Medscape Logo Search Drugs & Diseases ____________________ No instant look-up matches. Search within full reference content by clicking the "SEARCH" button or pressing enter. News & Perspective Drugs & Diseases CME & Education Log In Register https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfess ionalProfile&urlCache=aHR0cDovL2VtZWRpY2luZS5tZWRzY2FwZS5jb20vYXJ0aWNsZ S8yODgyNTktdHJlYXRtZW50 processing.... IFRAME: xmlFrame Schizophrenia Treatment & Management * Author: Frances R Frankenburg, MD; Chief Editor: Eduardo Dunayevich, MD more... * Overview * Presentation * DDx * Workup * Treatment * Medication * Updated: Dec 22, 2014 What would you like to print? * Print this section * Print the entire contents of * Approach Considerations * Antipsychotic Pharmacotherapy * Other Pharmacotherapy * Psychosocial Interventions * Diet and Activity * Prevention * Other Treatments * Show All Multimedia Library References Approach Considerations Treatment of schizophrenia requires integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and probably is best carried out by a multidisciplinary team, including some combination of the following: a psychopharmacologist, a counselor or therapist, a social worker, a nurse, a vocational counselor, and a case manager. Clinical pharmacists and internists can be valuable members of the team. It is important not to neglect the medical care of the person with schizophrenia. Obesity, diabetes, cardiovascular disease, and lung diseases are prevalent in schizophrenia, and the person with schizophrenia often does not receive adequate medical care for such conditions.^[78] Antipsychotic medications (also known as neuroleptic medications or major tranquilizers) diminish the positive symptoms of schizophrenia and prevent relapses. Approximately 80% of patients relapse within 1 year if antipsychotic medications are stopped, whereas only 20% relapse if treated. Children, pregnant or breastfeeding women, and elderly patients present special challenges. In all of these cases, medications must be used with particular caution. The choice of which drug to use for treatment of a patient with schizophrenia depends on many issues, including effectiveness, cost, side-effect burden, method of delivery, availability, and tolerability. Many studies have compared antipsychotic drugs with one another, but no broad consensus has been reached. In the absence of clinical or pharmacogenetic predictors of treatment response, the current treatment approach is largely one of trial and error across sequential medication choices. Although treatment is primarily provided on an outpatient basis, patients with schizophrenia may require hospitalization for exacerbation of symptoms caused by noncompliance with pharmacotherapy, substance abuse, adverse effects or toxicity of medications, medical illness, psychosocial stress, or the waxing and waning of the illness itself. Hospitalizations are usually brief and are typically oriented towards crisis management or symptom stabilization. Treatment of patients with schizophrenia, particularly during a psychotic episode, may raise the issue of informed consent. Consent is a legal term and should be used with respect to specific tasks. A person who is delusional in some but not all areas of life may still have the capacity to make medical and financial decisions. Insurance concerns In the United States, patients with schizophrenia who are unable to work may be eligible for governmental programs, such as Medicare and Medicaid. These programs pay the cost of medical care. Unfortunately, if individuals begin to work and earn a sufficient salary, they may lose these benefits—an especially problematic occurrence when, as is often the case, their job provides minimal or no health benefits. This situation is complicated and must be monitored closely by professionals with a good understanding of health benefits. The impact of the American Affordable Care Act (ACA) on the care of schizophrenia has yet to be determined. Some parts of the ACA, such as the removal of exclusion of preexisting conditions as a barrier to getting insurance, and the removal of annual and lifetime benefit limits, will be helpful. The ACA mandates parity between care for medical and psychiatric illnesses. However, health plans in the new exchanges might not provide all of the services that are mentioned here, such as supported employment. As well, in the states that have chosen not to expand their Medicaid programs, patients with Medicaid as their insurer may continue to have difficulty in accessing care.[#Antipsychotic] Next Antipsychotic Pharmacotherapy Before beginning antipsychotic medications, clinicians should warn patients and their families of adverse effects, and the slowness of response. The patient may be calmer and less agitated almost immediately, but alleviation of the psychosis itself often takes several weeks. Some clinicians routinely perform electrocardiography (ECG) before beginning treatment with antipsychotic medications and then as often as seems appropriate, for example if doses are increased or agents change. Because suicide is not uncommon in patients with psychotic illnesses, clinicians should write prescriptions for the lowest dosage that is consistent with good clinical care. Patients should be urged to avoid substance abuse. All medications should be given at lower dosages in children and elderly patients and used with great caution in women who are pregnant or breastfeeding. The first antipsychotic medications, chlorpromazine and haloperidol, were dopamine D2 antagonists. These and similar medications are known as first-generation, typical, or conventional antipsychotics. Other antipsychotics, beginning with clozapine, are known as second-generation, atypical, or novel antipsychotics. The conventional antipsychotic agents are available in generic forms and are less expensive than the newer agents. They are available in a variety of vehicles, including liquid and intramuscular (IM) preparations. Some of these agents (haloperidol and fluphenazine) are also available as depot preparations, meaning that a person can be given an injection of a medication every 2-4 weeks. Of the second-generation agents, risperidone is available as a long-acting injection that uses biodegradable polymers; olanzapine, paliperidone, and aripiprazole are also now available in long-acting injectable forms.