Schizophrenia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Key Recommendations

Management should be viewed as lifelong and involves establishing a stable maintenance antipsychotic regimen and psychosocial interventions supported by a comprehensive follow-up plan. Treatment nonadherence is an important challenge in this population, as patients frequently have diminished insight into their condition.[1][91] Early detection and treatment is important, as it can reduce the duration of psychosis and may predict more favorable outcomes.[53][54][55][56][57][58][59] Schizophrenia is associated with an increased frequency of physical illnesses. It is also associated with a reduced life span of around 14.5 years compared with the general population, with an average reduction of 15.9 years for men and 13.6 years for women.[92] The net effect of treatment with antipsychotics seems to be a reduction in long-term mortality.[93] However, managing the adverse effects of medications used to treat schizophrenia is crucial, as many of these further increase the risk of physical illness.

Management of an acute psychotic episode

An acute psychotic episode may occur in one of three settings:

The first psychotic episode
Psychotic decompensation, caused by treatment nonadherence or stressors
Inadequate response to current antipsychotic medication despite adequate dosing.

The patient often requires hospitalization; specific indications include:[65]

The patient posing a serious threat of harm to self or others or being unable to care for themself, and needing constant supervision or support as a result
Psychiatric or other medical issues that make outpatient treatment unsafe or ineffective
New onset of psychosis that warrants initial inpatient stabilization to reduce acute symptoms and permit engagement in treatment.

In cases of extreme agitation and violence, short-acting intramuscular antipsychotic medication can be given, often in combination with an injectable benzodiazepine such as lorazepam. [ ] Note, however, that concomitant use of intramuscular olanzapine with a parenteral benzodiazepine is not recommended.[65][94]

If the acute episode is the first presentation, the patient needs to be established on antipsychotic medication (see Pharmacologic therapy sections, below). As these patients are usually naive to antipsychotic medications and more prone to developing extrapyramidal symptoms, they should be started on low doses.[95]

If the acute episode was due to psychotic decompensation from the patient’s current antipsychotic medication, the medication dosage may need to be increased or a new antipsychotic medication started. If the patient has previously had a good response to a specific agent, the same medication can be reconsidered.

There is some evidence that electroconvulsive therapy (see below) combined with antipsychotic drugs may improve overall mental state and increase likelihood of discharge from the hospital, although these benefits are not sustained over the medium to long term.[96]

Pharmacologic therapy: overarching principles

Patients with schizophrenia should be treated with an antipsychotic medication and monitored for effectiveness and adverse effects. If symptoms improve with an antipsychotic medication, patients should continue to be treated with this medication.

Early intervention can decrease risk of relapse or rehospitalization. Delayed treatment predicts worse outcome.[94][97][98]

The minimum antipsychotic dose that controls symptoms should be utilized, with adequate follow-up for possible medication adjustments and adverse effect monitoring.[65][99] Medication should be continued indefinitely but titrated or discontinued if adverse effects are intolerable.[65] Intermittent, or discontinuation of, antipsychotic treatment may increase the risk for symptom exacerbation and relapse and is not recommended.[94][100] Benefits and adverse effects of treatment should be assessed on an ongoing basis to determine the need for adjustments to medication doses or changes in medications.[65] There is no correlation between the dose and therapeutic effect, but the risk of extrapyramidal signs (e.g., akathisia, parkinsonism, and dystonia) increases with increases in dose.

Antipsychotics are available in oral, inhalation, transdermal, and short- or long-acting intramuscular formulations, depending on location. Long-acting intramuscular formulations of antipyschotics may be offered as an initial treatment in some patients. However, it is important to note that patients must be started on the oral formulation of the drug initially to establish tolerability before the long-acting formulation is started. Long-acting intramuscular formulations are often under-utilized in the treatment of schizophrenia, but the general consensus is that they may be considered as a suitable initial treatment.

