Schizophrenia and Related Psychotic Disorders

Clinical Snapshot

Psychotic disorders — schizophrenia and the related conditions on its spectrum — are brain disorders that distort or interrupt a person's contact with reality, affecting thought, perception, emotion, and behaviour. Symptoms cluster into four domains that must each be assessed and treated: positive symptoms (delusions, hallucinations, disorganized thinking, speech, and behaviour), negative symptoms (social withdrawal, apathy, anhedonia, and emotional blunting), cognitive symptoms (impaired attention, concentration, and memory), and mood symptoms (dysphoria, anxiety, and emotional lability).^[1] Onset is typically in late adolescence or early adulthood, and a longer duration of untreated psychosis before treatment starts is associated with worse short- and long-term outcomes — this is why early detection and rapid referral to a specialized early psychosis program, where available, is a central emphasis of current Canadian practice.^[2] Antipsychotic medications are the cornerstone of treatment across every phase of illness, but are only fully effective when integrated with psychosocial interventions and ongoing physical health monitoring, since antipsychotics carry a substantial metabolic, cardiovascular, and movement-disorder burden that pharmacists are well positioned to catch early. A patient whose illness does not respond to two adequate trials of a non-clozapine antipsychotic has treatment-resistant schizophrenia and should be offered clozapine, the only antipsychotic with proven efficacy in that setting.^[3]

Recognize the Condition

The four symptom domains of psychosis

Positive symptoms

Delusions (fixed, false beliefs), hallucinations (most often auditory), disorganized thinking and speech, and disorganized or grossly abnormal behaviour. These are the symptoms antipsychotics treat most reliably.

Negative symptoms

Social withdrawal, apathy, anhedonia (reduced capacity for pleasure), avolition (reduced motivation), alogia (reduced speech output), and blunted or flat affect. Harder to treat than positive symptoms and a major driver of long-term functional disability.

Cognitive symptoms

Impaired attention, concentration, working memory, and executive function (abstract thinking, reasoning, problem-solving, judgment). Often present before the first psychotic episode and can persist even when positive symptoms remit.

Mood symptoms

Dysphoria, anxiety, and emotional lability. Depressive symptoms are common in the prodromal phase and can also emerge later as postpsychotic depression during stabilization.

Prodromal symptoms (clinical high risk)

No single symptom is diagnostic, but the following pattern — especially when it represents a clear change from the person's baseline — should prompt assessment for clinical high-risk/prodromal psychosis: reduced concentration and attention; reduced drive, motivation, and energy; depressed mood; sleep disturbance; anxiety; social withdrawal; deterioration in day-to-day functioning; and irritability.^[2] Structured tools (e.g., the Structured Interview for Prodromal Syndromes, the Scale of Prodromal Symptoms) can support this assessment where available.

First-episode psychosis

In addition to the prodromal pattern above, features suggesting an evolving first psychotic episode include: rapid mood fluctuation (emotional lability) or markedly reduced facial expression; unreasonable suspiciousness; insomnia, restlessness, and pacing at night; unusual or bizarre behaviour; unusual perceptual experiences (hypersensitivity, illusions, brief intermittent hallucinations); and new difficulty organizing or expressing thoughts.^[1]

Substance use — particularly cannabis — is common around the time of a first psychotic episode and can make the diagnosis harder to pin down; a substance-induced psychosis can be misdiagnosed when the true picture is an emerging primary psychotic disorder that a substance has unmasked or precipitated. Suspect a primary (functional) psychosis rather than a purely substance-induced one when symptoms precede the onset of substance use, are bizarre or accompanied by marked thought disorder, or persist well beyond the expected period of intoxication or withdrawal.

Risk Factors

Family history of a psychotic disorder.
Childhood trauma.
Obstetric complications, including extreme prematurity and hypoxia/ischemia at birth.
Cannabis use, particularly heavier and higher-potency use, which can trigger onset in a genetically vulnerable individual.
Prenatal/perinatal factors: maternal malnutrition, maternal viral illness (e.g., influenza), maternal obesity, prenatal x-ray radiation exposure, prenatal exposure to Toxoplasma gondii (cat feces), certain analgesic exposure (e.g., ASA) in pregnancy, season of birth (proposed link to reduced sunlight/vitamin D exposure), maternal-fetal Rh incompatibility, and low birth weight.
Comorbid substance use disorder more broadly — associated with poorer treatment adherence and outcomes once illness is established.

Red Flags & Refer

Refer or escalate urgently for any of the following:

Acute agitation or aggression with danger to self or others — arrange urgent psychiatric assessment and, if necessary, involuntary hospitalization under the applicable provincial mental health legislation.
Active suicidal ideation or behaviour, or serious aggressive/violent ideation or behaviour.
Signs of neuroleptic malignant syndrome: fever, severe muscle rigidity (distinct from the milder cogwheel rigidity of drug-induced parkinsonism), autonomic instability (fluctuating blood pressure, tachycardia), altered level of consciousness, and markedly elevated creatine kinase — a medical emergency requiring immediate antipsychotic discontinuation and supportive care.
Signs of clozapine-associated agranulocytosis: fever, sore throat, mouth ulcers, or other signs of infection in a patient on clozapine — obtain an urgent absolute neutrophil count and withhold clozapine pending the result.
Signs of catatonia: mutism, stupor, unusual posturing, waxy flexibility, negativism, or extreme psychomotor agitation or immobility — this is a psychiatric and, in its malignant form (with fever and autonomic instability), medical emergency requiring urgent assessment; it is not simply "severe" psychosis and can require a distinct treatment approach (e.g., benzodiazepines, electroconvulsive therapy) directed by a psychiatrist.
Suspected clozapine-induced myocarditis: chest pain, dyspnea, tachycardia, or fever, especially within the first month of clozapine therapy — discontinue clozapine immediately and refer for cardiology assessment.
Suspected first-episode psychosis in any patient — urgent referral to a psychiatrist, community mental health clinic, or specialized early psychosis program.
New psychosis presenting during pregnancy or in the postpartum period — a psychiatric emergency requiring immediate assessment given the risk to both patient and infant.
Signs of drug reaction with eosinophilia and systemic symptoms (DRESS): rash, fever, swollen lymph nodes, and facial swelling, which can occur with several antipsychotics — stop the antipsychotic and provide supportive care.

Assessment & Diagnosis

Differentiating psychotic disorders on presentation

Disorder	Key distinguishing features
Schizophrenia	Continuous signs of illness for 6 months or longer, with active psychotic symptoms (delusions, hallucinations, or disorganized speech) for at least 1 month, plus social/occupational dysfunction.
Schizophreniform disorder	The same presentation as schizophrenia, but total illness duration is at least 1 month and under 6 months.
Schizoaffective disorder	An uninterrupted period of illness with concurrent schizophrenia symptoms and a major mood episode; delusions or hallucinations for at least 2 weeks in the absence of a major mood episode at some point in the illness; and a major mood episode present for more than half of the total illness duration.
Delusional disorder	Nonbizarre delusions for at least 1 month, without meeting full criteria for schizophrenia.
Brief psychotic disorder	Psychotic symptoms lasting at least 1 day but under 1 month, sometimes triggered by a marked stressor, with an eventual full return to premorbid functioning.
Substance-induced psychotic disorder	Delusions or hallucinations developing during or within 1 month of substance intoxication or withdrawal, or clearly linked to a medication, and not better explained by a primary psychotic disorder.
Psychotic disorder due to another medical condition	Delusions or hallucinations that are a direct physiological consequence of a medical condition, occurring without delirium.
Major depression or bipolar disorder with psychotic features	Delusions or hallucinations occurring specifically during a major depressive or manic episode.
Psychotic disorder not otherwise classified	Psychotic symptoms are present, but criteria for a specific disorder are not met, or the available information is insufficient or contradictory.

