work sup­port, occupational and recreational therapies, and work therapy (farming, carpentry shop, cafeteria, laundry, etc.). For SMI, these services are the psychosocial counterpart of various physical rehabilitation therapies for stroke patients that no one would ever dare to eliminate.

Persons with schizophrenia and other SMI have suffered tragically with rupture of the main compo­nents of the therapeutic placenta that existed for decades before the advent of medications. The massive home­lessness, widespread incarceration, persistent poverty, rampant access to alcohol and drugs of abuse, early death due to lack of primary care, and absence of meaningful opportu­nities for vocational rehabilitation are all consequences of a neglectful soci­ety that refuses to fund a therapeutic placenta for the SMI population.

The public mental health system in charge of SMI patients is broken, disconnected, and failing to provide the necessary components of a therapeutic placenta. It should not be surprising to witness the terribly stressful life and premature mortality of SMI patients, who are modern-day les misérables.

The Table lists what I consider to be the necessary spectrum of health care services through the life of an SMI patient that an optimal therapeutic pla­centa must provide until an effective pre­vention or a cure for SMI is discovered.

Reasons to be hopeful
Admittedly, encouraging steps are being made toward establishing a therapeutic placenta for SMI:

The RAISE Study³and Navigate Program⁴ demonstrate that implement­ing a comprehensive program of acute treatment and psychosocial interven­tions and rehabilitation yields better outcomes in SMI.

The Institute of Medicine released a landmark report on psychosocial interventions for mental illness and substance abuse disorders. It outlines a new model for establishing the effec­tiveness of intervention and the imple­mentation of psychosocial strategies in clinical practice.⁵

The 21st Century Cures Act, if passed by Congress and signed by the President, will increase funding for the National Institutes of Health, which in turn will bolster the budgets of the National Institute of Mental Health, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism and enhance the chances of discovering better treatments and prevention of SMI. 

The Helping Families in Mental Health Crisis Act, more directly relevant to men­tal health and psychiatry, proposes, if passed, to:
   • enhance evidence-based and sci­entifically validated interventions in the public sector
   • raise the profile of mental health within the federal government by creat­ing a position of Assistant Secretary for Mental Health in the U.S. Department of Health and Human Services, who will have oversight of both research and mental health care within the fed­eral government.

Unacceptable disparity must be remedied
Planning an effective therapeutic pla­centa is imperative if health care for SMI patients is to approach the comprehen­sive spectrum of treatment, rehabilita­tion, and prevention available to stroke patients. Although stroke is regarded as a sensory-motor brain disorder, it is also associated with mental symp­toms, just as schizophrenia is associ­ated with sensory-motor symptoms. Both are disabling brain disorders: one, physically and cognitively; the other, mentally and socially. Both require a therapeutic placenta: Stroke is sup­ported by one; schizophrenia is not. This is an unacceptable disparity that must be addressed—soon.

Consider stroke. Guidelines for acute treatment, access, intervention, pre­vention of post-hospitalization relapse, and rehabilitation are extensively spelled out and implemented.¹ (The Box outlines Mayo Clinic guidelines for stroke management, as a demonstration of the comprehensive­ness of the approach.)

Schizophrenia and related severe mental illnesses (SMI) need a similar all-inclusive system that seamlessly provides the myriad components of care needed for this vulnerable population. I propose the term “therapeutic placenta” to describe what people with a dis­abling SMI brain disorder deserve, just as stroke patients do.

Closing asylums: Psychosocial abruptio placentae
In a past Editorial,² I described the appalling consequences of eliminat­ing the asylum, an entity that I believe must be a key component of the SMI therapeutic placenta. The asylum is to schizophrenia as the skilled nurs­ing home is to stroke. SMI patients suffered extensively when asylums were shut down; they lost a medical refuge with psychiatric and primary care, nursing and social work sup­port, occupational and recreational therapies, and work therapy (farming, carpentry shop, cafeteria, laundry, etc.). For SMI, these services are the psychosocial counterpart of various physical rehabilitation therapies for stroke patients that no one would ever dare to eliminate.

Persons with schizophrenia and other SMI have suffered tragically with rupture of the main compo­nents of the therapeutic placenta that existed for decades before the advent of medications. The massive home­lessness, widespread incarceration, persistent poverty, rampant access to alcohol and drugs of abuse, early death due to lack of primary care, and absence of meaningful opportu­nities for vocational rehabilitation are all consequences of a neglectful soci­ety that refuses to fund a therapeutic placenta for the SMI population.

The public mental health system in charge of SMI patients is broken, disconnected, and failing to provide the necessary components of a therapeutic placenta. It should not be surprising to witness the terribly stressful life and premature mortality of SMI patients, who are modern-day les misérables.

The Table lists what I consider to be the necessary spectrum of health care services through the life of an SMI patient that an optimal therapeutic pla­centa must provide until an effective pre­vention or a cure for SMI is discovered.

Reasons to be hopeful
Admittedly, encouraging steps are being made toward establishing a therapeutic placenta for SMI:

The RAISE Study³and Navigate Program⁴ demonstrate that implement­ing a comprehensive program of acute treatment and psychosocial interven­tions and rehabilitation yields better outcomes in SMI.

The Institute of Medicine released a landmark report on psychosocial interventions for mental illness and substance abuse disorders. It outlines a new model for establishing the effec­tiveness of intervention and the imple­mentation of psychosocial strategies in clinical practice.⁵

The 21st Century Cures Act, if passed by Congress and signed by the President, will increase funding for the National Institutes of Health, which in turn will bolster the budgets of the National Institute of Mental Health, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism and enhance the chances of discovering better treatments and prevention of SMI. 

The Helping Families in Mental Health Crisis Act, more directly relevant to men­tal health and psychiatry, proposes, if passed, to:
   • enhance evidence-based and sci­entifically validated interventions in the public sector
   • raise the profile of mental health within the federal government by creat­ing a position of Assistant Secretary for Mental Health in the U.S. Department of Health and Human Services, who will have oversight of both research and mental health care within the fed­eral government.

Unacceptable disparity must be remedied
Planning an effective therapeutic pla­centa is imperative if health care for SMI patients is to approach the comprehen­sive spectrum of treatment, rehabilita­tion, and prevention available to stroke patients. Although stroke is regarded as a sensory-motor brain disorder, it is also associated with mental symp­toms, just as schizophrenia is associ­ated with sensory-motor symptoms. Both are disabling brain disorders: one, physically and cognitively; the other, mentally and socially. Both require a therapeutic placenta: Stroke is sup­ported by one; schizophrenia is not. This is an unacceptable disparity that must be addressed—soon.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.