^[79, 80, 81, 82] The first-generation antipsychotic drugs tend to cause extrapyramidal adverse effects and elevated prolactin levels. The second-generation drugs are more likely to cause weight gain and abnormalities in glucose and lipid control; in addition, they are often more expensive than the first-generation drugs. Comparative efficacy of agents For some years, it was believed that the newer antipsychotic drugs were more effective, but there is now some uncertainty about that. An exception is clozapine, which consistently outperforms the other antipsychotic drugs. Phase 1 of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, a large nationwide trial that compared the first-generation antipsychotic perphenazine with the second-generation drugs olanzapine, risperidone, quetiapine, and ziprasidone, found that olanzapine was slightly better than the other drugs in terms of the patients choosing to stay on it, and number of hospitalizations, but also was associated with significant weight gain. Surprisingly, perphenazine performed about as well as the other 3 second-generation agents.^[83] In this and other studies the primary outcome, stopping the drug, may seem to be unusual. It is used because it reflects the “real-world” decision of the clinician and patient that the agent is either no longer tolerable or effective. In CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study), a study from the United Kingdom, more than 200 patients who were about to change antipsychotic medication were randomly assigned to either a first-generation or a second-generation agent. In this study, the first-generation drugs seemed to perform slightly better than the newer ones, as measured by the Quality-of-Life Scale.^[84] First-episode schizophrenia EUFEST (European First Episode Schizophrenia Trial) was a year-long open-label study conducted in nearly 500 patients in 13 European countries and Israel that, as did CATIE, used treatment discontinuance as the main outcome measure. The study found that patients were more likely to stop low-dose haloperidol than to stop olanzapine, quetiapine, ziprasidone, or amisulpride (not available in the United States); however, all medications were associated with similar decreases in symptoms.^[85] Similarly, the randomized, double-blind CAFE (Comparison of Atypicals for First Episode) study found few differences between olanzapine, quetiapine, and risperidone in 400 patients experiencing a first episode of psychosis, with all-cause treatment discontinuance rates in the vicinity of 70% by week 52. Drowsiness and weight gain were along the most common adverse events with all 3 drugs; in addition, insomnia was seen with olanzapine, a longer sleep time with quetiapine, and menstrual irregularities in women with risperidone.^[86] The Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland recommended that any antipsychotic medication, with the exceptions of clozapine and olanzapine, can be used as first-line treatment for patients with schizophrenia who are experiencing their first episode of acute positive symptoms.^[87] According to a comprehensive review carried out by the Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland, early treatment with any antipsychotic medication is associated with significant symptom reduction; first- and second-generation antipsychotics may have equivalent significant short-term efficacy. However, because of the adverse adverse-effect profile of clozapine and the significant metabolic risks associated with olanzapine, PORT advised that neither drug should be considered as a first-line treatment for first-episode schizophrenia.^[87] Noting that both responsiveness to treatment and sensitivity to adverse effects are greater in patients with first-episode schizophrenia than in those who have had multiple episodes, PORT recommended starting antipsychotic treatment for the former at doses lower than those recommended for the latter. An exception is quetiapine, which may not be effective in lower doses; in addition, low doses of aripiprazole or ziprasidone have not been evaluated in first-episode schizophrenia.^[87] Wunderink and colleagues followed just over 100 subjects participating in a study of first episode psychosis. Subjects were randomly assigned to antipsychotic medication dose reduction or dose maintenance. At 7 years follow-up, they found that those treated with lower doses or no antipsychotics had more relapses and hospitalizations. This was not an unexpected finding. However, they also found that these lightly medicated patients overall were functioning better. They concluded that it seems that there are different responses of symptoms and functioning to medication.^[88] The National Institute of Mental Health (NIMH) has initiated a research project, Recovery After an Initial Schizophrenia Episode (RAISE), to determine whether coordinated and aggressive treatment in the earliest stages of illness can prevent long-term disability from schizophrenia. The RAISE Early Treatment Program (ETP), an integrated program delivered in community clinics, will be compared with the RAISE Connection program, a program offered in Baltimore and Manhattan in partnership with state mental health programs. Choice of agent There is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the most effective medication but is not recommended as first-line therapy because it has a high burden of adverse effects, requires regular blood work, and has not outperformed other medications in first-episode patients.^[89, 90] Numerous guidelines or algorithms for the treatment of schizophrenia are available. Treatment guidelines are recommendations that require clinical judgment in their application and must be regularly updated on the basis of new evidence.^[91] Few studies have examined the outcome of treatment using these algorithms. In a study from Canada, Agid et al described the outcome of treatment among 244 patients with first-episode schizophrenia who were treated according to a 2003 algorithm.^[92] If no response to the first antipsychotic was observed, a second antipsychotic was used. Most patients were treated with olanzapine or risperidone. Response rates fell from about 75% in the first trial to less than 20% in the second trial.