Because symptoms can evolve during the early phase of illness, treat the initial diagnosis as provisional and re-evaluate as the clinical picture unfolds — many first presentations are reclassified once the required duration criteria are, or are not, ultimately met.^[1]

History

A thorough history of the presenting problem, with attention to the onset and course of prodromal symptoms and the onset, character, and severity of psychotic symptoms.
Changes in behaviour and day-to-day functioning.
History of suicidal ideation or behaviour, and of aggressive or violent ideation or behaviour.
Substance use in relation to the onset and course of psychotic symptoms.
Collateral information from family or other sources whenever possible — people with psychotic disorders are often poor historians, and interviewing family with the patient's consent (or accepting unsolicited collateral information without disclosing confidential details back) adds essential information.
Assess capacity to consent to treatment in every acutely psychotic patient; if capacity is lacking, a substitute decision-maker (usually a family member) must be involved as required by provincial legislation.

Rating scales and functional assessment

Use validated tools at baseline and at intervals to track symptomatic and functional recovery: the Clinical Global Impression Scales for Severity (CGI-S) and Change (CGI-C), and the Social and Occupational Functioning Assessment Scale (SOFAS), are simple enough for routine use; the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS) require specific training to use reliably. The Calgary Depression Scale for Schizophrenia (CDSS) is validated specifically to distinguish a genuine major depressive episode from negative symptoms or antipsychotic-induced emotional blunting in this population — a score of 6 or higher is clinically significant and warrants specific treatment for depression rather than simply adjusting the antipsychotic.^[1]

Baseline and targeted investigations

Test	When
CBC/differential, electrolytes, kidney and liver function, fasting glucose and lipid profile, TSH, baseline prolactin, routine urinalysis	Baseline in every first-episode and recurrent acute episode.
Urine drug screen; testing for STIs, HIV, and hepatitis	When clinically indicated by history.
CT brain	When signs or symptoms suggest intracranial pathology, or when the age of onset is later in life than typical for a first episode.
Genetic testing (e.g., a polygenic risk score, where available)	Consider in first-episode psychosis based on history and physical examination — not a routine test.

Routine neuroimaging and genetic testing are not required for a typical-age first episode with a normal neurological examination — reserve them for atypical presentations.^[1]

Treatment Targets

Prevent progression to psychosis in patients at clinical high risk.
Reduce psychotic agitation during acute episodes.
Achieve remission of positive, negative, cognitive, and mood symptoms — not positive symptoms alone.
Reduce the risk of psychiatric comorbidity, particularly suicide and depression.
Reduce the risk of physical comorbidity, including metabolic syndrome and cardiovascular disease.
Reduce substance use.
Reduce the risk of harm to self or others.
Reduce social isolation from family, friends, and community supports.
Facilitate recovery of functioning and healthy development.
Prevent or minimize recurrence of psychotic episodes.

Choose Initial Treatment

Direct treatment rule

Clinical high risk / prodromal syndrome

1st line cognitive behavioural therapy (CBT), following the staged Canadian approach for individuals who meet clinical high-risk criteria.^[2]

2nd line — use when CBT alone does not control distressing symptoms add a low-dose second-generation antipsychotic (SGA).^[2]

First episode or recurrent acute psychotic episode

1st line a second-generation antipsychotic (SGA), started at a low dose and titrated gradually over 1-2 weeks up to the usual therapeutic range — the exceptions are ziprasidone and extended-release quetiapine, which are titrated rapidly to avoid adverse reactions. First-episode patients respond to, and should be started on, lower doses than multi-episode patients.^[3]

If a first-generation antipsychotic (FGA) is preferred use an intermediate-potency agent (e.g., loxapine or perphenazine) to minimize the greater extrapyramidal and hyperprolactinemia burden of high-potency FGAs.

Continue the chosen antipsychotic for at least 2 weeks before judging response, unless a significant tolerability problem forces an earlier change; confirm adherence and rule out ongoing substance use before concluding the patient has not responded. An adequate trial is 4-6 weeks at a dose within the therapeutic range — reassess a partial responder again at 8 weeks before switching, but a patient with no response at all by 4 weeks is unlikely to benefit from a longer trial at that dose.^[3]

Acute agitation

If the patient can and will take oral medication, a rapid-dissolving oral olanzapine tablet is as effective as intramuscular (IM) haloperidol.

Parenteral therapy needed IM haloperidol, alone or combined with IM lorazepam, or combined with IM promethazine, is a well-established option; IM olanzapine has similar efficacy to IM haloperidol in mildly-to-moderately agitated patients and causes less extrapyramidal side effects (EPS).

Never combine parenteral olanzapine with a parenteral benzodiazepine — this combination has caused excessive sedation and cardiorespiratory depression, including death.^[3]

Severe agitation/aggression, antipsychotic-experienced patients only zuclopenthixol acetate IM has a pharmacokinetic profile that can reduce the number of injections needed; it must not be used in antipsychotic-naive patients.

Long-acting injectable (depot) antipsychotics

Offer a long-acting injectable (LAI) antipsychotic as an option in every phase of illness, including the first episode, once tolerability has been established with the oral formulation — LAIs are not a last-resort option reserved for severe or repeatedly nonadherent illness, and withholding them because of clinician unfamiliarity or an assumption that patients will refuse an injection is not evidence-based.^[3]

Maintenance treatment duration

Continue maintenance antipsychotic therapy for at least 1-2 years after a first episode achieves symptom remission and functional recovery; extend to 2-5 years when the duration of untreated psychosis was long, illness was more severe, response was slow, substance use is ongoing, or there is a history of suicidal or aggressive behaviour. For a patient with 2 or more lifetime episodes, continue maintenance therapy until the patient has been stable and relapse-free for at least 5 years — many patients ultimately need indefinite treatment. Use the lowest effective acute-phase dose for maintenance, and do not reduce the dose further in a stable, multi-episode patient, since this raises relapse risk without a compensating benefit.^[3]

Treatment-resistant schizophrenia

Confirmed treatment resistance — failure to achieve a meaningful reduction in positive symptoms despite 2 or more adequate trials (each at least 6 weeks, at a therapeutic dose) of a non-clozapine antipsychotic — start clozapine. It is the only antipsychotic with proven efficacy in treatment-resistant schizophrenia, including for reducing hostility/aggression and persistent suicidality, and is reserved for this setting specifically because of its agranulocytosis risk and the intensive blood monitoring it requires.^[3]

Once a patient is successfully stabilized on clozapine, do not switch to another antipsychotic or add a second antipsychotic — neither has been shown to provide additional benefit in a clozapine responder.

