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INTRODUCTION — Schizophrenia is a psychiatric disorder involving chronic or recurrent psychosis. It is commonly associated with impairments in social and occupational functioning . It is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease .
Antipsychotic medications are first-line medication treatment for schizophrenia. They have been shown in clinical trials to be effective in treating symptoms and behaviors associated with the disorder. Antipsychotic medications have significant side effects; assessment and management of these adverse effects are an important part of treatment. Evidence-based psychosocial interventions in conjunction with pharmacotherapy can help patients achieve recovery.
This topic addresses the pharmacotherapy of schizophrenia in acute and maintenance phase treatment. Discussed separately are the use of long-acting antipsychotics and management of side effects during pharmacotherapy for schizophrenia; the epidemiology, pathogenesis, clinical manifestations, and diagnosis of schizophrenia; psychosocial interventions for schizophrenia; and common comorbid presentations of schizophrenia. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Pharmacotherapy for schizophrenia: Side effect management" and "Schizophrenia in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Psychosocial interventions for schizophrenia" and "Anxiety in schizophrenia" and "Depression in schizophrenia" and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis" and "Guidelines for prescribing clozapine in schizophrenia".)
ACUTE PHASE SYMPTOMS — The focus of treatment in schizophrenia changes as individuals enter different phases of the illness. An acute phase occurs when patients with a prior history of schizophrenia have a psychotic relapse, or during the first episode of psychosis. At this time, the focus is on reducing the severity of psychotic thoughts and behaviors. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Clinical manifestations'.)
Pre-treatment assessment — When feasible, patients who are started on an antipsychotic medication should receive a baseline physical examination with a neurological exam. Particular attention should be focused on factors that may be affected adversely by antipsychotic medication: (See "Pharmacotherapy for schizophrenia: Side effect management".)
●Body mass index (BMI)
●Signs of a movement disorder:
•Extrapyramidal symptoms (EPS): akathisia, parkinsonism, dystonias
•Tardive dyskinesia: abnormal movements of the face, peri-oral areas, tongue, extremities
When feasible, laboratory evaluations should be initiated before starting an antipsychotic. With the exception of patients treated with clozapine, the antipsychotic can usually be started before the results of laboratory tests are available.
●CBC, electrolytes, fasting glucose, lipid profile, liver, renal and thyroid function tests
●White blood cell (WBC) count with differential for patients treated with clozapine
Drug efficacy — Antipsychotic drugs are first-line treatment for schizophrenia. Randomized trials have shown that antipsychotics reduce positive symptoms of schizophrenia, such as hallucinations, delusions, and suspiciousness, compared to placebo . Antipsychotics eliminate or reduce these symptoms to a tolerable level in about 70 percent of patients with schizophrenia . (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Positive symptoms'.)
Neither antipsychotic medications nor other drugs have shown efficacy in treating negative symptoms in schizophrenia, which include decreased expressiveness, apathy, flat affect, and a lack of energy. A meta-analysis studied the efficacy of medication treatment for negative symptoms in 12,318 patients with schizophrenia in 168 randomized trials . Small statistically significant reductions in negative symptoms were found for second-generation antipsychotics, antidepressants, glutamatergic agents, and combinations of these medications, but not for first-generation antipsychotics and brain stimulation. None of the beneficial effects for any of the medication strategies were considered to be of a clinically significant magnitude. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Negative symptoms'.)
With the exception of clozapine, careful systematic reviews and meta-analyses have not found convincing evidence that any of the antipsychotics are more effective than any other for acute schizophrenia . Clozapine is more effective for patients who do not respond fully to other antipsychotics, but due to increased risk of agranulocytosis is reserved for those who do not respond well to or cannot tolerate other antipsychotics. (See 'Treatment-resistant schizophrenia' below and "Evaluation and management of treatment-resistant schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)
Antipsychotic selection — There are important differences among the antipsychotics in areas other than efficacy, including side effects and available formulations (table 1 and table 2). As a result, the selection of an antipsychotic is often based on these considerations. The selection may vary for select populations including individuals in a first psychotic episode, individuals who are only partial responders to antipsychotics, patients who are agitated, and individuals who are sensitive to particular side effects such as weight gain, EPS, or sedation. (See 'Poor response to initial treatment' below and 'First-episode psychosis' below and 'Acutely agitated' below and "Pharmacotherapy for schizophrenia: Side effect management".)