It may take between 2 and 4 weeks for antipsychotic medication to elicit an initial response, and longer periods of time for a full or optimal response.[65]

The minimum length of an adequately-dosed antipsychotic treatment trial is 2 weeks before a nonresponse can be determined.[101] Limited evidence suggests that patients showing not even a minimal improvement after 2 weeks of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change.[101][102]

Until antipsychotic medications take effect, benzodiazepines may help relieve emotional distress, insomnia, and other behavioral disturbances secondary to psychosis.[94]

Long-term treatment with antipsychotic medications is associated with a greater incidence of weight gain, diabetes and hyperlipidemia, sedation, and movement disorders. It may be possible to mitigate these risks by preventive interventions (e.g., early intervention for weight gain, screening for lipid and glucose abnormalities) and careful monitoring for adverse effects of medication. As treatment proceeds, the benefits and risks of continuing treatment with an antipsychotic medication should be reviewed with the patient in the context of shared decision-making. It will typically be beneficial to include family members or other persons of support in such discussions.[65]

Pharmacologic therapy: first episode of psychosis

First-generation (typical) antipsychotics or second-generation (atypical) antipsychotics are the treatment of choice (olanzapine is not recommended first-line).[65]

The choice of a specific antipsychotic agent will typically occur in the context of discussion with the patient and should incorporate:[65]

Patient preferences
The patient’s past responses to treatment (including therapeutic response and tolerability)
The medication’s likely benefits and adverse-effect profile
The presence of physical health conditions that may be affected by medication adverse effects
Other medication-related factors such as available formulations, potential for drug-drug interactions, receptor-binding profiles, and pharmacokinetic considerations.

Although there may be clinically meaningful distinctions in the response to, and tolerability of, different antipsychotic medications in an individual patient, there is no definitive evidence that one antipsychotic will have consistently superior efficacy compared with another; clinical trial designs are significantly heterogeneous, there are limited head-to-head comparisons of antipsychotic drugs, and limited clinical trial data for several antipsychotic medications.[65]

Lower antipsychotic doses are typically required to treat a first episode than to treat chronically ill or relapsed patients.[94]

Pharmacologic therapy: acute exacerbation

Information on previous antipsychotic treatment, including dose, duration of treatment, and response to each particular agent, should be gathered. Medication is selected after considering the clinical presentation, prior medication response and adherence, immediate- and longer-term adverse effects of the medications, and patient preference.[100][103][104]

If acute exacerbation is the result of nonadherence and the medication that has been previously used was effective, the medication should be restarted and may be adjusted as needed.

In people with multi-episode schizophrenia who are experiencing an acute exacerbation, a new antipsychotic agent must be considered.

Pharmacologic therapy: aggression or agitation secondary to acute psychosis

Adjunctive therapies that can be used for psychosis-associated aggression and agitation include:

Inhaled loxapine, a dibenzoxazepine antipsychotic; this option has a rapid onset of action, is well tolerated, is easy to administer, and may be better accepted (by patients and caregivers) compared with oral or intramuscular antipsychotics[105]
A short-acting intramuscular antipsychotic (e.g., olanzapine, ziprasidone)[106][107]
Intramuscular lorazepam[106]
Intramuscular lorazepam and haloperidol in combination.[94]

Concomitant use of intramuscular olanzapine with a parenteral benzodiazepine is not recommended due to the potential for excessive sedation and cardiorespiratory depression.[65][94]

For patients who continue to be at significant risk for aggressive behavior despite other treatments, clozapine appears to confer some benefit in ameliorating aggression.[108] Use of clozapine may also lead to an indirect reduction in aggressive behavior through management of contributory risk factors for aggression, including hallucinations and delusions.[65][109]

Treatment response and resistance

Partial response

Patients may take between 2 and 4 weeks to show an initial response and longer periods of time to show full or optimal response.[65] Dose titration of the initial antipsychotic may be required. The possibility of nonadherence with medication should be considered in patients who have only partial response to initial treatment.

For patients who have some symptomatic improvement with their initial antipsychotic treatment, a combination approach may be appropriate, for example:[110][111]

A second antipsychotic medication may be added to the initial antipsychotic medication, or
The initial antipsychotic might be combined with an antidepressant, a mood stabilizer, or electroconvulsive therapy.