^[92] The patients who did not respond to either trial were offered clozapine, and 75% responded. Unanswered questions from this study include the respective roles of first-generation and second-generation antipsychotic medications and when clozapine should be used. If the patient has not responded to a medication, physicians can switch medications or add another one. Using 2 or even 3 different antipsychotic agents together is common, though this practice lacks a compelling evidence base and does increase the complexity of the medication regimen. Nonetheless, in one large study, discontinuance of 1 of 2 antipsychotics was followed by treatment discontinuance more often and more quickly than continuation of both antipsychotics were continued.^[93] A meta-analysis of 19 studies involving more than 1200 subjects found a modest advantage for antipsychotic polypharmacy.^[94] Physicians sometimes choose what seems to be a simpler option than switching or adding medication, which is to increase the dose of the original medication. For example, quetiapine is sometimes prescribed at higher than approved doses for patients with schizophrenia or schizoaffective disorder. Honer et al found that dosages higher than 800 mg/day did not show any advantage over dosages in the approved range.^[95] In a recent Cochrane review, authors studied quetiapine compared with other antipsychotics.^[96] Quetiapine seemed slightly less effective, but overall to have a slightly lower burden of adverse effects. Sixty percent of the patients started on quetiapine stopped taking it within a few weeks. The authors also noted that the clinical meaning of these many findings, many of them quite modest, remains unclear. PORT provided a detailed review addressing the choice of antipsychotic medications, including recommendations and discussions regarding acute, maintenance, first-episode, and targeted intermittent treatment, as well as treatment of individual symptoms.^[87] Maximization of compliance Noncompliance with or nonadherence to pharmacologic therapy is difficult to estimate but is known to be common, and it is one of the reasons for the use of intramuscular (IM) preparations of antipsychotic medications. A regular routine of IM medication, such as every 2-4 weeks, is preferred by some patients since it obviates the need to take medication every day. As well, it permits easier monitoring of medication adherence by the clinician. IM medication is less widely used in the United States than in Europe. Whether IM medication is superior to oral medication is not clear. A large trial that compared long-acting injectable risperidone with the psychiatrist’s choice of oral antipsychotic agent found, somewhat to the surprise of many, that injectable risperidone was not superior to the oral form and was associated with more side effects.^[97] In a meta-analysis of 21 randomized, controlled studies involving more than 5000 patients, the long-acting injectable agents were similar to the oral antipsychotics with regard to relapse prevention.^[98] However, in 10 studies using first-generation long-acting injectables, as well as studies published in or before 1991 (8 fluphenazine or long-acting injectable studies), the primary outcome with the long-acting injectable agents was superior to that with oral antipsychotics. Adherence is usually overestimated by both patient and physician. Nonadherence can be partial or complete, but even partial adherence is associated with relapse.^[99] In the past, nonadherence was thought to be due at least in part to the side effects of the conventional antipsychotic agents, such as akathisia. Nevertheless, nonadherence remains a major clinical problem, even with second-generation antipsychotic agents. Family members of people with schizophrenia, as well as clinicians providing care for them, should encourage them to take their medication, while at the same time respecting their autonomy. This is a difficult balance to achieve. Adverse effects Patients tend not to be very adherent to antipsychotic medications, and this may, in part, be due to their adverse effects. Patients sometimes report they feel less like themselves, or less alert, when taking these medications. One troubling possibility is that while they are used to combat psychosis and in that sense to preserve brain functioning, these medications can actually interfere with the usual processes of the brain. Indeed, some practitioners have gone so far as to call haloperidol “neurotoxic” and suggest that it not be used. However, there may be adverse neurological effects with all of the antipsychotic medications, not just the conventional ones. For example, in an open-label 6-month pilot study in Canada, the reduction of risperidone or olanzapine dose by 50% improved cognitive function for stable patients with schizophrenia and did not lead to worsening of psychotic symptoms.^[100] The following are adverse effects typically associated with conventional antipsychotic agents and with the atypical antipsychotic risperidone at dosages higher than 6 mg/day: * Akathisia * Dystonia * Hyperprolactinemia * Neuroleptic malignant syndrome (NMS) * Parkinsonism * Tardive dyskinesia (TD) Akathisia is a subjective sense of inner restlessness, mental unease, irritability, and dysphoria. It can be difficult to distinguish from anxiety or an exacerbation of psychosis. Dystonia consists of painful and frightening muscle cramps, which affect the head and neck but may extend to the trunk and limbs. Dystonia usually occurs within 12-48 hours of the beginning of treatment or an increase in dose. Muscular young men are typically affected. Hyperprolactinemia is an elevation of the hormone prolactin in the blood, caused by the lowering of dopamine. (Dopamine inhibits the release of prolactin from the pituitary.) It is associated with galactorrhea, gynecomastia, and osteoporosis. In women it is associated with amenorrhea, and in men it is associated with impotence. NMS is marked by fever, muscular rigidity, altered mental state, and autonomic instability. Laboratory findings include increased creatine kinase levels and myoglobinuria. Acute kidney injury may result. Mortality is significant. NMS is thought to be less