Antipsychotic medications are commonly grouped into two categories, with “second-generation” (or “atypical”) applied to clozapine and all antipsychotics first marketed after clozapine was approved in 1989, and “first-generation” applied to antipsychotics marketed previously. Recent clinical research, however, has strongly suggested that the distinction between first- and second-generation antipsychotics has questionable validity and is confusing . The pharmacologic properties, therapeutic effects, and adverse effects are not distinct between and are heterogeneous within the groups. Nevertheless, the terms first- and second-generation antipsychotic are still in widespread use. A valid distinction is that the newer (second-generation) antipsychotics tend to cause fewer extrapyramidal side effects than the older ones, particularly at the high end of approved dosage ranges.
Administration — The dose of most antipsychotic drugs should be titrated from an initial dose to the therapeutic range as quickly as tolerated. Quetiapine, clozapine, and iloperidone need to be increased gradually before reaching a therapeutic dose. The timeframe for titration differs for each drug and also depends on the individual patient’s tolerance of the drug’s tendency to cause sedation and hypotension. In most cases, patients can reach a therapeutic level in five or six days with quetiapine and iloperidone, and two to three weeks with clozapine. Suggested dosing and side effect profiles for each antipsychotic drug are shown in tables (table 1 and table 2).
Because identifying the appropriate dose range can be difficult in the pre-marketing phases of drug development, the antipsychotic doses listed (table 2) deviate somewhat from those approved by the US Food and Drug Administration, reflecting more recent research findings or clinical experience. Examples include:
●Haloperidol is effective and most useful at doses drastically below the FDA-specified maximum of 100 mg/day. Optimal haloperidol dosages are usually below 10 mg/day and almost always below 20 mg/day.
●Optimal dosages of risperidone are lower than the approved 16 mg/day; typically, a maximum dose for risperidone is 6 to 8 mg/day.
Resolution of psychotic symptoms generally occurs over several days and may take as much as four to six weeks. Clinicians should avoid the impulse to change the medication or dose prematurely. Once the dose reaches the therapeutic range, the decision to increase the dose should follow at least several days of treatment during which the individual shows little or no improvement. Higher dosing should be accompanied by careful observation of the patient for side effects. If patients fail to show improvement on doses above the usual therapeutic range, the dose should be reduced.
As an example, a patient treated with risperidone can be started on 2 mg administered as a single daily dose or 1 mg twice a day. If this dose is well tolerated (ie, minimal sedation, hypotension, or akathisia) the dose can be increased to 3 mg on the second day and 4 mg on the third day. Since 4 mg is in the therapeutic range for most patients, the clinician may then choose to continue this dose for an additional two weeks before considering an increase. If the patient shows only minimal or no improvement, the dose can be increased up to 8 mg daily with careful monitoring for clinical response and side effects. Doses of risperidone above 8 mg daily are associated with substantial risk of EPS.
Because of dose-related toxicities, antipsychotics should be used at the lowest dose that is effective for an individual. The toxicities of antipsychotic drugs typically increase with higher doses while therapeutic effects can reach a maximum. At high doses, the adverse effects of an antipsychotic may surpass the marginal benefit of dosage increases. As a result, increasing the dose of antipsychotic for a patient who is already experiencing significant EPS is unlikely to result in additional symptom reduction [7-9].
Course of response — When a patient with schizophrenia is administered an antipsychotic medication, the initial response is often a side effect such as sedation, restlessness, or postural hypotension. It is important to explain this to patients, or they may conclude that the medication is ineffective or worsening their condition. Most patients who will improve on an antipsychotic show the most rapid improvement in the first two weeks . Although the rate of improvement may slow after two weeks, patients will often continue to improve during subsequent weeks and months.
During the first weeks of treatment, patients may first experience a decrease in the severity of symptoms. As a result, the impact of symptoms on patient behavior may be reduced . Hallucinations or delusions may be less frightening or the patient may find that they can distract themselves by focusing their attention elsewhere . Delusions that are based on misinterpretations from an earlier time may linger, whereas the tendency to misinterpret new information may be reduced.