Antipsychotic polypharmacy

Avoid routine use of more than 1 antipsychotic at a time — the only 2 evidence-supported exceptions are a deliberate, time-limited cross-titration when switching between antipsychotics, and adjunctive therapy for a partial responder to clozapine, and even these should occur only under psychiatrist direction given the added risk of drug interactions, side effects, and reduced adherence.^[3]

Non-Pharmacologic Treatment

Choose the least restrictive treatment setting possible while ensuring safety; acutely agitated patients at imminent risk of harm to self or others require hospitalization, involuntarily if necessary, under the applicable provincial mental health legislation.
See outpatients at least weekly for the first 4-6 weeks after an acute episode to build rapport, provide psychoeducation and practical support, promote adherence, and monitor both response and adverse effects.
Foster a collaborative relationship between the patient, family/caregivers, and the treatment team, and maintain continuity of care with the same clinician or team whenever possible.
Provide individual and family psychoeducation, cognitive behavioural therapy (CBT — also effective for residual psychotic symptoms and for comorbid depression/anxiety), motivational interviewing, social and vocational skills training, supported employment programs, and peer support groups; these improve functional outcome and adherence and help prevent relapse.
Refer patients with serious, ongoing illness, significant functional disability, or comorbid substance use to an Assertive Community Treatment (ACT) team where available.
Provide dietary and exercise counselling to help prevent and manage antipsychotic-associated weight gain and metabolic side effects; structured exercise and tai chi may also improve psychiatric symptoms and motor coordination.
Actively encourage smoking cessation at every visit — smoking is disproportionately common in this population and is a major contributor to the markedly increased cardiovascular risk pharmacists should be watching for. Nicotine replacement therapy, bupropion, and varenicline are all appropriate options; monitor for mood or behavioural changes when starting varenicline or bupropion, particularly in patients with a history of suicidal ideation, depressed mood, or agitation/hostility.
Use a harm-reduction approach incorporating motivational interviewing for comorbid substance use, and refer patients with persistent substance use to an integrated mental health/addiction program.

Pharmacologic Treatment Options

Two antipsychotic tracks

First-generation antipsychotics (FGAs)

"Typical"/"conventional" agents, classified by chemical structure or by dopamine D2-receptor binding potency (low/intermediate/high). Low-potency agents (chlorpromazine, methotrimeprazine) cause more sedation, cardiovascular effects, anticholinergic effects, and weight gain; high-potency agents (fluphenazine, haloperidol) cause more EPS, neuroleptic malignant syndrome, and hyperprolactinemia.

Second-generation antipsychotics (SGAs)

"Atypical" agents with greater serotonin 5-HT2A receptor affinity relative to D2 affinity, generally chosen first given more favourable tolerability. Aripiprazole, brexpiprazole, and cariprazine are sometimes further classified as third-generation antipsychotics because of their partial dopamine agonist activity.

All FGAs and SGAs except clozapine have broadly similar efficacy against positive symptoms — the choice between them is driven by tolerability and adverse-effect profile, not by an expectation of superior symptom control.^[3]

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Risperidone Preferred	SGA, first episode or recurrent psychosis	Initial 1-2 mg/day PO, titrate by 0.5-2 mg every 3-7 days to a usual 4-6 mg/day (max 10 mg/day)	EPS (highest among SGAs), hyperprolactinemia, orthostatic hypotension	Give once daily, preferably at bedtime. Also available as long-acting injections.
Olanzapine Preferred	SGA, first episode or recurrent psychosis	Initial 5-10 mg/day PO, titrate by 2.5-5 mg every 3-4 days to a usual 10-20 mg/day	Greatest weight gain/metabolic risk among SGAs, sedation	Also available as a rapid-dissolving tablet and an IM injection for acute agitation.
Quetiapine Preferred	SGA, first episode or recurrent psychosis	Immediate-release: initial 50-100 mg/day, titrate by 100 mg/day to a usual 600 mg/day. Extended-release: initial 300 mg QHS (200 mg for first-episode psychosis), usual 400-800 mg/day	Sedation, orthostatic hypotension, weight gain	Give the extended-release formulation once daily in the evening; can be titrated rapidly, unlike most SGAs.
Aripiprazole Preferred	SGA, first episode or recurrent psychosis	Initial 10-15 mg/day PO (2-5 mg in first-episode psychosis, titrated up), usual 10-15 mg/day, max 30 mg/day	Akathisia, insomnia/activation, GI upset	Take in the morning given its activating effects. Also available as 2 long-acting injections.
Paliperidone Preferred	SGA, active metabolite of risperidone	Initial 3-6 mg/day PO, titrate by 3 mg every 5 days, max 12 mg/day	Hyperprolactinemia, EPS, insomnia	Not hepatically metabolized — minimal drug-interaction risk. Also available as monthly and every-3-month long-acting injections.
Haloperidol Alternative	High-potency FGA; oral or IM for acute agitation	Oral: initial 1.5-3 mg/day, usual 4-12 mg/day, max 20 mg/day. IM (acute agitation): 2-5 mg, may repeat every 4-8 hours	EPS, neuroleptic malignant syndrome, hyperprolactinemia	Lower doses (e.g., 2-5 mg) are as effective as much higher doses and better tolerated. Also available as a long-acting injection.
Loxapine Alternative	Intermediate-potency FGA; preferred FGA choice when an FGA is used	Initial 10-20 mg/day PO, usual 60-100 mg/day, max 250 mg/day	EPS, sedation, anticholinergic effects	Also available as an IM injection for agitation.
Clozapine Special situation	Treatment-resistant schizophrenia only	Initial 12.5-25 mg/day PO, titrate slowly, usual 300-600 mg/day, max 900 mg/day	Agranulocytosis, dose-related seizures, myocarditis, severe constipation, marked weight gain/metabolic risk	Requires mandatory baseline and ongoing ANC monitoring — see Monitoring & Follow-up. Never stop and restart without checking the required re-titration/re-monitoring rules.
Risperidone long-acting injection Special situation	Adherence support, any phase after oral tolerability is established	Initial 25 mg IM every 2 weeks (with oral overlap for the first 3 weeks), titrate to a usual 25-37.5 mg every 2 weeks, max 50 mg every 2 weeks	Same as oral risperidone; injection-site pain is common	Offer proactively, not only after repeated nonadherence.
Paliperidone palmitate long-acting injection Special situation	Adherence support, monthly or every-3-month dosing	Initial 150 mg IM day 1, 100 mg IM day 8, then 25-150 mg monthly (or, once stable on the monthly product for 4 or more months, 175-525 mg every 3 months)	Same as oral paliperidone	No oral overlap required — a genuine adherence advantage over other LAIs.
Aripiprazole long-acting injection Special situation	Adherence support, monthly or every-2-month dosing	400 mg IM monthly (or 960 mg IM every 2 months for the extended-release product), with 14 days of oral aripiprazole overlap after the first injection	Same as oral aripiprazole	Confirm oral tolerability before the first injection.
Lorazepam Alternative	Adjunct for acute agitation/anxiety during antipsychotic titration	1-2 mg IM or PO, may repeat	Sedation, respiratory depression with opioids	Never combine parenteral lorazepam with parenteral olanzapine.
Propranolol Preferred	Antipsychotic-induced akathisia	10-120 mg/day PO in divided doses	Bradycardia, hypotension, bronchospasm	Treatment of choice for akathisia once dose reduction has been tried or is not feasible; monitor heart rate and blood pressure.
Benztropine Alternative	Drug-induced parkinsonism/acute dystonia	1-2 mg PO or IM, up to 6 mg/day	Anticholinergic effects, confusion (especially in older adults)	Not effective for, and can worsen, tardive dyskinesia. Do not use prophylactically.