Evidence supporting the superiority of combination antipsychotic treatment over monotherapy is mixed. [ ]

If symptoms are resistant to these approaches, clozapine may be required. A trial of clozapine for treatment-resistant schizophrenia should not be delayed by multiple attempts at augmentation therapy.[65]

Treatment resistance

Approximately 20% to 30% of patients with schizophrenia have symptoms that are considered resistant to treatment.[94] Treatment-resistant schizophrenia (TRS) is defined by the American Psychiatric Association as symptoms that have shown no response, or partial and suboptimal response, to two antipsychotic medication trials of at least 6 weeks each at an adequate dose of medication.[65]

Clozapine is recommended for TRS.[65] Clozapine is also recommended if the risk of suicide attempts or suicide remains substantial despite other treatments.[65] Clozapine can be considered if the risk for aggressive behavior remains substantial despite other treatments.[65][108]

One systematic review found that the risk of hospitalization was 18% lower for people taking clozapine compared with those taking other oral second-generation antipsychotics, despite more severely ill patients being treated with clozapine.[112]

Clozapine resistance

Up to 60% of patients treated with clozapine do not respond adequately.[113] The Treatment Response and Resistance in Psychosis (TRRIP) Working Group defines clozapine-resistant schizophrenia (CRS) as persistence of either positive, negative, or cognitive symptoms of schizophrenia of at least moderate severity after an adequate trial of clozapine. Clozapine should be offered for a duration of at least 3 months, raising clozapine plasma level to ≥350 nanograms/mL.[114]

For patients with CRS, the TRRIP Working Group recommends:[115]

For refractory positive symptoms, consideration should be given to either augmenting clozapine with a second antipsychotic (e.g., aripiprazole) or with electroconvulsive therapy (ECT).
- ECT is particularly useful in patients who also have catatonia or significant suicide risk or who require a rapid response because of the severity of their psychiatric or medical condition.[65][116] This recommendation is supported by specific evidence for benefits of ECT in combination with clozapine as compared with clozapine alone. Reports of headache and memory impairment were more frequent with the combination of clozapine and ECT than with clozapine alone. However, symptomatic improvement and rates of remission at the end of treatment were significantly greater in patients who received combination treatment.[65][116][117][118][119][120][121][122] For patients who show a response to ECT, treatment with ECT on a maintenance basis could be considered as an adjunct to clozapine.[65]
For refractory negative symptoms or suicidality, augmentation with an antidepressant should be considered; for refractory suicidality, augmentation with a mood-stabilizer should be considered.

In patients with an extensive history of poor or uncertain treatment adherence, and particularly those with co-occurring substance use, long-acting injectable antipsychotic agents may be especially useful.[65][123][124] These agents may reduce the risk of relapse and the risk of rehospitalization compared with oral antipsychotics.[125][126] The procedure for transitioning from an oral to an injectable long-acting formulation varies according to the specific medication.

Second-generation (atypical) antipsychotics

Second-generation antipsychotics include:

Clozapine[127]
Olanzapine
Aripiprazole[128][129][130]
Paliperidone[131][132]
Quetiapine[133][134]
Risperidone[135]
Ziprasidone[136]
Asenapine[137]
Lurasidone[138][139]
Iloperidone
Brexpiprazole[140][141]
Cariprazine[142]
Lumateperone.[143][144]

Paliperidone is an active metabolite of risperidone.[145][146][147][148] Risperidone, paliperidone, olanzapine, and aripiprazole are available as long-acting injectable formulations as well as oral formulations.[148][149][150][151][152][153][154]

Although doses higher than the approved maximum dose of these agents may be used in practice, the evidence is insufficient to support the use of these higher doses.[100][155]