POOR RESPONSE TO INITIAL TREATMENT — Patients should be observed on a stable dose of an antipsychotic for two to six weeks before concluding the drug is ineffective. The duration of the trial will vary depending on a number of factors:
●Although patients improve most rapidly during the first two weeks, they may continue to improve for several weeks or even months on a stable dose .
●However, recent evidence suggests that if patients show only a minimal response to an antipsychotic drug during the first two weeks, it is unlikely that the individual will have a robust response . The 2009 Schizophrenia PORT recommends that trials last for two to six weeks. This timeframe will be slightly longer for antipsychotics such as iloperidone and quetiapine, which require slow titration.
Dose adjustments — In cases of nonresponse or partial response, the antipsychotic dose can be gradually increased toward the high end of the recommended range (table 2).
Most careful studies of doses above the recommended range have not found higher doses to be more effective than the maximal recommended dose [14,15]. If used, trials of higher doses should be time limited, with reassessment planned within three months. Unless clear evidence of improvement is seen, high doses should not be continued .
A dose reduction can be helpful in cases where side effects, such as akathisia, parkinsonism, sedation, or insomnia have obscured the benefit of a higher antipsychotic dose, or have been mistaken for signs of ineffective treatment, such as agitation or negative symptoms.
Changing to another antipsychotic — Switching antipsychotics can be helpful when a poor response is related to side effects. As an example, in the large US effectiveness study of antipsychotic treatment for schizophrenia, the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE), patients who gained weight during the first phase of antipsychotic treatment frequently lost weight when they were changed to ziprasidone, an antipsychotic that is not associated with weight gain .
Switching antipsychotics is less clearly beneficial when the initial medication lacked effectiveness. Most studies have shown that poor responders to one antipsychotic are likely to be poor responders to another antipsychotic except when the second agent is clozapine. (See 'Treatment-resistant schizophrenia' below.)
As an example, an analysis of patients who were on olanzapine, quetiapine, or risperidone prior to the CATIE trial showed that the patients on olanzapine or risperidone who were randomly assigned to continue the same antipsychotic had better outcomes than patients who were randomly assigned to change antipsychotics .
Two basic strategies for changing antipsychotics are [19,20]:
●A standard cross-titration for a stable patient: Simultaneous taper of the current medication with titration of the replacement drug in three to four steps over several days to several weeks.
●For patients at higher risk of relapse, the current medication is maintained at its full dose as the new medication is increased. Once the second drug has reached its target dose, the first medication may be gradually decreased and discontinued. In most cases this change can be managed in one to two weeks.
Discontinuation of antipsychotic medications is generally well tolerated, except for clozapine, for which both cholinergic rebound and withdrawal-emergent movement disorders have been reported [21-23]. A slow taper of clozapine over one to two weeks is recommended. Chlorpromazine and thioridazine can also cause cholinergic rebound and should be reduced over a week or more.
Adding a second antipsychotic — Clinicians often add a second antipsychotic when patients have a suboptimal response to a single drug. Little empirical evidence supports this practice . Although some randomized trials indicated that augmentation of clozapine with another antipsychotic may have some benefit, a meta-analysis of this practice found the supporting evidence to be weak .
TREATMENT-RESISTANT SCHIZOPHRENIA — Patients with schizophrenia who respond inadequately to an initial antipsychotic, dose adjustments, or a change in antipsychotics are classified as having treatment-resistant schizophrenia. The efficacy of interventions for treatment-resistant schizophrenia, including clozapine, is discussed separately. Guidelines for clozapine prescribing, dosing, monitoring, and side-effect management are described separately. (See "Evaluation and management of treatment-resistant schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)
Persistent suicidality — Clozapine has been shown in randomized trials to reduce suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide . A patient with schizophrenia who has persistent suicidal ideation warranting clinician concern may benefit from a trial of clozapine. Guidelines for clozapine prescribing, dosing, monitoring, and side-effect management are described separately. Management of suicidal patients is described separately. (See "Guidelines for prescribing clozapine in schizophrenia" and "Suicidal ideation and behavior in adults".)