Special Populations

Pregnancy

Screen every patient with a psychotic disorder for pregnancy risk and provide contraception/pregnancy counselling early in the illness course — if pregnancy is planned, arrange psychiatrist consultation to weigh the risks and benefits of maintenance antipsychotic therapy before conception where possible. A first psychotic episode occurring during pregnancy is a psychiatric emergency: psychosis in pregnancy is associated with worse obstetric and neonatal outcomes, and untreated psychosis carries real risk to both patient and fetus, so treat with the same urgency as in a non-pregnant patient. No randomized trial data exist for antipsychotics in pregnancy, and major congenital malformations have not been demonstrated with antipsychotic use, though gestational diabetes risk may be increased, particularly with agents carrying the highest metabolic burden (olanzapine, quetiapine).^[1] For most pregnant patients on maintenance antipsychotic therapy, continuing at the lowest effective dose is recommended over stopping, since an acute relapse itself carries real risk to the pregnancy and may ultimately expose the fetus to higher medication doses used to treat a breakthrough episode. Manage every pregnancy in a patient with schizophrenia as high-risk, with combined obstetric and mental-health follow-up.^[1]

Postpartum period

Relapse risk is high in the postpartum period, especially in the first 3 months after delivery, and higher still after a prior episode of postpartum psychosis — restart antipsychotic therapy immediately after delivery if it was stopped during pregnancy, and monitor patients on low-dose maintenance therapy closely for early signs of relapse, since the postpartum dose requirement may be higher than the pregnancy dose. Postpartum psychosis is a psychiatric emergency because of the risk of suicide and infanticide; if hospitalization is required and it is safe to do so, keep the patient and infant together, ideally in a specialized unit. For an infant exposed to clozapine in utero, obtain a neutrophil count; for an infant exposed to a high-potency FGA in the third trimester, monitor for extrapyramidal symptoms for the first several days of life.^[1]

Breastfeeding

Antipsychotics pass into breast milk at levels generally considered compatible with breastfeeding, though long-term infant outcome data remain limited — discuss the individual risk/benefit balance with each patient. Among the SGAs, olanzapine has the most reassuring breastfeeding data (the largest number of documented cases with low infant exposure), and quetiapine also shows low infant exposure; risperidone is associated with greater infant exposure and is not preferred if an alternative is suitable. Breastfeeding is not recommended while taking clozapine. If any antipsychotic is used during breastfeeding, monitor the infant for poor feeding, lethargy, excess drowsiness, and delayed developmental milestones.^[1]

Older adults

Antipsychotics carry an increased risk of cerebrovascular events and death when used specifically for dementia-related behavioural symptoms — reserve them for that indication only when non-pharmacologic measures have failed and the risk/benefit has been explicitly discussed. In older adults generally, start at a lower dose, titrate more slowly, and monitor more closely for orthostatic hypotension, sedation, falls, and anticholinergic burden; low-potency FGAs and the most anticholinergic SGAs (clozapine, olanzapine, quetiapine) warrant particular caution.

Children and youth

First-episode patients of any age are more responsive to lower antipsychotic doses and more prone to side effects than multi-episode adults — start low and titrate gradually. Pediatric- and youth-specific dosing, monitoring, and psychosocial program considerations are covered by a dedicated Canadian pediatric schizophrenia guideline; involve a psychiatrist experienced in pediatric psychosis for any patient under 18.

Renal and hepatic impairment

Most antipsychotics are primarily hepatically metabolized; use caution and consider lower starting doses in significant hepatic impairment. Paliperidone is minimally hepatically metabolized (an advantage in hepatic impairment) but requires dose adjustment in renal impairment — consult product-specific dosing for renal impairment for any antipsychotic in a patient with reduced kidney function.

Monitoring & Follow-Up

Routine monitoring schedule

The following schedule applies across the first-episode, recurrent-episode, stabilization, and stable phases of illness.^[1]

Parameter	Baseline	Ongoing
Psychopathology (CGI-S/C, BPRS, PANSS)	Every first or recurrent acute episode	Weekly for the first 4-8 weeks of an acute episode; monthly for the first 6 months of stabilization; every 3 months once stable
Functioning (SOFAS)	Premorbid and current functioning	Monthly for the first 6 months after an acute episode; every 3 months once stable
Substance use (CAGE, CAGE-AID, AUDIT)	Every acute episode	Every visit during stabilization and stable phases
Extrapyramidal side effects	Before starting or changing an antipsychotic	Weekly for 2-4 weeks after starting/changing therapy; every visit or every 6 months once stable (more often in higher-risk patients: FGA use, erratic adherence, older age, affective disorder, substance use, diabetes)
Weight, BMI	Baseline	Monthly for 6 months after starting/changing an antipsychotic, then every 3 months
Waist circumference	Baseline	Annually
Blood pressure	Baseline	At 12 weeks, then annually (more often if clinically indicated)
Fasting glucose	Baseline	At 12 weeks after starting/changing an antipsychotic, then annually (more often with weight gain or symptoms)
Fasting lipid profile	Baseline	At 12 weeks, then annually (every 6 months if LDL or triglycerides are above the normal range)
Prolactin	Baseline, before starting a prolactin-raising agent	Monthly for 3 months after starting a prolactin-raising antipsychotic, then yearly
ECG	In patients with cardiovascular risk factors for QTc prolongation, or before starting chlorpromazine, pimozide, or ziprasidone	With significant dose changes to a QTc-prolonging agent, or when adding another QTc-prolonging drug in an at-risk patient

Clozapine-specific hematological monitoring

Clozapine carries a real risk of agranulocytosis and requires mandatory, dedicated absolute neutrophil count (ANC) monitoring for the entire duration of therapy through the Clozapine Support and Assistance Network (CSAN) program in Canada — a prescription cannot be dispensed without a current, in-range result.^[4]

ANC result	Required action
Green: ANC ≥ 2.0 × 10⁹/L	Continue clozapine. Monitor weekly for the first 26 weeks, every 2 weeks for the next 26 weeks, then every 4 weeks from week 52 onward, for as long as therapy continues.
Yellow alert: 1.5-1.99 × 10⁹/L	Continue clozapine, but increase monitoring to at least twice weekly until the ANC stabilizes or rises back into the green range.
Red alert: ANC < 1.5 × 10⁹/L	Withhold clozapine immediately and monitor closely; confirm the result within 24 hours. If confirmed, stop clozapine permanently — the patient is assigned non-rechallengeable status. Continue monitoring at least weekly after discontinuation until the ANC recovers to at least 2.0 × 10⁹/L.
ANC < 0.5 × 10⁹/L (agranulocytosis)	Consider protective isolation; investigate and treat any evidence of infection promptly — this threshold defines clozapine-induced agranulocytosis.

A 2025 international consensus (global Delphi panel) has proposed simplifying this schedule — moving to monthly monitoring after 18 weeks and discontinuing routine ANC monitoring altogether after 2 years of treatment, alongside a lower ANC threshold for considering permanent discontinuation. This has not yet been adopted into the mandatory Canadian CSAN monitoring requirement described above, so continue following the CSAN schedule for now — but expect Canadian practice to move toward less intensive long-term monitoring as this evidence is incorporated.^[5]

Ask about, and document, smoking status at every clozapine or olanzapine visit — smoking induces the CYP1A2 enzyme that metabolizes both drugs, so a patient who quits smoking (including during a smoke-free hospital admission) needs a dose reduction to avoid toxicity, and a patient who resumes smoking needs the dose reassessed upward; this interaction comes from combustion byproducts, not nicotine itself, so nicotine replacement therapy does not require the same dose adjustment.^[3]