As a group, second-generation antipsychotics appear to be better at improving patient-reported quality of life and preventing relapse compared with first-generation antipsychotics. However, this advantage has to be weighed against the potential metabolic adverse effects of some second-generation antipsychotics.[156][157]
Second-generation antipsychotics can cause weight gain, which is associated with an increased risk for metabolic syndrome and cardiovascular disease. Clozapine and olanzapine have the highest risk for weight gain. Asenapine, iloperidone, paliperidone, quetiapine, risperidone, and paliperidone carry a medium-level risk of weight gain. Aripiprazole, lurasidone, and ziprasidone have the lowest risk of weight gain.[158][159][160][161][162][163][164] Medications known to cause weight gain should be avoided in patients with a high risk for cardiovascular disease.
One systematic review and meta-analysis found that second-generation antipsychotics may cause short-term somatic serious adverse events (e.g., respiratory tract and lung infections, rhabdomyolysis, movement disorders, syncope); this effect appears to be mainly driven by results in older patients.[165] Another systematic review and meta-analysis found no evidence that second-generation antipsychotics increased short-term mortality in patients with schizophrenia. However, vulnerable populations (e.g., patients with dementia) might be at increased risk of death following treatment initiation.[166]
Second-generation antipsychotics differ in their likelihood of causing activating adverse effects (akathisia), versus sedating adverse effects, versus both, which may be a factor in selecting the optimal antipsychotic for any one patient. According to one study, lurasidone and cariprazine are predominantly activating; olanzapine, quetiapine, ziprasidone, asenapine, and iloperidone are predominantly sedating; and risperidone and aripiprazole have similar levels of activating and sedating effects.[167]
Olanzapine might be somewhat superior to other second-generation antipsychotics (except clozapine); however, this small increase in superiority needs to be carefully weighed against its higher risk for significant weight gain and metabolic syndrome when compared with all other antipsychotics except clozapine.[168][169] Olanzapine/samidorphan (olanzapine coformulated with the opioid antagonist samidorphan) results in less weight gain than using olanzapine alone.[170] The risk of orthostatic hypotension should be assessed for patients who require repeated doses of intramuscular olanzapine.
One meta-analysis found that cariprazine appears to be superior over other second-generation antipsychotics in the treatment of negative symptoms of schizophrenia.[171]
Risperidone has a higher risk of extrapyramidal symptoms compared with other second-generation antipsychotics, especially at doses >6 mg/day, but has a lower risk than first-generation antipsychotics.[172][173][174]
Clozapine can decrease the number of neutrophils and at times can lead to severe neutropenia. Enrollment into the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program and monitoring blood levels of absolute neutrophil count (ANC) are required in patients taking clozapine. The baseline ANC must be at least 1500/microliter for the general population, and at least 1000/microliter for patients with documented benign ethnic neutropenia (BEN, most commonly seen in individuals of African descent). The monitoring schedule is weekly for the first 6 months, every 2 weeks for the following 6 months, and monthly indefinitely thereafter if ANC remains at least 1500/microliter (at least 1000/microliter for BEN). If ANC <1500/microliter (<1000/microliter for BEN), the monitoring frequency and the clinical decision regarding the use of clozapine will be adjusted accordingly based on the actual ANC level following the established guideline.[65]
Lumateperone is a potent serotonin 5-HT2A receptor antagonist and dopamine modulator.[175] It was well-tolerated in two randomized, double-blind, placebo-controlled trials with a low risk of cardiometabolic and extrapyramidal adverse effects during short-term follow-up.[143][144][176]

First-generation (typical) antipsychotics

First-generation antipsychotics include:

Chlorpromazine
Perphenazine [ ]
Haloperidol [ ]
Fluphenazine [ ]

Several other agents are available but less commonly used.

Fluphenazine and haloperidol are available in long-acting injectable formulations.

The efficacy of first-generation antipsychotics is well established. However, they are generally not recommended as initial treatments for schizophrenia due to a high likelihood of extrapyramidal symptoms including tardive dyskinesia, and lack of effect on negative symptoms.

Pregnancy and postpartum period

If a woman becomes pregnant while taking an antipsychotic medication, consideration should be given to consulting an obstetrician-gynecologist or maternal/fetal medicine subspecialist.[65]

For most pregnant women with schizophrenia, the benefits of continued treatment with antipsychotic medications in minimizing relapse will generally outweigh the potential for fetal risk.[65][177][178] For many women, the eighth week of gestation will already have passed before obstetric care begins, and stopping medication will not avoid or reduce teratogenic risk (3-8 weeks gestation is associated with greatest risk for teratogenesis). The American College of Obstetricians and Gynecologists recommends against withholding or stopping medications for mental health based on pregnancy or lactation status alone.[178]

Available data for first- and second-generation antipsychotics suggest that these medications have minimal risk of teratogenic or toxic effects on the fetus.[65][179][180]

There does appear to be a risk of withdrawal symptoms or neurologic effects of antipsychotic medications in a newborn if an antipsychotic medication is used in the third trimester. Nevertheless, tapering of antipsychotic medication late in pregnancy is not advisable because of the associated risk of relapse.[65] In some newborns, the symptoms subside within hours or days and do not require specific treatment; others may require longer hospital stays.[65][181]

Some psychotropic medications that are commonly used in patients with schizophrenia are best avoided during pregnancy because of their teratogenic effects. For example, both valproic acid (and its derivatives) and carbamazepine carry an increased risk of fetus malformations, including neural tube defects, especially during the first trimester.[65][177][179] Valproate should not be used to treat women who are pregnant or who plan to become pregnant, or in women of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.[182][183] In such situations, effective contraception should be used.[183]

Adjunctive treatments for negative symptoms

There is no approved treatment for negative symptoms of schizophrenia.

