Relapse rates for patients who are off antipsychotic medications are estimated to be 60 per cent or higher over two years. Of patients with a first episode of psychosis, 80 per cent are at risk of a second episode in the first three to five years, with recovery from subsequent episodes being slower and often less complete. Following a second episode, it becomes highly unlikely that patients will remain relapse-free while off antipsychotic medication.

Addressing Inadequate Response to Pharmacotherapy

If the patient does not adequately respond to pharmacotherapy, re-evaluate the following areas:

• diagnosis
• treatment non-adherence (often due to poor insight into illness)
• substance use or substance use problems.

Pharmacological strategies for initial non-responders include:

• optimizing the antipsychotic dose
• substituting with another antipsychotic medication
• substituting with a long-acting intramuscular depot antipsychotic medication (if treatment adherence is a factor).

After referral, a specialist may:

• prescribe clozapine for treatment-resistant patients who have shown partial or total non-response to trials of at least two other antipsychotic medications
• augment clozapine (e.g., lamotrigine, valproic acid)
• offer adjunctive electroconvulsive therapy (ECT).

Managing Persistent Negative Symptoms

Persistent negative symptoms are a frequent feature of schizophrenia and schizoaffective disorder, characterized by enduring affective flattening, poverty of speech, social withdrawal and amotivation. They are important contributors to functional disability. It is important to evaluate whether these negative symptoms are a consequence of the underlying illness (i.e., primary) or whether they are secondary to other causes, including:

• residual paranoid delusions
• anxiety
• depression
• over-sedation
• antipsychotic-induced extrapyramidal symptoms
• antipsychotic-induced dysphoria

Currently, treatment options for primary negative symptoms are limited. There is limited evidence to support a benefit of SGAs over FGAs to treat these symptoms, although SGAs may be somewhat better in treating secondary negative symptoms attributable to extrapyramidal symptoms. Treating secondary negative symptoms with adjunctive medications or by optimizing antipsychotic medication is important.

There is also some evidence to suggest that adjunctive antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) may be beneficial for treating primary negative symptoms.

Managing Persistent Cognitive Deficits

Cognitive deficits are a common feature of schizophrenia and schizoaffective disorder, characterized by deficits in attention, memory, processing speed, problem solving and social cognition (e.g., theory of mind, emotion identification and attribution). These deficits tend to be stable over the course of the illness and contribute to the functional disability that patients experience. Cognitive remediation therapy is an option for treating cognitive deficits, although there is inconsistent evidence that improvements as a result of  this treatment are sustained or translate into improvement in functional outcomes.

Avoiding Drug–drug Interactions

Numerous medications (e.g., psychotropic medications, antibiotics, antifungal agents) and natural products may affect hepatic metabolism through the cytochrome P450 (CYP 450) system, and thus interfere with antipsychotic medication metabolism. Consider the following points:

• In a patient population that has a high rate of cigarette smoking, induction of the CYP 450 system, particularly isoenzyme 1A2, can cause increased  metabolism of some antipsychotic medications, including clozapine and olanzapine, thus requiring somewhat higher doses with patients who smoke.
• Abrupt smoking cessation can cause a gradual reduction in metabolism of antipsychotic medications through CYP 1A2, with the gradual emergence of signs and symptoms of antipsychotic toxicity if antipsychotic dosages are not monitored and adjusted accordingly (especially with clozapine).
• Fluvoxamine can markedly inhibit CYP 1A2 and can increase blood levels of drugs that are metabolized primarily by this isoenzyme (be cautious with patients treated with clozapine).
• Fluoxetine and paroxetine can inhibit CYP 2D6 and thus cause increased plasma levels for many antipsychotics that are metabolized through this isoenzyme (e.g., risperidone, aripiprazole, haloperidol, fluphenazine).
• Carbamazepine is a potent inducer of CYP 3A4 and thus can cause reduced plasma concentrations of several antipsychotics that are metabolized through this isoenzyme (e.g., quetiapine, ziprasidone).
• Ziprasidone is contraindicated in patients who are concurrently being treated with medications that can prolong the QT interval (e.g., quinidine, type  Ia and II antiarrhythmics, certain antibiotics).