Treatment Failure / Next Step

Confirm adherence and screen for ongoing substance use before concluding the antipsychotic has failed — both are common, correctable causes of apparent treatment failure.
Confirm the trial was adequate: at least 4-6 weeks at a dose within the therapeutic range. Reassess a partial responder again at 8 weeks before switching; a patient with no response at all by 4 weeks is unlikely to benefit from continuing longer at that dose.
If a single adequate trial has failed, switch to a different antipsychotic using a gradual cross-titration (2 weeks to 3 months) rather than an abrupt switch, to avoid unnecessary polypharmacy and withdrawal-related symptoms; a Canadian online tool (SwitchRx) can guide the crossover schedule.
If 2 or more adequate trials (each at least 6 weeks) of different non-clozapine antipsychotics have failed to produce a meaningful reduction in positive symptoms, this is treatment-resistant schizophrenia — start clozapine.^[3]
If clozapine produces only a partial response despite an adequate dose and, where available, a therapeutic plasma level, consider adding a second antipsychotic as an adjunct under psychiatrist direction — this is one of only 2 evidence-supported antipsychotic polypharmacy scenarios. Do not switch a stabilized clozapine responder to a different antipsychotic.
If extrapyramidal symptoms or tardive dyskinesia are limiting therapy on an FGA, switch to an SGA; for persistent, severe tardive dyskinesia despite switching, consider a clozapine trial (clozapine carries the lowest EPS/TD risk of any antipsychotic) or a psychiatrist-directed trial of clonazepam or tetrabenazine, both of which have limited but real supporting evidence in this setting.^[6]
If postpsychotic depression or persistent suicidality is present despite antipsychotic treatment, add an antidepressant in the stabilization or stable phase (evidence does not support starting an antidepressant in the acute phase), and give specific consideration to a clozapine trial when suicidality is persistent.

Common Errors to Avoid

Combining parenteral olanzapine with a parenteral benzodiazepine — this combination has caused severe sedation and cardiorespiratory depression, including death.
Using zuclopenthixol acetate (short-acting depot) in an antipsychotic-naive patient — reserve it for antipsychotic-experienced patients with severe acute agitation.
Assuming rapid dose escalation or very high doses produce a faster or better response — for most patients this is not true and simply adds side effects; the main exceptions needing rapid titration are ziprasidone and extended-release quetiapine.
Using anticholinergic medication prophylactically, or using it to treat tardive dyskinesia — anticholinergics do not prevent EPS reliably enough to justify routine use, are not effective for tardive dyskinesia, and can make tardive dyskinesia worse.
Reducing the antipsychotic dose below the effective acute-phase dose in a stable, multi-episode patient — this raises relapse risk without benefit.
Treating only positive symptoms and overlooking negative, cognitive, and mood symptoms, which drive much of the long-term functional disability in this illness.
Stopping antipsychotic therapy during pregnancy without a specific discussion of the relapse risk this creates, or failing to restart it promptly after delivery — the postpartum period carries a particularly high relapse risk.
Missing a needed clozapine or olanzapine dose adjustment when a patient's smoking status changes (starting, stopping, or restarting) — this is a CYP1A2 induction effect from smoke, not nicotine, so nicotine replacement therapy does not trigger the same adjustment.
Treating long-acting injectable antipsychotics as a last-resort option for repeatedly nonadherent patients rather than offering them proactively in any phase, including the first episode.
Missing a baseline prolactin, fasting glucose, or lipid panel before starting an antipsychotic, which removes the ability to tell whether a later abnormal value is treatment-related.
Missing the mandatory ANC check before dispensing a clozapine prescription, or missing the twice-weekly monitoring escalation required for a yellow-alert result.

Clinical Decision Algorithm

Acute psychotic episode: initial treatment and agitation management

Suspected first-episode or recurrent acute psychotic episode

Assess safety, agitation level, and ability/willingness to take oral medication; choose the least restrictive appropriate treatment setting

Acute agitation, unable or unwilling to take oral medication

IM haloperidol alone, or combined with IM lorazepam or IM promethazine; or IM olanzapine alone

Never combine parenteral olanzapine with a parenteral benzodiazepine

Severe agitation in an antipsychotic-experienced patient: zuclopenthixol acetate IM is an alternative (not for antipsychotic-naive patients)

Able and willing to take oral medication

Start a second-generation antipsychotic (SGA) at a low dose; titrate gradually over 1-2 weeks (exceptions: ziprasidone, extended-release quetiapine — titrate rapidly)

If a first-generation antipsychotic (FGA) is preferred, use an intermediate-potency agent (loxapine or perphenazine) to limit adverse effects

Continue for at least 2 weeks unless a significant tolerability issue arises; confirm adherence and substance use before judging non-response

Adequate trial = 4-6 weeks at a therapeutic dose. Partial response at 4 weeks: reassess at 8 weeks. No response at all by 4 weeks: consider switching and consult a psychiatrist^[3]

Maintenance treatment and the long-acting injectable option

Symptom remission achieved on an oral antipsychotic

Offer a long-acting injectable (LAI) antipsychotic in any phase, including first episode, once oral tolerability is established

First episode, in remission

Continue maintenance therapy at the lowest effective acute-phase dose for at least 1-2 years; extend to 2-5 years for long duration of untreated psychosis, severe illness, slow response, substance use, or suicidal/aggressive history

2 or more lifetime episodes

Continue maintenance therapy until stable and relapse-free for at least 5 years; many patients require indefinite treatment

Do not reduce the dose further in a stable multi-episode patient — raises relapse risk without benefit

If discontinuing: taper by no more than 20% every 2-4 weeks, over 6-12 months (first episode) or 6-24 months (2 or more episodes); restabilize promptly at the previously effective dose at the first sign of relapse

Treatment resistance and the clozapine pathway

Inadequate response despite an adequate antipsychotic trial (at least 6 weeks at a therapeutic dose)

Confirm adherence, substance use, dose, and duration before concluding the trial failed

First inadequate trial

Switch to a second, different antipsychotic using a gradual cross-titration (2 weeks to 3 months)

Second adequate trial of a different non-clozapine antipsychotic also inadequate

Treatment-resistant schizophrenia confirmed — start clozapine, the only antipsychotic proven effective in this setting^[3]

Titrate clozapine slowly per product monograph; begin mandatory ANC monitoring before the first dose

Good response

Continue clozapine indefinitely — do not switch a stabilized responder to another antipsychotic

Partial response despite an adequate dose

Consider adding a second antipsychotic as an adjunct under psychiatrist direction — one of only 2 evidence-supported polypharmacy scenarios

Recognizing and managing antipsychotic-induced movement disorders and NMS

New or worsening abnormal movement, rigidity, or restlessness on an antipsychotic

Akathisia (subjective/objective restlessness)

Reduce the antipsychotic dose, or switch to a lower-EPS-risk agent, first

If ineffective: propranolol 10-120 mg/day (treatment of choice) or a benzodiazepine — anticholinergics are not effective for akathisia

Parkinsonism or acute dystonia

Acute dystonia: benztropine or diphenhydramine IM immediately

Parkinsonism: reduce dose or switch to an SGA; if it persists, add an anticholinergic (benztropine, procyclidine, or trihexyphenidyl) — do not use anticholinergics prophylactically

Tardive dyskinesia (repetitive involuntary orofacial, limb, or trunk movements)

No reliably effective treatment exists — prevention is key. Do not use anticholinergics, which can worsen tardive dyskinesia^[6]

Switch to an SGA and consult a psychiatrist; for persistent severe TD, consider a clozapine trial or a psychiatrist-directed trial of clonazepam or tetrabenazine

Fever, severe rigidity, autonomic instability, altered consciousness, or elevated CK at any point: treat as neuroleptic malignant syndrome — stop the antipsychotic immediately, provide supportive care (hydration, cooling), and give dantrolene or bromocriptine

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. All antipsychotics carry a common counselling point: advise patients about antipsychotic-associated body temperature dysregulation and heat-stroke prevention (hydration, sun protection). Select any drug name to open its complete Pharmasist Drug Database page.

