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Psychosis: Pharmacotherapy

Acute treatment

The goals for acute treatment of a patient presenting with psychosis include:

  • diagnostic assessment
  • assessing the potential for danger to self or others
  • engaging the patient and caregivers in the treatment process, including a discussion about risks and benefits of treatment
  • initiating pharmacologic treatment as soon as possible

The goal of treatment is full remission of symptoms and return to baseline function. Second-generation antipsychotic medications (SGAs) are the first-choice treatments, especially for previously unmedicated patients who are particularly sensitive to acute extrapyramidal and sedative side-effects caused by antipsychotics.

The SGAs, including olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, are first-line medications and offer improved tolerability, particularly with regard to extrapyramidal symptoms, compared with first-generation antipsychotics (FGAs) (see Table 7.1: First and second generation antipsychotic medications).

Choosing the right medication

Usually there is not one definite choice of medication for any given patient, since there is much individual variability in efficacy and side-effects. The choice is based primarily on individual profiles of efficacy and tolerability. Consider these factors when choosing an antipsychotic medication:

  • All SGAs except clozapine appear to be equally effective in treating psychosis in schizophrenia, with some recent evidence suggesting the possibility of a slight advantage in effectiveness for olanzapine.
  • There is emerging evidence that SGAs and FGAs may be equally effective in treating schizophrenia or schizoaffective disorder.
  • Clozapine appears to be a unique SGA that exhibits superiority in treating treatment-resistant patients with schizophrenia or schizoaffective disorder (patients who have not benefited from previous trials of two antipsychotics).
  • All antipsychotics carry a risk of extrapyramidal symptoms and tardive dyskinesia, although the risk appears to be higher with FGAs compared to SGAs. Of the SGAs, the risk of extrapyramidal symptoms seems to be highest with risperidone.
  • All antipsychotics carry a risk of weight gain and metabolic abnormalities, although the risk appears to be higher with SGAs, particularly olanzapine, quetiapine and clozapine.
  • Risperidone is the SGA most commonly associated with elevated prolactin levels and subsequent amenorrhea and sexual dysfunction.
  • Ziprasidone carries a potential risk of QTc prolongation, and as such is contraindicated in patients with a prolonged QTc interval.
  • Clozapine treatment carries a risk of agranulocytosis, which requires regular monitoring of white blood cell and neutrophil counts (weekly for the first six months, biweekly for the next six months, monthly thereafter). The risk is approximately 0.5 to two per cent, and appears to be greatest in the early stages of treatment initiation.
  • For schizoaffective disorder, treatment typically combines an antipsychotic with a medication aimed at treating the mood disturbance (see "The patient who is depressed"  and "The patient who is manic"). 

Note: Monitor metabolic and cardiovascular risk factors for all patients prescribed antipsychotic medicatioon. (see Table 7.2: Recommended monitoring guidelines)

Maintenance treatment

The goals for maintenance treatment of schizophrenia or schizoaffective disorder are:

  • improvement in functional recovery
  • prevention of relapse and recurrence
  • treatment adherence

Discontinuing medication

Following treatment of a first episode of psychosis, with symptom remission and functional recovery while on medications for approximately two years, consider a trial of no medications. However, which patients can safely and permanently discontinue antipsychotic medications cannot be predicted. Medication should be withdrawn gradually over six to 12 months, and symptoms and functioning monitored closely.

Relapse rates are estimated at 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 within the first three to five years, with recovery from subsequent episodes being slower and often less complete. Following a second psychotic episode, it becomes highly unlikely that patients will remain relapse-free if they go off antipsychotic medication.

Addressing inadequate response to pharmacotherapy

If the patient is not adequately responding to medication, re-evaluate the following:

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

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)

If the patient is referred to a specialist, the specialist may follow other strategies:

  • prescribe clozapine for treatment-resistant patients who have shown partial or total non-response to previous 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. They include enduring affective flattening, poverty of speech, social withdrawal and amotivation. For these patients, 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, such as:

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

There is limited evidence to support a benefit of SGAs over FGAs for treating primary negative symptoms, although they may be somewhat better with respect to secondary negative symptoms attributable to extrapyramidal symptoms. Treating secondary negative symptoms with adjunctive medications or optimizing antipsychotic medication is important.

There is some evidence to suggest adjunctive antidepressant treatment with SSRIs may be of some benefit for primary negative symptoms

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. Be aware of the following interactions:

  • In a patient population characterized by a high smoking rates, the 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 among 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 increase blood levels of drugs that are metabolized primarily by this isoenzyme. Caution is recommended in 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).

Combining medication with brain stimulation treatment

Electroconvulsive therapy (ECT), in combination with antipsychotic medication, may offer some benefit for treatment-resistant psychotic symptoms. There is also emerging evidence to suggest that repetitive transcranial magnetic stimulation (rTMS) may benefit some patients with treatment-resistant psychotic symptoms.


Related Portico Network topics

Understanding psychiatric medications (patient handouts):

  • Antidepressants
  • Antipsychotics
  • Mood stabilizers
  • Benzodiazapines

Psychiatry in primary care toolkit

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Frequently asked questions

Clinical guidelines

Treatment of schizophrenia (CPA, 2005)