Module 3 Indications for Antipsychotic Drugs In this section I discuss indications for antipsychotic drugs. There are three additional sections in this module: the use of antipsychotics in schizophrenia, bipolar disorder and in unipolar depression. Flavio Guzmán, MD

Use in psychotic disorders Use in non-psychotic disorders Outline Use in psychotic disorders Use in non-psychotic disorders This outline shows the two main groups of disorders that we’ll be discussing in this section. I’ll describe the use of antipsychotics for psychotic as well as for non-psychotic disorders. Some of the clinical uses are FDA approved, other uses are off-label. When possible, we’re going to review the evidence for off-label uses.

Indications for antipsychotic drugs Psychosis Schizophrenia Schizophreniform disorder Schizoaffective disorder Delusional disorder Brief psychotic disorder Medical conditions Mood disorders with psychotic symptoms The primary indication for antipsychotics is the presence of psychotic symptoms. Psychosis can be part of a number of psychiatric disorders, including: Schizophrenia Schizophreniform disorder Schizoaffective disorder Delusional disorder Brief psychotic disorder Psychoses secondary to a nonpsychiatric medical condition Mood disorders with psychotic symptoms The use of antipsychotics for schizophrenia, bipolar disorder and depression is discussed in other sections. Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Use for non-psychotic disorders Off-label use Generalized anxiety disorder Post-traumatic stress disorder Obsessive-compulsive disorder Borderline personality disorder Dementia Other uses What about using antipsychotics for non psychotic disorders? Off label use is common for psychotropic medications, specially for antipsychotic drugs. Ideally, the decision of using a drug for a condition other than it was approved by the FDA, should be justified by clinical evidence. Examples of off label use for non psychotic disorders include: Generalized anxiety disorder Post-traumatic stress disorder Obsessive-compulsive disorder Borderline personality disorder Dementia Other uses We’ll review current evidence for each indication in the next slides.

Generalized Anxiety disorder Benefit comparable to other approved drugs More rapid onset of action than SRIs Greater risk of weight gain, metabolic effects than approved medications Advantages Disadvantages Potential indication for quetiapine Off label use FDA panel recommended against its approval for GAD The first in our list is generalized anxiety disorder. The off-label use of antipsychotics for generalized anxiety disorder has been best studied for quetiapine. However, the FDA recommended against its approval for this disorder. In this graphic we can see the advantages and disadvantages of quetiapine for this clinical use. Clinical trials showed benefit comparable to other approved drugs. One advantage is that they have a more rapid onset of action than SRIs. On the other hand, they have greater risk of weight gain and metabolic effects than other approved medications. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Post-Traumatic Stress Disorder Strength of evidence: Moderate : risperidone Low: Olanzapine Quetiapine: very low There is no evidence that antipsychotics improve the core symptoms of PTSD. They can be useful adjunctive agents for the management of agitation, irritable aggression, anxiety and sleep difficulties. Antipsychotics are also prescribed for the treatment of post-traumatic stress disorder. There are different levels of evidence available for each antipsychotic. For risperidone, the strength of evidence is moderate, for olanzapine is low and for quetiapine very low. There is no evidence that antipsychotics improve the core symptoms of PTSD. However, antipsychotics can be useful for the management of agitation, irritable aggression, anxiety and sleep difficulties. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Obsessive-compulsive disorder Resistant OCD: augmentation with antipsychotics. There is evidence that the addition of olanzapine or risperidone to a selective reuptake inhibitor helps some patients. Serotonin reuptake inhibitors are the first line treatment for obsessive compulsive disorder. In some cases, despite continued treatment, residual symptoms sometimes remain. This is the reason why antipsychotics have been tried as augmentation therapy for treatment resistant OCD. So, what do we know about antipsychotics for OCD? There is evidence that the addition of olanzapine or risperidone to a selective reuptake inhibitor helps some patients. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Borderline personality disorder Psychotherapy is the mainstay of treatment. Antipsychotics may be useful as adjunctive therapy in some cases. Should not be routinely used. Antipsychotics have also been used for borderline personality disorder. For this personality disorder psychotherapy is the mainstay of treatment, antipsychotics may be useful as adjunctive therapy in some cases. One concept worth noting is that in borderline personality disorder pharmacotherapy aims at improving symptoms, not the personality disorder itself. That’s why antipsychotics should not be routinely prescribed and their use should be carefully assessed . Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Borderline personality disorder Olanzapine has shown superiority over placebo for symptoms such as: Anxiety Depression Anger and hostility Impulsive aggression Interpersonal sensitivity There is not convincing information suggesting that any antipsychotic agent changes the underlying character structure of patients with BPD In clinical trials olanzapine has shown superiority over placebo for symptoms such as: Anxiety Depression Anger and hostility Impulsive aggression Interpersonal sensitivity. There is no convincing information suggesting that any antipsychotic agent changes the underlying character structure of patients with BPD. Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Antipsychotics in Dementia Used for behavioral disturbances. Aripiprazole, olanzapine and risperidone have modest but defined efficacy. Off-label use The FDA reported in a public health advisory that the use of SGAs is associated with increased mortality. Dementia, whether due to AD or other causes, can be associated with behavioral disturbances and psychosis. Since antipsychotics don’t improve cognitive impairment in dementia, they are used mainly for the management of behavioral symptoms, delusions and hallucinations. Current evidence shows that aripiprazole, olanzapine and risperidone have modest but defined efficacy. However, antipsychotics are used off-label for dementia, since the FDA hasn’t granted approval for this indication. In fact, in 2005, the FDA reported in a public health advisory that the use of second generation antipsychotics is associated with increased mortality. A question worth asking is: How antipsychotics might increase mortality in this group of patients?