First-generation antipsychotics — low potency

Greater sedation, cardiovascular effects, anticholinergic effects, and weight gain than higher-potency FGAs.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Chlorpromazine	Initial: 50-100 mg/day PO Usual: 200-400 mg/day PO Maximum: 1000-2000 mg/day PO, divided 1-4 times daily; limited added benefit above 1000 mg/day	Sedation, orthostatic hypotension, anticholinergic effects, weight gain, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine) can raise levels; CYP450 inducers (e.g., carbamazepine, phenytoin) can lower levels; may inhibit levodopa's effect	Baseline ECG recommended given QTc-prolongation potential.
Methotrimeprazine	Initial (oral): 25-75 mg/day PO Usual (oral): 50-200 mg/day PO, divided 1-3 times daily, max 1000 mg/day Acute agitation (IM): 75-100 mg IM given as 3-4 deep injections into a large muscle; switch to oral as soon as practical — greater EPS risk with IM administration	Sedation, orthostatic hypotension, anticholinergic effects, weight gain, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 inhibitors can raise levels; CYP450 inducers can lower levels

First-generation antipsychotics — intermediate potency

The preferred FGA subgroup when an FGA is used, given a lower EPS burden than high-potency agents.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Loxapine	Initial (oral): 10-20 mg/day PO Usual (oral): 60-100 mg/day PO; some patients maintained on 20-60 mg/day Maximum (oral): 250 mg/day PO, divided 2-3 times daily Acute agitation (IM): 12.5-50 mg IM every 4-6 hours or longer; twice-daily dosing is often sufficient	EPS, sedation, anticholinergic effects, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above
Perphenazine	Initial: 4-12 mg/day PO Usual: 12-24 mg/day PO Maximum: 48-64 mg/day PO, divided 2-3 times daily	EPS, sedation, anticholinergic effects, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above
Zuclopenthixol	Initial (oral): 10-50 mg/day PO, divided 2-3 times daily Usual (oral): 20-60 mg/day PO, max 100 mg/day Decanoate LAI (maintenance): 150-300 mg IM every 2-4 weeks (range 100-400 mg)	EPS, sedation, anticholinergic effects, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above	The decanoate long-acting injection is a maintenance option; do not confuse with the short-acting acetate injection below.
Zuclopenthixol acetate	Dosing: 50-150 mg IM every 2-3 days, to a cumulative maximum of 400 mg or 4 injections	EPS, sedation, anticholinergic effects	Additive CNS depression with other depressants/anticholinergics	Not for use in antipsychotic-naive patients. Intended for up to 2 weeks of use in severe acute agitation.

First-generation antipsychotics — high potency

Greater risk of EPS, neuroleptic malignant syndrome, and hyperprolactinemia than lower-potency FGAs.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Haloperidol	Initial (oral): 1.5-3 mg/day PO Usual (oral): 4-12 mg/day PO Maximum (oral): 20 mg/day PO, divided 1-3 times daily Acute agitation (IM lactate): 2-5 mg IM every 4-8 hours PRN, max 20 mg/day Decanoate LAI (maintenance): 50-300 mg IM every 4 weeks, max 450 mg every 4 weeks — approximately 10-15 times the daily oral dose	EPS, neuroleptic malignant syndrome, hyperprolactinemia, lowered seizure threshold	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above	Lower doses (e.g., 2-5 mg) are as effective as much higher doses with fewer side effects.
Fluphenazine	Initial: 2.5-10 mg/day PO, divided 3-4 times daily Usual: 1-5 mg/day PO Maximum: 20 mg/day PO	EPS, neuroleptic malignant syndrome, hyperprolactinemia, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above
Flupentixol	Initial (oral): 3 mg/day PO Usual (oral): 3-6 mg/day PO, divided 3 times daily, max 12 mg/day Decanoate LAI (maintenance): 20-40 mg IM every 2-3 weeks, range 20-100 mg every 2-3 weeks	EPS, neuroleptic malignant syndrome, hyperprolactinemia, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above
Pimozide	Initial: 2-4 mg/day PO Usual: 2-12 mg/day PO Maximum: 20 mg/day PO (4 mg/day in CYP2D6 poor metabolizers)	EPS, neuroleptic malignant syndrome, hyperprolactinemia, QTc prolongation (dose-related, doses above 8 mg/day)	Avoid with sertraline and other agents that prolong QTc; CYP2D6 poor metabolizers require a lower maximum dose	Once-daily dosing.
Trifluoperazine	Initial: 2-15 mg/day PO, divided 2-3 times daily Usual: 15-20 mg/day PO Maximum: 40 mg/day PO	EPS, neuroleptic malignant syndrome, hyperprolactinemia, lowered seizure threshold, photosensitivity	Additive CNS depression with other depressants/anticholinergics; CYP450 interactions as above