Acutely agitated — Clinical management of the acutely agitated patient with schizophrenia is a common objective on inpatient units and other settings. Agitation can be defined as a state characterized by motor restlessness, excitement, and mental tension.
Treatment of agitation in patients with schizophrenia should be guided by the cause, which can include extrapyramidal symptoms (EPS), substance use, or psychosis:
●Extrapyramidal symptoms — Akathisia can be difficult to distinguish from psychotic agitation when patients are unable to describe the experience of restlessness . Akathisia can be treated with a benzodiazepine; eg, lorazepam can be started at 0.5 mg orally twice daily and incrementally increased to a maximum of 6 to 10 mg/day.
●Substance use — Up to half of individuals with schizophrenia have a comorbid substance use disorder . Use of stimulants such as phencyclidine (PCP), methamphetamine, and cocaine can cause agitation, as can withdrawal from alcohol or benzodiazepines. Agitation from substance use or withdrawal can be diagnosed by a history, physical exam, and toxicology. (See 'Comorbid disorders' below and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)
●Psychosis — Psychotic symptoms of schizophrenia, such as frightening delusions, suspiciousness, and command hallucinations can cause patients to become agitated. The agitation associated with psychosis can be treated with an antipsychotic or an antipsychotic combined with a benzodiazepine. The selection of a drug and the route of administration depend on a number of considerations including the urgency of calming the patient and the cooperativeness of the patient . As noted below, the choice of an antipsychotic depends on the formulation selected. It is important to note that the treatment goal is to induce a calmer state, which can often be accomplished without inducing sedation.
Although antipsychotic medications can take days to weeks before having a robust antipsychotic effect, they generally have a calming effect within minutes for agitated patients. The route of administration influences time to onset, as described below (table 3). (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)
●Standard oral formulations: Although many clinicians tend to favor sedating antipsychotics for agitated patients, non-sedating agents can also be effective for reducing agitation. Risperidone 1 to 2 mg or olanzapine 5 to 10 mg will usually be effective in these circumstances.
●Oral rapidly dissolving formulations: Oral rapidly dissolving formulations are available for risperidone, olanzapine, asenapine, and aripiprazole. These formulations are helpful when a patient is willing to take a pill by mouth, but either cannot or does not swallow it. Dosing for these formulations is the same as for standard oral formulations, eg, risperidone 1 to 2 mg or olanzapine 5 to 10 mg.
●Short-acting intramuscular (IM) injectable formulations (eg, haloperidol, olanzapine, aripiprazole, and ziprasidone): Olanzapine 5 or 10 mg administered intramuscularly is a good choice under most circumstances. IM haloperidol is effective but should be given with benztropine or diphenhydramine to reduce the risk of severe EPS including dystonias.
•We advise against the use of IM chlorpromazine, which can induce severe postural hypotension.
•Akathisia from any IM antipsychotic can contribute to agitation.
•Injectable IM antipsychotics have two potential advantages over oral antipsychotics. First, they can be administered safely to uncooperative individuals. Second, patients reach an effective plasma concentration sooner than with oral formulations. For example, patients may experience a calming effect within 10 to 30 minutes following IM administration. Calming effects may take 30 to 60 minutes following oral administration.
Although repeat administration of an oral or intramuscular antipsychotic is common when the prior dose does not sufficiently reduce agitation, the overall antipsychotic dose should be limited, because these medications can cause significant side effects such as hypotension, EPS, and sedation, particularly at high doses over a brief period of time . Maximum antipsychotic doses are shown in a table (table 3).
To limit the amount of antipsychotic used, most physicians either start with a combination of an antipsychotic and benzodiazepine or use a benzodiazepine when patients fail to respond to one or two doses of an antipsychotic for agitation. Lorazepam can be administered as 1 to 2 mg orally or 0.5 to 1 mg intramuscularly for calming.
First-episode psychosis — Patients in a first psychotic episode tend to have higher response rates than patients who have experienced multiple psychotic episodes. These individuals also respond to lower antipsychotic doses . At the same time, younger patients and first episode patients have a greater vulnerability to side effects such as weight gain and extrapyramidal side effects (EPS) . Since many first episode patients are also reluctant to take an antipsychotic, it is important to minimize adverse effects.