Antipsychotics and stroke risk Reported risk Sink et al. 2005 Brodaty et al. 2003 Wooltorton et al. 2004 Did not report risk Herrmann et al., 2004 Barnett et al. 2007 Different groups of researchers addressed the possible link between antipsychotic use and an increase of stroke risk. The results are conflicting, as you can see in this diagram, three papers reported increased risk of stroke and the other two papers didn’t.

Antipsychotics for Dementia For each patient, an individual assessment and documentation of risks and benefits of therapy is necessary. The use should be assessed in a case-by-case basis. Can we draw a practical conclusion from the information just presented? The answer is that the decision of prescribing an antipsychotic depends on the clinical situation. For each patient, an individual assessment and documentation of risks and benefits is necessary. The use of antipsychotics for the management of behavioral symptoms should be addressed in a case-by-case basis.

Tourette Syndrome Pathophysiology: thought to involve dysfunction of basal ganglia. Antipsychotics can be effective in reducing motor and vocal tics Haloperidol and pimozide have been the most commonly used drugs for moderate to severe tics. The SGAs risperidone and ziprasidone were superior to placebo in small RCTs. Tourette syndrome is a neuropsychiatric disorder with typical onset in childhood. This disorder is characterized by chronic occurrence of motor and vocal tics. It can lead to serious impairments of both quality of life and psychosocial functioning, particularly for those individuals displaying complex tics. Antipsychotics can be effective in reducing of motor and vocal tics. Haloperidol and pimozide have been the most commonly used drugs for moderate to severe tics. Regarding second generation antipsychotics: risperidone and ziprasidone were superior to placebo in small RCTs. Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Substance-abuse disorders Case reports, open label studies, and a few RCTs suggest SGAs may have a role in reducing substance abuse when it is comorbid with a psychotic disorder (dual diagnosis). When a psychotic disorder is not present , antipsychotics are not generally efficacious. Regarding the use of antipsychotics for substance-abuse disorders, case reports, open label studies and a few randomized controlled trials suggest that second generation antipsychotics may have a role in reducing substance abuse when it’s comorbid with a psychotic disorder. This clinical situation is also known as dual diagnosis. However, when a psychotic disorder is not present, antipsychotics aren’t generally efficacious. Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Other uses Delirium: Huntington’s disease: APs used as symptomatic treatment. Psychotic symptoms and agitation. Huntington’s disease: Patients might progress to delusional state or manic episodes. Other clinical uses include: Delirium, Huntington’s disease, pervasive developmental disorders and impulse control disorders. Delirium or acute confusional state is a common syndrome affecting cognition and attention combined with disturbances of the sleep-wake cycle and psychomotor behavior. It’s important to note that there are a number of medical conditions that can cause delirium, so treatment should always address the underlying cause. That being said, antipsychotics can be used as symptomatic treatment of psychotic symptoms and agitation. Patients suffering from Huntington’s disease can have psychiatric symptoms that include cognitive impairment, depression and obsessive-compulsive symptoms. Some of them might progress to a psychotic delusional state or sometimes are followed by manic or hypomanic episodes. Antipsychotics can be used for the management of these symptoms. Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Other uses Pervasive Developmental Disorders Impulse Control Disorders Few controlled studies SGAs have shown some efficacy Impulse Control Disorders Appropriate only when other measures failed Pervasive developmental disorders (PDDs) include a spectrum of behavioral problems commonly associated with autism. Patients with pervasive developmental disorders may demonstrate periods of hyperactivity, screaming, and agitation with combativeness. Although there are few controlled studies for this disorder, SGAs have shown some efficacy. However, there is concern that they are overprescribed in some settings. There is a long-standing, but controversial, practice of prescribing first generation antipsychotics for individuals with extremely poor impulse control and a propensity for violent behavior. This practice is not supported by controlled clinical trials and may be appropriate only when other measures such as the use of selective serotonin reuptake inhibitors (SSRIs), carbamazepine, lithium, or ß-blockers has failed. Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

References and further reading Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010. Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010 Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008