common in patients taking clozapine or other atypical antipsychotic agents. Parkinsonism consists of some combination of tremor, bradykinesia, akinesia, and rigidity. Tardive dyskinesia (TD) consists of involuntary and repetitive (but not rhythmic) movements of the mouth and face. Chewing, sucking, grimacing, or pouting movements of the facial muscles may occur. People may rock back and forth or tap their feet. Occasionally, diaphragmatic dyskinesia exists, which leads to loud and irregular gasping or “jerky” speech. The patient is often not aware of these movements. The incidence of TD is as high as 70% in elderly patients treated with antipsychotic agents. Risk factors for TD include older age, female sex, and negative symptoms. Physicians should warn patients, especially those being treated with conventional antipsychotic agents, about the risk of TD. Regular examinations, using the abnormal involuntary movement scale (AIMS), should be performed to document the presence or absence of TD. Anticholinergic effects Anticholinergic side effects occur with most antipsychotics (though risperidone, aripiprazole, and ziprasidone are relatively free of them). Such effects include the following: * Dry mouth * Acute exacerbation of narrow- or closed-angle glaucoma (if undiagnosed or untreated) * Confusion * Decreased memory * Agitation * Visual hallucinations * Constipation QT interval prolongation The QT interval is the interval between the beginning of the QRS complex and the end of the T wave on ECG. It reflects the time required for the ventricles to depolarize and repolarize. The QT interval corrected for heart rate is called the QTc. A prolonged QTc interval puts a person at risk for torsades de pointes, a malignant arrhythmia associated with syncope and sudden death. QTc intervals are lengthened by the conventional antipsychotic agents thioridazine, pimozide, and mesoridazine and, to a lesser extent, by the novel antipsychotic agent ziprasidone. (Mesoridazine is no longer available in the United States.) Risk is increased by individual susceptibility, heart failure, bradycardias, electrolyte imbalance (especially hypokalemia), hypomagnesemia, and female gender.^[101] No cases of torsades de pointes were reported in a large trial of more than 18,000 patients in 18 countries who were randomly assigned to receive either ziprasidone or olanzapine, though the event is so rare that this finding is not entirely surprising.^[102] No increase in nonsuicide mortality was reported. In particular, no increase in cardiac mortality was found, which is somewhat reassuring with respect to the cardiac safety of ziprasidone. Haloperidol has only a small influence on the ECG. Nevertheless, this agent has been implicated, albeit very rarely, in causing torsades de pointes.^[103] Clinicians should be alert to the ability of antipsychotic medications to cause ECG changes in patients with any of the above risk factors or in patients taking other medications that can lengthen the QTc interval. Particular caution is advised with regard to using these medications in patients who are elderly or medically ill. Altered glucose and lipid metabolism and weight gain Altered glucose and lipid metabolism, with or without weight gain, may occur with most antipsychotic agents, as can weight gain itself.^[104] Aripiprazole and ziprasidone are the antipsychotic drugs least likely to lead to these adverse effects, whereas olanzapine and clozapine are the drugs most likely to do so. The newer agents, asenapine, iloperidone, and lurasidone, may also share a lower liability for weight gain and metabolic disturbances. The mechanism of weight gain associated with psychotropic drugs is not understood. Sensitivity to insulin may be increased, or increased leptin levels may be present. A Danish study of the risk for diabetes with antipsychotics compared nearly 346,000 individuals who purchased antipsychotics and nearly 1.5 million unexposed individuals and concluded that the rate ratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the RR varied widely for second-generation antipsychotics (1.32; range, 1.17-1.57).^[105] Stroup et al studied 215 patients whose psychotic symptoms were stabilized on olanzapine, quetiapine, or risperidone.^[106] After 24 weeks, those who switched to aripiprazole had improved cholesterol levels and other metabolic factors, and they lost more weight than those who stayed on their original medication. Relapse or worsening of psychotic symptoms occurred no more frequently in patients who switched medications than in those who stayed on their original medication. However, patients who switched to aripiprazole were more likely to discontinue the assigned medication: 43.9% of those who switched discontinued their medication, whereas 24.5% of those who stayed on their original medication discontinued it. They concluded patients experiencing cardiovascular or metabolic adverse effects of an antipsychotic medication may fare better if they switch to a different agent, provided they are closely monitored. Weight gain is associated both with psychological problems (eg, decreased self-esteem) and with medical problems (eg, diabetes, coronary artery disease, and arthritis). Education about nutrition and exercise should be provided. Cognitive-behavioral therapy can be tried. It is unclear whether weight-reducing drugs should be added to antipsychotic therapy. In one randomized, placebo-controlled study conducted in 72 patients with first-episode schizophrenia who gained more than 7% of their predrug weight, metformin (1000 mg/day) was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance.^[107] Miscellaneous adverse effects All antipsychotic agents may be associated with esophageal dysmotility, thus increasing the risks of aspiration, choking, and the subsequent risk of pneumonia. Orthostatic hypotension can be problematic at the beginning of therapy, with dose increases, and in elderly patients. This problem is related to alpha[1] -blockade and seems to be particularly severe with risperidone and clozapine. Venous thromboembolism may be associated with the use of antipsychotic drugs. Patients treated with clozapine may be at particular risk for this complication; however, the reasons for this possible association are not understood.