Cariprazine appears to be superior over other second-generation antipsychotics in the treatment of negative symptoms.[169]

Adding an antidepressant (e.g., citalopram, fluvoxamine, mirtazapine) might be more effective in treating the negative symptoms of schizophrenia than antipsychotics alone.[184] Data demonstrate reduced risk of psychiatric hospitalization and emergency department visits.[110][184] Some selective serotonin-reuptake inhibitors may increase serum antipsychotic levels; therefore, antipsychotic dosages may need to be reduced in these patients.[185][186]

Limited evidence exists for other adjunctive agents: for example, glutamatergic compounds (e.g., glycine, D-serine), minocycline, dopamine agonists (e.g., selegiline, modafinil), acetylcholinesterase inhibitors (e.g., galantamine, donepezil), memantine, and ondansetron.[187][188][189][190][191][192][193][194][195][196]

Adjunctive treatments for affective symptoms

Several adjunctive medications are available to treat the affective symptoms associated with schizophrenia:

Depression: antidepressants may be used. One meta-analysis suggests that the addition of antidepressant medications results in small beneficial effects on symptoms of depression, positive and negative symptoms of schizophrenia, and quality of life.[184] These effects were more prominent in patients with more severe depressive symptoms.[65] Antidepressant treatment did not appear to be associated with exacerbation of psychosis or increase in adverse effects.[184] Caution is advised if antidepressants are prescribed, including avoiding prompt discontinuation if there is a lack of a positive response.[100] Nonpharmacologic treatments for depression in schizophrenia have been less well studied but could also be incorporated into treatment planning.[197][198]
Mood swings and overt impulsivity: mood stabilizers are used to control mood swings and overt impulsivity that is unresponsive to antipsychotic medication for patients with associated bipolar disorder. Up to 20% of patients with schizophrenia take mood stabilizers, although the supporting data are controversial.[199] There is evidence against the use of carbamazepine in schizophrenia.[94] However, it may be used for patients who have a history of a prior response for other symptoms such as aggression.
Anxiety: anxiolytics may be considered for patients with anxiety symptoms.[65]

Electroconvulsive therapy (ECT)

There is mixed evidence to suggest that ECT, combined with antipsychotic medications, may provide benefits in improving mental status of patients with schizophrenia and the likelihood of discharge from the hospital. These benefits are not usually sustained over the medium- to long-term.[121][122][200][201][202] ECT may result in memory deterioration.[201][203] [ ] [Evidence C]

ECT can be considered for clozapine-resistant schizophrenia, particularly in patients who also have catatonia or significant suicide risk or who require a rapid response because of the severity of their psychiatric or medical condition.[65][116][204] This recommendation is supported by specific evidence for benefits of ECT in combination with clozapine as compared with clozapine alone. Reports of headache and memory impairment were more frequent with the combination of clozapine and ECT than with clozapine alone. However, symptomatic improvement and rates of remission at the end of treatment were significantly greater in patients who received combination treatment.[65][116][117][118][119][120][121][122][204] For patients who show a response to ECT, treatment with ECT on a maintenance basis could be considered as an adjunct to clozapine.[65]

Psychosocial interventions

Psychosocial interventions are key components of long-term management. Addressing issues such as tenuous housing, low income, inadequate work skills, poor social support, and restricted access to health care can aid medication adherence. Studies have shown that intensive case management and community-based psychosocial interventions may decrease symptom severity; reduce the risk of relapse, hospitalization, and hospital readmissions; and improve adherence to care, communication skills, social relationships, quality of life, and daily functioning.[205][206][207]

Suicide prevention is a key aspect of management and should include monitoring for depressive symptoms and risk factors of suicide.[70][71]

Recommended psychosocial interventions for schizophrenia include:[65]