Second-generation antipsychotics

Preferred first-line class given more favourable tolerability overall; clozapine is reserved for treatment-resistant disease. See Special Populations and Monitoring & Follow-up for pregnancy/breastfeeding and metabolic monitoring detail.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Aripiprazole	Initial (adults): 10-15 mg/day PO (2-5 mg/day in first-episode psychosis, titrated up over 2+ weeks) Maximum: 30 mg/day PO LAI, monthly (Abilify Maintena): 400 mg IM monthly after establishing oral tolerability, with 14 days of oral overlap after the first dose; may reduce to 300 mg monthly for tolerability LAI, every 2 months (Abilify Asimtufii): 960 mg IM every 2 months, with 14 days of oral overlap after the first dose; may reduce to 720 mg every 2 months	EPS (particularly akathisia), dizziness, orthostatic hypotension, headache, GI upset, insomnia/activation	Strong CYP2D6/CYP3A4 inducers (carbamazepine, rifampin) can significantly lower levels; strong CYP2D6/CYP3A4 inhibitors (ketoconazole, quinidine, fluoxetine, paroxetine) can significantly raise levels	Best taken in the morning given activating effects. Also classified by some as a third-generation antipsychotic (partial D2/5-HT1A agonist).
Asenapine	Initial: 5 mg SL BID Maximum: 10 mg SL BID	Oral hypoesthesia/paresthesia after dosing (usually resolves within 1 hour), orthostatic hypotension, sedation, insomnia, EPS, constipation; minimal weight/glucose/lipid effect	Strong CYP1A2 inhibitors (e.g., fluvoxamine) increase levels	Sublingual only — do not chew or swallow; avoid food/drink for 10 minutes after dosing; take last if combined with other oral medications.
Brexpiprazole	Day 1-4: 1 mg/day PO Day 5-7: 2 mg/day PO Day 8 onward: 4 mg/day PO if tolerated and clinically indicated	Headache, insomnia or sedation, nausea, constipation, orthostatic hypotension, EPS	Strong CYP2D6/CYP3A4 inhibitors (ketoconazole, quinidine, fluoxetine, paroxetine) can significantly raise levels; strong CYP3A4 inducers can lower levels; reduce the maximum dose to 3 mg/day in moderate-severe hepatic or renal impairment	Partial D2/D3/5-HT1A agonist with 5-HT2A antagonism (third-generation profile).
Cariprazine	Initial: 1.5 mg/day PO Usual: 1.5-6 mg/day PO, increased gradually in 1.5 mg increments Maximum: 6 mg/day PO	EPS, akathisia, insomnia, restlessness, aggression, headache, hypertension	Contraindicated with moderate/strong CYP3A4 inhibitors or inducers, and for at least 2 weeks after stopping a CYP3A4 inhibitor, given extensive CYP3A4 metabolism and a long half-life	Adverse effects and dose adjustments may lag several weeks behind a dose change because of the long half-life. Higher D3-receptor affinity has been proposed to help with cognitive symptoms and anhedonia.
Clozapine	Initial: 12.5-25 mg/day PO Titration: Increase by 25-50 mg/day as tolerated Usual: 300-600 mg/day PO, divided 1-3 times daily Maximum: 900 mg/day PO	Agranulocytosis (mandatory ANC monitoring — see Monitoring & Follow-up), dose-related seizures, sedation, orthostatic hypotension, tachycardia, fever, hypersalivation, weight gain, constipation (can progress to bowel obstruction), increased diabetes/dyslipidemia risk, myocarditis	Additive sedation with CNS depressants; CYP1A2 inhibitors (diltiazem, fluvoxamine, propranolol) or CYP3A4 inhibitors (clarithromycin, erythromycin, grapefruit juice, prednisone) can raise levels; CYP1A2/CYP3A4 inducers (carbamazepine, phenytoin, rifampin, smoking) can lower levels; avoid with bone marrow suppressants and other drugs that lower seizure threshold; respiratory depression risk with higher-dose benzodiazepines	Reserved for treatment-resistant schizophrenia. Titrate slowly; re-titrate from the initial dose if therapy is interrupted for 48 hours or more. Smoking status changes require a dose reassessment (CYP1A2 induction).
Lurasidone	Initial: 40 mg/day PO with food Usual: 40-80 mg/day PO Maximum: 160 mg/day PO — psychiatrist consultation recommended before exceeding 80 mg/day	Nausea and vomiting (often peaking 2-3 hours post-dose), sedation, EPS, orthostatic hypotension, insomnia	Do not use with strong CYP3A4 inhibitors (e.g., ketoconazole) or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin); reduce the maximum dose with moderate CYP3A4 inhibitors	Administer with a substantial meal to maximize absorption. Nausea can be managed by splitting the dose (e.g., BID rather than once daily) or dosing at bedtime.
Olanzapine	Initial (oral): 5-10 mg/day PO Usual (oral): 10-20 mg/day PO Acute agitation (IM): 5-10 mg IM; a second dose of 5-10 mg IM may be given 2 hours after the first, max 20 mg/day (oral and IM combined), no more than 3 injections in 24 hours	Greatest weight gain/metabolic risk among SGAs, sedation, anticholinergic effects, transaminase elevation, orthostatic hypotension, EPS (especially akathisia)	CNS depressant additive sedation; CYP1A2/CYP2D6 inhibitors (diltiazem, fluvoxamine, paroxetine) can raise levels; CYP1A2/CYP3A4 inducers (barbiturates, carbamazepine, phenytoin, rifampin, smoking) can lower levels; do not give parenteral olanzapine with a parenteral benzodiazepine	Also available as a rapid-dissolving tablet.
Paliperidone	Initial (oral): 3-6 mg/day PO Maximum (oral): 12 mg/day PO LAI, monthly (Invega Sustenna): 150 mg IM day 1, 100 mg IM day 8 (deltoid), then 25-150 mg IM monthly (deltoid or gluteal) LAI, every 3 months (Invega Trinza): 175-525 mg IM every 3 months, only after 4+ months stable on the monthly product (dose = 3.5 times the established monthly dose)	Insomnia, headache, weight gain, orthostatic hypotension, rhinitis, anxiety, dose-related hyperprolactinemia, EPS; risk of intraoperative floppy iris syndrome during cataract surgery	Not hepatically metabolized (minimal interaction risk); carbamazepine may decrease paliperidone levels	The active metabolite of risperidone, with less orthostatic hypotension and weight gain but more insomnia than the parent drug.
Quetiapine	Immediate-release, initial: 50-100 mg/day PO Immediate-release, usual: up to 600 mg/day PO, divided 1-3 times daily Extended-release, initial: 300 mg PO QHS (200 mg for first-episode psychosis) Extended-release, usual: 400-800 mg/day PO, once daily in the evening	Sedation, dizziness, weight gain, orthostatic hypotension, transaminase elevation, possible cataract risk, may lower thyroid hormone levels	Additive sedation with CNS depressants; strong CYP3A4 inhibitors (clarithromycin, erythromycin, grapefruit juice, ketoconazole, prednisone) raise levels; strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin) lower levels	Extended-release can be titrated rapidly, unlike most SGAs.
Risperidone	Initial (oral): 1-2 mg/day PO Usual (oral): 4-6 mg/day PO Maximum (oral): 10 mg/day PO (8 mg/dose) LAI, every 2 weeks (Consta): Initial 25 mg IM every 2 weeks with oral overlap for the first 3 weeks; titrate by 12.5 mg every 4-8 weeks to a usual 25-37.5 mg every 2 weeks, max 50 mg every 2 weeks LAI, monthly (Okedi): 75-100 mg IM monthly once oral tolerability is established; equivalent to 3-4 mg/day PO — regimens outside this range may not be eligible for this product	Highest EPS risk among SGAs, sedation, headache, weight gain, orthostatic hypotension, rhinitis, dose-related hyperprolactinemia; risk of intraoperative floppy iris syndrome during cataract surgery	Additive sedation with CNS depressants; CYP3A4/CYP2D6 inhibitors can raise levels; CYP3A4 inducers can lower levels	Give once daily, preferably at bedtime.
Ziprasidone	Adults, initial: 40 mg PO BID with food (20 mg BID if antipsychotic-naive first-episode psychosis) Usual (rapid titration over the first week): up to 120-160 mg/day PO	Orthostatic hypotension, EPS, sedation, insomnia, QTc prolongation (modest but real)	Contraindicated with other QTc-prolonging drugs (certain antibiotics, antiarrhythmics, lithium, methadone, venlafaxine)	Requires rapid titration and administration with a substantial meal to maximize absorption; monitor for an activation syndrome (anxiety, restlessness, insomnia, hypomanic-like symptoms) at lower doses early in treatment.