^[108, 109] Results from a prospective study indicated that in children and adolescents, long-term use of risperidone can negatively affect bone mass.^[110] Neurotoxic effects Some studies have explored the potential neurotoxic effects of antipsychotic medications; however, no clear conclusions have been reached. For example, Ho et al performed structural brain imaging in more than 200 patients with schizophrenia over 7 years and found that whereas patients treated with higher doses of antipsychotic medications seemed to lose gray matter throughout their brain (except the cerebellum), those treated with lower doses seemed to have a small increase in white matter.^[111] The clinical significance of these findings is unclear. It is not known whether these changes are directly associated with any clinical symptoms and whether they are reversible. It also is not known whether the higher medication doses were in response to the gray-matter loss or whether it was the other way around. Monitoring of blood levels Regular measurement of blood medication levels in the blood would be helpful in schizophrenia, for the following reasons: * Patients may not always take their medications, and checking drug levels can detect this noncompliance * Patients may not always be the best reporters of side effects, and monitoring medication levels can occasionally help the clinician detect toxicity * Smoking tobacco products induces the liver enzyme CYP1A2 (though nicotine patches, nicotine inhalers, and chewing tobacco do not); this enzyme metabolizes a number of antipsychotic drugs, so that, for example, patients who stop smoking while being treated with clozapine or olanzapine often experience increased antipsychotic levels; a patient who has stopped smoking may have a variety of complaints, and checking drug levels can help determine their etiology For most antipsychotic medications, however, clear dose-response curves have not been established, and in clinical practice, drug levels are rarely monitored. There are 2 exceptions to this general statement. Plasma concentrations of haloperidol are correlated to some degree with clinical effects, and levels in the range of 15-25 ng/mL are thought to be optimal. Plasma concentrations of clozapine in the range of 300-400 ng/mL may be optimal. Previous Next Other Pharmacotherapy Anticholinergic agents (eg, benztropine, trihexyphenidyl, and diphenhydramine) and amantadine are often used in conjunction with the conventional antipsychotic agents to prevent dystonic movements or to treat extrapyramidal symptoms. Akathisia is particularly difficult to treat, but it occasionally responds to an anticholinergic agent, a benzodiazepine, or a beta blocker. Many patients with schizophrenia are treated with other psychotropic medications in addition to antipsychotic agents. Polypharmacy in schizophrenia is supported by little rigorous evidence but is widely practiced nonetheless. Medications often used include antidepressants, mood stabilizers, and anxiolytic agents. Carbamazepine and clozapine should not be used together. Benzodiazepines are often used and are perceived as being quite safe. Nevertheless, they can be addictive and can lead to falls, especially in the elderly. There has long been a concern that they might increase mortality.^[70] Previous Next Psychosocial Interventions Psychosocial treatment is essential for people with schizophrenia and includes a number of approaches, such as social skills training, cognitive-behavioral therapy, cognitive remediation, and social cognition training.^[112] PORT (see Antipsychotic Pharmacotherapy) also provides a detailed review of psychosocial interventions.^[113] Psychosocial treatments are currently oriented according to the recovery model. According to this model, the goals of treatment for a person with schizophrenia are as follows: * To have few or stable symptoms * To avoid hospitalization * To manage his or her own funds and medications * To be either working or in school at least half-time Hope, empowerment, choice, and community integration are emphasized in this treatment approach. A large study from China demonstrated the advantages of medication plus psychosocial intervention over medication alone.^[114] In the psychosocial intervention arm, each month patients and their families received 1 day of 4 types of evidence-based interventions: psychoeducation, family intervention, skills training, and cognitive-behavioral therapy. After 1 year, the patients in the group receiving the extra interventions were more compliant with their medications, had fewer rehospitalizations, and experienced better quality of life. Cognitive remediation, vocational rehabilitation, assertive community treatment, and family intervention are reviewed. Cognitive remediation Cognitive impairment, a core feature of schizophrenia, is less dramatic than other symptoms of the disease (eg, hallucinations and delusions) but interferes with work, social relationships, and independent living. Cognitive impairment is not improved by medication. Cognitive remediation is a treatment modality derived from principles of neuropsychological rehabilitation and is based, in part, on the ideas that the brain has some plasticity and that brain exercises can encourage neurons to grow and can develop the neurocircuitry underlying many mental activities. Numerous different models of cognitive remediation are available. Some models use drill-based practicing of isolated cognitive skills with the aid of computers, whereas others help people develop strategies for overcoming areas of weakness. Other forms of this therapy are known as cognitive rehabilitation, cognitive enhancement, or metacognitive therapy. Cognitive remediation works best when patients are stable. Improvement occurs across numerous cognitive functions, and changes are found on brain imaging that reflect these changes in brain functioning. Cognitive remediation techniques are time-intensive and labor-intensive. Because cognitive deficits are multiple and vary from person to person, such techniques seem to work best when specifically tailored to each patient. When combined with other therapies, such as supported employment, cognitive remediation leads to clinically relevant improvements.