The Schizophrenia Patient Outcomes Research Team (PORT) recommended treating first episodes with antipsychotics other than clozapine or olanzapine. Both of these medications are associated with more weight gain, insulin resistance and dyslipidemia than other antipsychotics . In addition, clozapine can cause agranulocytosis.
The Schizophrenia PORT recommended that first-episode patients receive antipsychotic doses in the lower half of the recommended dose range . As examples, a first-episode patient would be treated with 1 to 3 mg of risperidone or 10 mg of aripiprazole daily. An exception to this recommendation should be made for quetiapine, which may require titration to 500 to 600 mg daily.
MAINTENANCE PHASE — Patients with schizophrenia who have recovered from an acute psychotic episode will usually reach a stable or maintenance phase in which psychotic symptoms are reasonably well controlled. The goal of maintenance antipsychotic treatment of schizophrenia is to minimize symptoms and functional impairments, avoid relapses, and promote recovery that allows self-determination, full integration into society, and pursuit of personal goals.
Efficacy of antipsychotic medication — For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely, even for patients who have achieved remission from a first psychotic episode. This suggestion is in accordance with the recommendation of the Schizophrenia PORT . The lowest effective dose that achieves therapeutic goals should be used. Patients should participate in the clinical decision-making regarding the duration of antipsychotic drug treatment.
Multiple randomized trials have found that maintenance antipsychotic medication reduces the risk of relapse over a period of up to two years. A meta-analysis of 6493 patients with schizophrenia in 65 randomized trials of 7 to 12 months duration found that patients who continued on an antipsychotic experienced a lower relapse rate compared to patients withdrawn from an antipsychotic and receiving placebo (27 versus 64 percent; number needed to treat to benefit = 3, 95% CI 2–3) . Other studies of up to two years have found similar results .
A seven-year follow-up assessment of patients randomly assigned to either a dose reduction strategy or to maintenance antipsychotic treatment found results that conflict with the studies of up to two years. Two reports that follow describe an intervention and follow-up assessment of patients who experienced a first episode of psychosis and subsequently met criteria for remission prior to enrollment in the trial [33,34].
●The initial trial randomly assigned 128 patients to continue maintenance treatment or to a dose reduction strategy . After two years, patients assigned to the dose reduction strategy had a higher rate of relapse, without offsetting advantages, compared to patients continuing on maintenance treatment.
●A subsequent assessment at seven years follow-up included 103 of the 128 patients (81 percent) who participated in the trial . Patients who had originally been assigned to the dose reduction strategy experienced a higher rate of recovery (ie, symptomatic and functional remission) compared to patients originally assigned to maintenance treatment.
More studies of longer term outcomes of maintenance treatment versus dose reduction are needed before we would suggest an approach other than indefinite continuation of maintenance treatment for patients with schizophrenia following an acute episode of psychosis.
As these trials demonstrate, some people with schizophrenia do well without continuous antipsychotic treatment; however, they are not identifiable prospectively .
Other considerations regarding selection of antipsychotic medication for maintenance treatment mirror those for pharmacotherapy during the acute phase. (See 'Drug efficacy' above.)
Medication adherence — Long-acting injectable antipsychotics may be useful for patients with schizophrenia who experience frequent relapses due to non-adherence to antipsychotic medications. They also may be helpful for patients who will not take oral antipsychotics regularly. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)
Other strategies to promote better adherence to antipsychotics include simplifying medication regimens (eg, fewer medications, fewer pills, fewer daily doses) and active engagement of patients in treatment planning (ie, shared decision making).
Cognitive impairment — Improving cognitive impairment has increasingly become an objective of treatment for schizophrenia. Preliminary studies suggest that antipsychotic medication may improve cognition when received early in the course of schizophrenia [36,37]. Studies of patients with chronic schizophrenia have generally found less improvement in cognition during antipsychotic treatment [37-40]. Trials of other medications (including n-methyl-d-aspartate (NMDA) glutamatergic receptor agonists, glycine, D-serine, ampakine CX516, D-cycloserine, donepezil, rivastigmine, and galantamine) have failed to show significant benefit [41-49].