Coordinated specialty care (CSC) for first-episode psychosis: a comprehensive treatment package, incorporating family involvement and education, individual resiliency training, supported employment and education, and individualized medication treatment.[65]
Assertive community treatment (ACT): recommended if there is a history of poor engagement with services leading to frequent relapse or social disruption (e.g., homelessness; legal difficulties, including imprisonment).[65]
Cognitive behavioral therapy (CBT): recommended for all patients with schizophrenia.[65] One systematic review reported CBT reduced the risk of relapse compared with treatment as usual (without CBT) at 1-year follow-up.[206] Studies have suggested that CBT is more efficacious in decreasing positive symptoms, and social skill training is efficacious in decreasing negative symptoms.[208][209]
Cognitive remediation: used either alone or combined with CBT and/or group sessions, can improve cognitive function and social adjustment, and help with supported employment and competitive work.[65][210][211] Evidence suggests that cognitive remediation can have a small to moderate effect in reducing negative symptoms and can decrease global aggressive attitudes and physical assaults in people with schizophrenia.[212][213]
Psychoeducation: an important tool that may contribute to adherence.[214] Peer-led advocacy groups (such as the National Alliance on Mental Illness [NAMI) in the US) may be particularly helpful in providing practical and emotional support for patients and their families. Such peer support services can provide information about the condition, caregivers, community resources (including other support groups, opportunities for volunteering, job training, and employment), and economic and legal matters. National Alliance on Mental Illness Opens in new window
Family interventions: family treatment or family psychoeducation is useful to help families deal with the stress and social stigma associated with the illness and to deal with affect-laden communication within the family (involving critical, angry, and emotionally charged interactions).[215][216] A stressful home environment can negatively impact the wellbeing and recovery of patients.[65] Family interventions might decrease the levels of expressed emotion within the family, improve general social impairment, reduce the risk of relapse, and improve adherence with medication.[215][217] [ ]
Supported employment: can help maintain employment, increase productivity, and reduce hospitalization.[65][218][219] Access to employment plays an important role in the recovery and function of people with schizophrenia.[65] Evidence from one large meta-analysis suggests that participating in a psychosocial treatment to enhance employment outcomes increases the chance of patients receiving an offer of employment, and has a positive impact on number of hours worked.[220] Vocational rehabilitation may help improve function in the workplace, although long-term stable employment is seldom achieved.[221]
Social skills training: should be considered for patients with a therapeutic goal of enhanced social functioning.[65] There is limited evidence suggesting that social skills training may improve patient skills with social interaction and communication.[222] Interventions aimed at developing self-management skills and enhancing person-oriented recovery should be considered.[65]
Supportive psychotherapy: should be considered if the patient is not suitable for or interested in other evidence-based psychosocial treatments.[65] Although there is limited evidence to support supportive psychotherapy, these techniques are commonly used as part of usual care.

Physical health maintenance

Physical health and comorbid medical conditions should be monitored in patients with schizophrenia.[65]

A 2017 meta-analysis and systematic review found that worldwide, on average, people with schizophrenia die 14.5 years earlier than the general population. The number of years of potential life lost was greater for men than for women (15.9 years vs. 13.6 years).[92] A 2018 meta-analysis found that women with schizophrenia have a 31% increased risk of breast cancer.[223]

The net effect of treatment with antipsychotics appears to be a reduction in long-term mortality.[93] However, monitoring and managing the adverse effects of these medications is crucial:

Patients should be monitored for the development of extrapyramidal symptoms (dystonia, akathisia, parkinsonism, and tardive dyskinesia), which are particularly common in those taking first-generation antipsychotics. Assessment with a structured instrument (e.g., the Abnormal Involuntary Movement Scale [AIMS]), is recommended at a minimum of every 6 months in patients with a high risk of tardive dyskinesia and at least every 12 months in other patients.[65][224]
Antipsychotic medication with higher dopamine blockade (e.g., haloperidol, fluphenazine, risperidone) can cause elevated prolactin, leading to galactorrhea, gynecomastia, changes in libido, irregular menstrual cycle or amenorrhea in women, and erectile or ejaculatory dysfunction in men.[65][225] Clinicians should remain alert for these effects and screen for possible symptoms at each clinic visit; prolactin levels should be checked if clinically indicated. Decreasing the dose of antipsychotic medication or switching to an alternative may be necessary. Limited evidence suggests that adding aripiprazole may have a prolactin-lowering effect.[226]
QT prolongation, T-wave flattening, and torsades de pointes have been reported to occur with antipsychotic use. A baseline ECG may be required, particularly if there are cardiac risk factors such as a personal or family history of cardiac disease (conduction abnormalities and/or structural cardiac abnormalities).[227]
Clozapine can decrease the number of neutrophils and may lead to severe neutropenia. In the US, all patients taking clozapine must be enrolled into the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program and be monitored for changes to absolute neutrophil count (ANC) levels. The baseline ANC must be at least 1500/microliter for the general population, and at least 1000/microliter for patients with documented benign ethnic neutropenia (BEN, most commonly seen in individuals of African descent). The monitoring schedule is every week for the first 6 months, every 2 weeks for the following 6 months, and monthly indefinitely thereafter if ANC remains to be at least 1500/microliter (at least 1000/microliter for BEN). If ANC <1500/microliter (<1000/microliter for BEN), the monitoring frequency and the clinical decision regarding the use of clozapine should be adjusted accordingly based on the actual ANC level.[65]
Postural hypotension associated with antipsychotic treatment is dose-related and is usually transitory in the first hours or days of treatment. Older people are particularly vulnerable to postural hypotension, as are patients in the dose-titration phase of clozapine therapy and those with peripheral vascular disease, diabetes with preexisting autonomic neuropathy, or compromised cardiovascular function. When severe, orthostatic hypotension can cause syncope, dizziness, or falls.[65][228] Supportive measures include use of support stockings and increased dietary salt and fluid intake. Slower dose titration, decreasing or dividing doses of antipsychotic medication, or switching to an alternative antipsychotic may be required.[65] Patients should be counseled to assume upright positions slowly as a precautionary measure.
Anticholinergic adverse effects of antipsychotic treatment can be divided into peripheral (e.g., dry mouth, constipation, blurred vision, urinary retention) and central (e.g., delirium, impaired learning and cognition). Patients usually develop tolerance to dry mouth; rinsing with water or chewing sugarless gum may help. For blurred vision, a temporary reduction of the medication dosage may be indicated. If acute urinary retention or delirium occurs, antipsychotic medication needs to be discontinued. If constipation develops, initial treatment can include stool softeners or osmotic laxatives.[65] Anticholinergic adverse effects are often dose-related and may improve with lowering of the dose or administering the medications in divided doses.[65]

Patients with schizophrenia are at increased risk of obesity, diabetes, hyperlipidemia and hypertension, cardiovascular disease, and premature death. Diabetes, hypertension, and metabolic syndrome are significantly associated with global cognitive impairment in people with schizophrenia, suggesting that metabolic syndrome may contribute to the functional decline experienced by some patients with schizophrenia over time.[229][230] Body mass index (BMI), a measure for obesity, should be assessed at baseline and every 4 weeks for the first 12 weeks after diagnosis, and then every 3 months thereafter.[65] An increase in BMI should prompt consideration of intervention by monitoring weight more closely, engaging the patient in a weight management program, using an adjunctive treatment to reduce weight, or changing the antipsychotic medication.[65] Waist circumference, a measure for abdominal obesity, should be assessed annually.[65][231] Fasting blood glucose and lipids should be obtained at baseline and at 12 weeks, then annually thereafter for all patients.[65][231] Strategies to prevent or mitigate antipsychotic treatment-associated metabolic disturbances include decreasing the dose of antipsychotic medication or switching to a more metabolic-neutral medication option. Some studies have suggested that adjunctive treatment with aripiprazole or metformin may counteract metabolic adverse effects.[232][233] Psychosocial interventions should also be considered. A behavioral weight-loss intervention is efficacious in overweight and obese adults with serious mental illness.[234] Health promotion coaching aimed at weight loss and improving cardiovascular fitness is an effective long-term management strategy for patients with schizophrenia.[235] Despite these strategies, patients may still need to be treated with antidiabetic or lipid-lowering medications as required. Effective screening for, and treatment of, hypertension is key. Results of one meta-analysis suggest that people with schizophrenia typically receive poorer care for hypertension (lower rates of screening and prescription, and higher rates of unaddressed medication adherence) than people without schizophrenia.[236]

There appears to be an increased risk of blood-borne viruses in patients with serious mental illness, including schizophrenia.[79][80] One Swedish population-based study found that, after accounting for sociodemographic factors, the odds of HIV were 2.57 times higher in people with serious mental illness than in the general population; the odds of hepatitis B virus were 2.29 times higher; and the odds of hepatitis C virus were 6.18 times higher. Substance use was found to contribute most to this increased risk, indicating a need to identify comorbid substance use in patients with serious mental illness, as well as to identify interventions to prevent infection with blood-borne viruses.[237]

Use of this content is subject to our disclaimer