^[115] These effects are durable, lasting even after the training has stopped.^[116] In a study by Grant et al, low-functioning patients with prominent negative symptoms were assigned to either recovery-oriented cognitive-behavioral therapy plus standard treatment or standard treatment; after 18 months, the authors found that both negative and positive symptoms had decreased in the group receiving the add-on cognitive therapy.^[117] The study was not blinded, and the treatment was delivered by enthusiastic doctoral level therapists; thus, the findings may not be widely generalizable. A study by Puig and colleagues also found cognitive remediation therapy to be effective. In the study, 50 patients between the ages of 12 and 18 years with early onset schizophrenia were randomized to either cognitive remediation therapy plus usual treatment or usual treatment alone. Patients in the cognitive remediation group showed significantly greater improvements than patients in the usual treatment group in verbal memory, working memory, executive function, and cognitive composite scores, at the end of treatment and at 3-month follow-up. The cognitive remediation group also had greater improvements in daily living skills, global adaptive functioning, and self-perceived family burden.^[118] Cognitive therapy may be effective as a standalone treatment for schizophrenia.^[119, 120] For schizophrenic patients who cannot or will not take antipsychotic medication, cognitive therapy may be the most viable option. According to data from the first randomized trial of cognitive therapy as a standalone therapy for schizophrenia, structured treatment with a therapist significantly reduced the severity of psychiatric symptoms and improved personal and social functioning and some dimensions of delusional beliefs and voice hearing.^[119, 120] The study involved 74 individuals aged 16 to 65 years with schizophrenia spectrum disorders who had decided not to take or had stopped taking antipsychotics for at least 6 months.^[119, 120] Half were randomly assigned to cognitive therapy (26 sessions during a 9-month period) plus treatment as usual and half to treatment as usual alone. After 18 months, 7 (41%) of 17 study participants receiving cognitive therapy had an improvement of more than 50% in the Positive and Negative Syndrome Scale (PANSS) total score compared with 3 (18%) of 17 receiving treatment as usual.^[119, 120] None of the antipsychotic medications currently available is particularly effective at addressing cognitive symptoms. A new initiative from NIMH, known as Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), is a collaboration between various programs to develop tools for measuring cognition in clinical trials and aiding development of drugs that target these symptoms. Vocational rehabilitation Most patients with schizophrenia would like to work; employment can improve income, self-esteem, and social status. However, few people with the disorder are able to maintain competitive employment.^[121] Supported employment programs currently thought to be most effective are those that offer individualized, supported, and rapid job assignments and that are integrated with other services. These programs are associated with higher rates of employment, but gains in other domains are surprisingly difficult to discern.^[122] Assertive community treatment Assertive community treatment is a form of case management that is typically used for patients who have had multiple hospitalizations. The treatment involves active outreach to patients. Case managers usually have a fairly small outpatient load (about 10 patients) and are able to go into the community to work with their clients. The managers coordinate and integrate care by doing the following: they identify indications for treatment, make referrals to appropriate services, and promote engagement with interventions. This form of treatment is expensive but may be associated with better clinical and social outcomes and lower hospitalization rates. Family intervention Schizophrenia affects the person’s whole family, and the family’s responses can affect the trajectory of the person’s illness. Familial “high expressed emotion” (hostile overinvolvement and intrusiveness) leads to more frequent relapses. Some studies have found that family therapy or family interventions may prevent relapse, reduce hospital admission, and improve medication compliance.^[123] The National Alliance for the Mentally Ill (NAMI) is a helpful advocacy group that is supportive for family members. NAMI also advocates funding and research. Smoking cessation Most patients with schizophrenia smoke. This may be a result of previous conventional antipsychotic treatment, in that nicotine may ameliorate some of the adverse effects of these drugs. Smoking may also be related to the boredom associated with hospitalizations, the peer pressure from other patients to smoke, or the anomie associated with unemployment. Whatever the cause of the high incidence of smoking, the health risks from smoking are well known, and all schizophrenic patients should be encouraged to stop smoking. Previous Next Diet and Activity Many psychotropic medications can cause weight gain and changes in glucose or lipid metabolism. Occasionally, a person with schizophrenia develops odd food preferences. Finally, many persons with schizophrenia have limited funds, do not cook for themselves, and live in areas where fast food outlets are abundant. Therefore, nutritional counseling is difficult but important. Because many psychotropic medications are associated with weight gain, and because of the many beneficial effects of exercise, persons with schizophrenia should be encouraged to be as physically active as possible. Previous Next Prevention Many have wondered whether patients with schizophrenia would have a better prognosis if treatment could be started as early as possible. A study from Scandinavia found that early detection and intervention in first-episode psychosis led to higher recovery and employment rates at 10-year follow-up.