Comorbid disorders — Depressive disorders and anxiety disorders can be challenging to diagnose in patients with schizophrenia. A primary comorbid disorder needs to be distinguished from symptoms of schizophrenia, antipsychotic drug side effects, and other clinical presentations. Properly diagnosed, however, these syndromes can respond to antidepressant and anxiolytic medications . (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)
Substance abuse and dependence occur at a high prevalence in schizophrenia . The combination of a severe mental illness and a substance use disorder (SUD), commonly described as “dual diagnosis”, is associated with increased morbidity, poorer functioning, decreased adherence to medication, and higher rates of relapse compared to either disorder individually . Integrated treatment strategies for dual diagnosis that include pharmacotherapy have been developed for individuals with schizophrenia and SUDs. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Schizophrenia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients treated with an antipsychotic for schizophrenia should be assessed prior to treatment if possible and at regular intervals for: (See 'Pre-treatment assessment' above.)
•Signs of a movement disorder including extrapyramidal symptoms and tardive dyskinesia
•Symptoms of metabolic syndrome including measurements of body mass index, waist circumference, hemoglobin A1c, serum lipids, and blood pressure
•ECG for patients with a history of cardiac disease or when starting an antipsychotic that prolongs the QT interval
●For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely at the lowest effective dose that achieves therapeutic goals (Grade 2C). This approach is suggested even for patients who have achieved remission from a first psychotic episode. (See 'Maintenance phase' above.)
●The selection of which antipsychotic medication to use for an individual patient with schizophrenia should be made based on patient clinical factors and the side effect profiles of antipsychotic drugs. With the exception of clozapine for patients with refractory symptoms, there is not convincing evidence to favor one antipsychotic over the others based on efficacy. (See 'Drug efficacy' above.)
•Because olanzapine is associated with significant weight gain and metabolic adverse effects, leading guidelines state that it should not be used as a first-line agent for first-episode patients, but should be considered for patients who fail treatment with a first-line agent.
●Other strategies for the patient with schizophrenia who has not adequately responded to an antipsychotic drug include:
•Changing to another antipsychotic has been shown to be an effective strategy for addressing side effect problems but is not clearly associated with improved efficacy, with the exception of clozapine. (See 'Changing to another antipsychotic' above.)
•Adding a second antipsychotic medication has not been proven efficacious in randomized trials. For patients with psychotic symptoms that do not respond to two trials of antipsychotic monotherapy, a trial of clozapine is strongly recommended before combining two antipsychotics. (See 'Adding a second antipsychotic' above.)
●Hospitalized patients with schizophrenia may require treatment for agitation. If agitation is associated with psychotic symptoms of schizophrenia, it can be treated with a standard oral formulation, rapid dissolving, or intramuscularly injected antipsychotic, depending on the level of patient participation. Other causes of agitation should be ruled out, including akathisia and substance abuse or withdrawal. (See 'Acutely agitated' above.)
●Long-acting injectable (LAI) antipsychotic medication may be useful for patients with schizophrenia when non-adherence to oral antipsychotics leads to frequent relapse. LAI antipsychotics are administered at two to four week intervals. As an example, fluphenazine decanoate can be administered at a dose between 6.25 to 50 mg intramuscularly every two weeks. Extrapyramidal symptoms can be prominent at higher doses. (See 'Medication adherence' above and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington 2013.
- Murray CJL, Lopez AD. The Global Burden of Disease, Harvard University Press, Cambridge, MA 1996. p.21.
- Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71.
- Dixon LB, Lehman AF, Levine J. Conventional antipsychotic medications for schizophrenia. Schizophr Bull 1995; 21:567.
- Fusar-Poli P, Papanastasiou E, Stahl D, et al. Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr Bull 2015; 41:892.
- Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31.
- McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991; 48:739.
- Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157:514.
- Stone JM, Davis JM, Leucht S, Pilowsky LS. Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT and PET in vivo receptor imaging literature. Schizophr Bull 2009; 35:789.
- Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60:1228.