Antipsychotic-induced movement disorder management

Prevention (favouring an SGA first-line) is the primary strategy — none of these agents reliably treats tardive dyskinesia, and anticholinergics can worsen it.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Propranolol	Akathisia (adjunct): 10-120 mg/day PO in divided doses	Bradycardia, hypotension, bronchospasm, fatigue	Additive bradycardia with other rate-slowing agents; can mask hypoglycemia symptoms in diabetes	Treatment of choice for akathisia once dose reduction of the causative antipsychotic has been tried or is not feasible.
Benztropine	Acute dystonia: 1-2 mg IM, may repeat Ongoing parkinsonism/EPS: 1-2 mg PO 1-2 times daily, up to 6 mg/day	Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention), confusion (especially in older adults)	Additive anticholinergic burden with other anticholinergic drugs	Not effective for, and can worsen, tardive dyskinesia. Do not use prophylactically.
Procyclidine	Parkinsonism/EPS: Initial 2.5 mg PO TID, usual 7.5-20 mg/day, max 30 mg/day	Anticholinergic effects, dizziness, mild sedation or, less commonly, stimulation	Additive anticholinergic burden with other anticholinergic drugs	Not effective for, and can worsen, tardive dyskinesia. Do not use prophylactically.
Trihexyphenidyl	Parkinsonism/EPS: Per current product-specific dosing guidance, titrated to effect	Anticholinergic effects, confusion (especially in older adults)	Additive anticholinergic burden with other anticholinergic drugs	Not effective for, and can worsen, tardive dyskinesia. Do not use prophylactically.
Diphenhydramine	Acute dystonia: 25-50 mg IM, may repeat	Sedation, anticholinergic effects	Additive CNS/anticholinergic depression with other such agents	Immediate-acting alternative to benztropine for acute dystonic reactions.
Dantrolene	NMS: 2-3 mg/kg IV TID-QID, maximum 10 mg/kg/day	Muscle weakness, hepatotoxicity, drowsiness	Additive CNS depression with other depressants; avoid with calcium channel blockers (risk of cardiovascular collapse)	For neuroleptic malignant syndrome, given with supportive care (hydration, cooling) after immediate antipsychotic discontinuation.
Bromocriptine	NMS: 2.5-5 mg PO TID, increasing by 2.5 mg TID every 24 hours to a maximum of 60 mg/day	Nausea, hypotension, hallucinations/confusion	Additive hypotension with other antihypertensives; avoid with other ergot derivatives	Alternative or adjunct to dantrolene for neuroleptic malignant syndrome.
Clonazepam	TD adjunct (specialist-directed): 0.5 mg PO BID, titrated as tolerated, generally to a maximum of 2-4 mg/day	Sedation, dependence with regular use, ataxia	Additive CNS/respiratory depression with opioids, alcohol, other sedatives	Limited evidence as an adjunct for tardive dyskinesia; not a first-line TD treatment.
Tetrabenazine	TD (specialist-directed): Per current product-specific dosing guidance, titrated to effect	Sedation, depression (including suicidal ideation), parkinsonism, akathisia	Avoid with MAOIs; additive sedation with CNS depressants; caution with other QTc-prolonging drugs	Limited evidence for persistent tardive dyskinesia; reserve for psychiatrist-directed use after an SGA switch has failed to control symptoms.

Acute agitation adjuncts

Given alongside, not instead of, an antipsychotic for acute psychotic agitation.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Lorazepam	Acute agitation: 1-2 mg IM or slow IV, may repeat in 30-60 minutes	Sedation, respiratory depression (especially combined with opioids), paradoxical agitation (uncommon)	Additive CNS/respiratory depression with opioids, alcohol, other sedatives; never combine parenteral lorazepam with parenteral olanzapine
Promethazine	Acute agitation, combined with haloperidol: 25-50 mg IM	Sedation, anticholinergic effects; severe tissue injury if given subcutaneously or intra-arterially	Additive CNS/respiratory depression with opioids, alcohol, other sedatives	IM injection into a large muscle only — never subcutaneous or intra-arterial. Contraindicated under age 2.

Metabolic monitoring adjunct and smoking cessation

Address the substantial metabolic and cardiovascular burden of antipsychotic therapy directly — see the Tobacco Use Disorder chapter for full smoking-cessation dosing detail.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Metformin	Dosing: Per current Diabetes Canada-aligned titration guidance	GI upset, rare lactic acidosis (renal impairment)	None specific to antipsychotic co-therapy	Consider as an adjunct for antipsychotic-associated weight gain when dietary/exercise counselling and an antipsychotic switch have not been sufficient or appropriate.
Varenicline	Dosing: Per standard smoking-cessation titration guidance	Nausea, insomnia, vivid dreams	None specific to antipsychotic co-therapy	Effective for smoking cessation in this population; monitor for mood/behavioural changes, particularly with a history of suicidal ideation, depression, or hostility.
Bupropion	Dosing: Per standard smoking-cessation titration guidance	Insomnia, dry mouth, lowered seizure threshold	Avoid combining with other drugs that lower seizure threshold; caution with CYP2D6 interactions	Effective for smoking cessation; use with particular caution given the additive seizure-threshold effect with clozapine.
Nicotine replacement therapy	Dosing: Per standard smoking-cessation product dosing	Local irritation (patch), mouth/throat irritation (gum/lozenge)	None specific to antipsychotic co-therapy	Does not require the clozapine/olanzapine CYP1A2 dose adjustment that stopping smoking itself does.

Mood-related adjuncts (schizoaffective disorder or specialist-directed augmentation)

Used for the mood component of schizoaffective disorder, or as specialist-directed augmentation in specific circumstances — not routine antipsychotic-alone therapy.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Valproic acid	Dosing: Per current mood-stabilizer dosing guidance, titrated to a therapeutic level	GI upset, tremor, weight gain, hepatotoxicity, thrombocytopenia	Additive sedation with CNS depressants; multiple CYP450 interactions	Avoid in patients of childbearing potential given teratogenicity risk unless no suitable alternative exists and effective contraception is confirmed.
Lithium carbonate	Dosing: Per current mood-stabilizer dosing guidance, titrated to a therapeutic level	Tremor, GI upset, hypothyroidism, nephrogenic diabetes insipidus, narrow therapeutic index	NSAIDs, ACE inhibitors/ARBs, and thiazide diuretics can raise lithium levels	Associated with congenital malformation risk in pregnancy — weigh carefully against relapse risk if used in a patient of childbearing potential.
Carbamazepine	Dosing: Per current mood-stabilizer dosing guidance, titrated to a therapeutic level	Sedation, ataxia, hyponatremia, rare severe cutaneous reactions	Potent CYP3A4 inducer — can substantially lower antipsychotic levels; multiple other CYP450 interactions	Associated with congenital malformation risk in pregnancy; its enzyme-inducing effect can undermine antipsychotic efficacy if added without a dose reassessment.

Evidence note: Drug inventory, dosing, adverse effects, and comments reflect standard Canadian practice, cross-checked against the current Canadian schizophrenia pharmacotherapy guideline and the 2021 American Psychiatric Association practice guideline.^[3]^[7]

References

Canadian Guidelines for the Assessment and Diagnosis of Patients With Schizophrenia Spectrum and Other Psychotic Disorders — Canadian Journal of Psychiatry, Canadian Psychiatric Association (Addington D, Abidi S, Garcia-Ortega I, Honer WG, Ismail Z). Can J Psychiatry 2017;62(9):594-603
Canadian Treatment Guidelines for Individuals at Clinical High Risk of Psychosis — Canadian Journal of Psychiatry, Canadian Psychiatric Association (Addington J, Addington D, Abidi S, Raedler T, Remington G). Can J Psychiatry 2017;62(9):656-661
Guidelines for the Pharmacotherapy of Schizophrenia in Adults — Canadian Journal of Psychiatry, Canadian Psychiatric Association (Remington G, Addington D, Honer W, Ismail Z, Raedler T, Teehan M). Can J Psychiatry 2017;62(9):604-616
Clozapine Support and Assistance Network (CSAN) Hematological Quick Reference Chart — HLS Therapeutics Inc.. February 2022
Absolute Neutrophil Count and Adverse Drug Reaction Monitoring During Clozapine Treatment: Consensus Guidelines From a Global Delphi Panel — The Lancet Psychiatry (Siskind D, Northwood K, Pillinger T, Chan S, Correll CU, Cotes RO, Every-Palmer S, Hahn M, Howes OD, Kane JM, Kelly D, Korman N, Lappin J, Mena C, Myles N, McCutcheon RA, et al.). Lancet Psychiatry 2025
Treatment Recommendations for Tardive Dyskinesia — Canadian Journal of Psychiatry (Ricciardi L, Pringsheim T, Barnes TRE, Martino D, Gardner D, Remington G, Addington D, Morgante F, Poole N, Carson A, Edwards M). Can J Psychiatry 2019;64(6):388-399
The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association Publishing, 3rd edition. Washington, DC: American Psychiatric Association Publishing; 2021

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.