^[124] The North American Prodrome Longitudinal Study is exploring whether the incorporation of biologic measures into prediction algorithms can provide more accurate identification of young people who are at greatest risk for developing a psychotic disorder. The goal of this study is to establish objective criteria that can be used to develop preventive approaches. There are several studies of prodromal schizophrenia under way to inform early intervention strategies. In the absence of highly reliable methods of predicting schizophrenia, however, intervention during the prodromal stage could result in the unnecessary administration of antipsychotic medication to young people who are mistakenly identified as being at risk for schizophrenia.^[125] One approach to this problem is to use psychological therapies rather than pharmacotherapy. A German study of young people at risk for schizophrenia showed that the use of a psychological intervention involving cognitive-behavioral therapy, group skills training, cognitive remediation and multifamily psychoeducation delayed the onset of psychosis for at least 2 years.^[126] Previous Next Other Treatments An entirely different kind of treatment for schizophrenia, still in its early stages, is transcranial magnetic stimulation (TMS). TMS involves the electromagnetic induction of an electric field in the brain. Standard TMS affects neurons within 1.5-2 cm from the scalp, and deep TMS can affect cells to a depth of 6 cm. The electric field changes the “excitability” of the neurons and seems to be safe with few adverse effects. TMS is mostly used for depression. However, early work suggests that TMS, in some cases, may decrease auditory hallucinations^[127] and negative symptoms^[128] in schizophrenia. Previous Proceed to Medication Contributor Information and Disclosures Author Frances R Frankenburg, MD Professor, Department of Psychiatry, Boston University School of Medicine; Chief of Inpatient Psychiatry and Consulting Psychiatrist, Edith Nourse Rogers Memorial Veterans Administration Medical Center; Associate Psychiatrist, McLean Hospital Frances R Frankenburg, MD is a member of the following medical societies: Alpha Omega Alpha and American Psychiatric Association Disclosure: Nothing to disclose. Chief Editor Eduardo Dunayevich, MD Executive Director, Clinical Development, Amgen Eduardo Dunayevich, MD is a member of the following medical societies: American Psychiatric Association Disclosure: Lilly Research Laboratories Salary Other Additional Contributors Ronald C Albucher, MD Chief Medical Officer, Westside Community Services; Consulting Staff, California Pacific Medical Center Ronald C Albucher, MD is a member of the following medical societies: American Psychiatric Association Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment References 1. Cassels, C. Antipsychotic Linked to Potentially Fatal Skin Reaction. Medscape Medical News. Available at http://www.medscape.com/viewarticle/836427. Accessed December 13, 2014. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). 4^th ed. Washington, DC: American Psychiatric Press; 2000. 3. Wright IC, Rabe-Hesketh S, Woodruff PW, et al. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. Jan 2000;157(1):16-25. [Medline]. 4. Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia. Am J Psychiatry. Oct 2010;167(10):1178-93. [Medline]. 5. Mattai A, Hosanagar A, Weisinger B, Greenstein D, Stidd R, Clasen L. Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients. Am J Psychiatry. Apr 2011;168(4):427-35. [Medline]. 6. Sigmundsson T, Suckling J, Maier M, et al. Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. Am J Psychiatry. Feb 2001;158(2):234-43. [Medline]. 7. Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. Mar 2009;108(1-3):3-10. [Medline]. 8. McIntosh AM, Owens DC, Moorhead WJ, Whalley HC, Stanfield AC, Hall J, et al. Longitudinal volume reductions in people at high genetic risk of schizophrenia as they develop psychosis. Biol Psychiatry. May 15 2011;69(10):953-8. [Medline]. 9. Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. Jul 1 2011;70(1):88-96. [Medline]. 10. Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry. Jan-Feb 1996;3(5):241-53. [Medline]. 11. Cioffi CL. Modulation of NMDA receptor function as a treatment for schizophrenia. Bioorg Med Chem Lett. Jul 19 2013;[Medline]. 12. Drexhage RC, Weigelt K, van Beveren N, Cohen D, Versnel MA, Nolen WA, et al. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int Rev Neurobiol. 2011;101:169-201. [Medline]. 13. Fan X, Goff DC, Henderson DC. Inflammation and schizophrenia. Expert Rev Neurother. Jul 2007;7(7):789-96. [Medline]. 14. Selten JP, Cantor-Graae E, Kahn RS. Migration and schizophrenia. Curr Opin Psychiatry. Mar 2007;20(2):111-5. [Medline]. 15. Bourque F, van der Ven E, Malla A. A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med. May 2011;41(5):897-910. [Medline]. 16. Kirkbride J, Coid JW, Morgan C, et al. Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health. Jun 2010;9(2):4-14. [Medline]. 17. Kety SS, Wender PH, Jacobsen B, et al. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark. Arch Gen Psychiatry. Jun 1994;51(6):442-55. [Medline]. 18. Brooks M. New Schizophrenia Genes Identified. Medscape Medical News [serial online]. Jul 22 2014;Accessed Jul 29 2014. Available at http://www.medscape.com/viewarticle/828655. 19. Biological insights from 108 schizophrenia-associated genetic loci. Nature. Jul 24 2014;511(7510):421-7. [Medline]. 20. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. May 15 2005;57(10):1117-27. [Medline]. 21. Shifman S, Johannesson M, Bronstein M, et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. Feb 2008;4(2):e28. [Medline]. 22. Wratten NS, Memoli H, Huang Y, Dulencin AM, Matteson PG, Cornacchia MA, et al. Identification of a schizophrenia-associated functional noncoding variant in NOS1AP. Am J Psychiatry. April/2009;166:434-41. [Medline]. 23. O'Brien NL, Way MJ, Kandaswamy R, et al. The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder. Psychiatr Genet. Jul 18 2014;[Medline]. 24. Bassett AS, Costain G, Fung WL, Russell KJ, Pierce L, Kapadia R, et al. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. Nov 2010;44(15):1005-9. [Medline]. 25. Bassett AS, Scherer SW, Brzustowicz LM. Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry. Aug 2010;167(8):899-914. [Medline]. [Full Text]. 26. Owen MJ, O'Donovan MC, Thapar A, Craddock N. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry. Mar 2011;198:173-5. [Medline]. 