- Mizrahi R, Kiang M, Mamo DC, et al. The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders. Schizophr Res 2006; 88:111.
- Mizrahi R, Bagby RM, Zipursky RB, Kapur S. How antipsychotics work: the patients' perspective. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:859.
- Kinon BJ, Chen L, Ascher-Svanum H, et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology 2010; 35:581.
- Kinon BJ, Volavka J, Stauffer V, et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. J Clin Psychopharmacol 2008; 28:392.
- Royal College of Psychiatrists. Consensus statement on high dose antipsychotic medication. CR138, Royal College of Psychiatrists, London 2006.
- UK National Institute for Health and Clinical Excellence Guidelines http://guidance.nice.org.uk/CG/WaveR/26.
- Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611.
- Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry 2006; 163:2090.
- Jibson MD, Tandon R. Treatment of acute psychotic episodes. In: Schizophrenia: a new guide for clinicians, Csernansky, JG. (Eds), Marcel Dekker, New York 2001. p.107.
- Kinon BJ, Basson BR, Gilmore JA, et al. Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry 2000; 61:833.
- Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997; 58:252.
- Ahmed S, Chengappa KN, Naidu VR, et al. Clozapine withdrawal-emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998; 59:472.
- Shiovitz TM, Welke TL, Tigel PD, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull 1996; 22:591.
- Gören JL, Parks JJ, Ghinassi FA, et al. When is antipsychotic polypharmacy supported by research evidence? Implications for QI. Jt Comm J Qual Patient Saf 2008; 34:571.
- Barbui C, Signoretti A, Mulè S, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35:458.
- Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60:82.
- Buckley PF. Treating movement disorders and akathisia as side effects of antipsychotic pharmacotherapy. J Clin Psychiatry 2008; 69:e14.
- Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes. Schizophr Res 1999; 35 Suppl:S93.
- Marder SR. Treatment of agitation in patients with schizophrenia. J Clin Psychiatry 2008; 69:e17.
- Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420.
- Leucht S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2012; :CD008016.
- Davis JM. Maintenance therapy and the natural course of schizophrenia. J Clin Psychiatry 1985; 46:18.
- Wunderink L, Nienhuis FJ, Sytema S, et al. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68:654.
- Wunderink L, Nieboer RM, Wiersma D, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913.
- Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med 2012; 42:2145.
- Davidson M, Galderisi S, Weiser M, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am J Psychiatry 2009; 166:675.
- Keefe RS, Sweeney JA, Gu H, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164:1061.
- Harvey PD, Patterson TL, Potter LS, et al. Improvement in social competence with short-term atypical antipsychotic treatment: a randomized, double-blind comparison of quetiapine versus risperidone for social competence, social cognition, and neuropsychological functioning. Am J Psychiatry 2006; 163:1918.
- Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64:633.
- Sergi MJ, Green MF, Widmark C, et al. Social cognition [corrected] and neurocognition: effects of risperidone, olanzapine, and haloperidol. Am J Psychiatry 2007; 164:1585.
- Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007; 164:1593.
- Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev 2006; :CD003730.
- Goff DC, Herz L, Posever T, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 2005; 179:144.
- Kohler CG, Martin EA, Kujawski E, et al. No effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. Cogn Neuropsychiatry 2007; 12:412.
- Mazeh D, Zemishlani H, Barak Y, et al. Donepezil for negative signs in elderly patients with schizophrenia: an add-on, double-blind, crossover, placebo-controlled study. Int Psychogeriatr 2006; 18:429.
- Freudenreich O, Herz L, Deckersbach T, et al. Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) 2005; 181:358.
- Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophr Res 2006; 85:73.
- Kumari V, Aasen I, ffytche D, et al. Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind fMRI study. Neuroimage 2006; 29:545.
- Buchanan RW, Conley RR, Dickinson D, et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry 2008; 165:82.
- Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull 2009; 35:383.
- Kessler RC, Nelson CB, McGonagle KA, et al. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry 1996; 66:17.
- Institute of Medicine. Improving the Quality of Health Care for Mental and Substance-Use Conditions: Quality Chasm Series, National Academy Press, 2006. p.210.