27. Sahoo T, Theisen A, Rosenfeld JA, et al. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med. Oct 2011;13(10):868-80. [Medline]. 28. Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J, et al. Confirmation and refinement of an 'at-risk' haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. Mol Psychiatry. Feb 2004;9(2):208-13. [Medline]. 29. Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lönnqvist J, et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry. Nov 2004;9(11):1037-41. [Medline]. 30. Hennah W, Thomson P, McQuillin A, Bass N, Loukola A, Anjorin A, et al. DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry. Sep 2009;14(9):865-73. [Medline]. 31. Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med. May 2009;15(5):509-18. [Medline]. [Full Text]. 32. Kirov G, Ivanov D, Williams NM, Preece A, Nikolov I, Milev R, et al. Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria. Biol Psychiatry. May 15 2004;55(10):971-5. [Medline]. 33. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry. May 2001;6(3):293-301. [Medline]. 34. Morris DW, Rodgers A, McGhee KA, Schwaiger S, Scully P, Quinn J, et al. Confirming RGS4 as a susceptibility gene for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. Feb 15 2004;125B(1):50-3. [Medline]. 35. Schindler KM, Pato MT, Dourado A, Macedo A, Azevedo MH, Kennedy JL, et al. Association and linkage disequilibrium between a functional polymorphism of the dopamine-2 receptor gene and schizophrenia in a genetically homogeneous Portuguese population. Mol Psychiatry. 2002;7(9):1002-5. [Medline]. 36. Shifman S, Bronstein M, Sternfeld M, Pisanté-Shalom A, Lev-Lehman E, Weizman A, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet. Dec 2002;71(6):1296-302. [Medline]. [Full Text]. 37. Stefansson H, Sarginson J, Kong A, et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet. Jan 2003;72(1):83-7. [Medline]. [Full Text]. 38. Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, et al. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. Jan 2011;16(1):59-66. [Medline]. [Full Text]. 39. Tang JX, Chen WY, He G, Zhou J, Gu NF, Feng GY, et al. Polymorphisms within 5' end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol Psychiatry. Jan 2004;9(1):11-2. [Medline]. 40. Williams HJ, Norton N, Dwyer S, Moskvina V, Nikolov I, Carroll L, et al. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry. Apr 2011;16(4):429-41. [Medline]. 41. Xu B, Roos JL, Dexheimer P, et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet. Aug 7 2011;43(9):864-8. [Medline]. 42. Girard SL, Gauthier J, Noreau A, et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. Jul 10 2011;43(9):860-3. [Medline]. 43. Brooks M. De Novo Gene Mutations Linked to Schizophrenia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/819742.. Accessed February 4, 2014. 44. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. Jan 22 2014;[Medline]. 45. Ripke S, O'Dushlaine C, Chambert K, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. Oct 2013;45(10):1150-9. [Medline]. [Full Text]. 46. Lencz T, Guha S, Liu C, Rosenfeld J, Mukherjee S, Derosse P. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nat Commun. Nov 19 2013;4:2739. [Medline]. 47. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. Dec 2003;60(12):1187-92. [Medline]. 48. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. Mar 2010;167(3):261-80. [Medline]. 49. Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. Aug 2004;61 (8):774-80. [Medline]. 50. Torrey EF, Bowler AE, Rawlings R, Terrazas A. Seasonality of schizophrenia and stillbirths. Schizophr Bull. 1993;19(3):557-62. [Medline]. 51. Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M. Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry. Sep 2009;166(9):1025-30. [Medline]. 52. Anderson P. Teen Marijuana Use Linked to Earlier Psychosis Onset. Medscape Medical News [serial online]. May 14 2014;Accessed May 20 2014. Available at http://www.medscape.com/viewarticle/825131. 53. Bhugra D. The global prevalence of schizophrenia. PLoS Med. May 2005;2(5):e151; quiz e175. [Medline]. [Full Text]. 54. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. May 2005;2(5):e141. [Medline]. [Full Text]. 55. Haro JM, Novick D, Bertsch J, et al. Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry. Sep 2011;199:194-201. [Medline]. 56. Hor K, Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol. Nov 2010;24(4 Suppl):81-90. [Medline]. [Full Text]. 57. Hoang U, Stewart R, Goldacre MJ. Mortality after hospital discharge for people with schizophrenia or bipolar disorder: retrospective study of linked English hospital episode statistics, 1999-2006. BMJ. Sep 13 2011;343:d5422. [Medline]. [Full Text]. 58. Xia J, Merinder LB, Belgamwar MR. Psychoeducation for schizophrenia. Cochrane Database Syst Rev. Jun 15 2011;CD002831. [Medline]. 59. Hyde TM, Deep-Soboslay A, Iglesias B, et al. Enuresis as a premorbid developmental marker of schizophrenia. Brain. Sep 2008;131:2489-98. [Medline]. [Full Text]. 60. Jones P, Rodgers B, Murray R, Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. Nov 19 1994;344(8934):1398-402. [Medline]. 61. Ho BC, Andreasen NC. Long delays in seeking treatment for schizophrenia. Lancet. Mar 24 2001;357(9260):898-900. [Medline]. 62. Green AI, Drake RE, Brunette MF, Noordsy DL. Schizophrenia and co-occurring substance use disorder. Am J Psychiatry. Mar 2007;164(3):402-8. [Medline]. 63. Foti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization. Am J Psychiatry. Aug 2010;167(8):987-93. [Medline]. 64. Yücel M, Bora E, Lubman DI, et al. The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample. Schizophr Bull. Mar 2012;38(2):316-30. [Medline]. [Full Text]. 65. Brauser D. Cannabis Not the Only Illicit Drug Linked to Schizophrenia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/807520. Accessed July 17, 2013. 66. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord. Sep 1982;4(3):173-93. [Medline]. 67. Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry. Sep 2010;197(3):174-9. [Medline]. 68. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. Jan 2003;60(1):82-91. [Medline]. 69. Shioiri T, Shinada K, Kuwabara H, Someya T. Early prodromal symptoms and diagnoses before first psychotic episode in 219 inpatients with schizophrenia. Psychiatry Clin Neurosci. Aug 2007;61(4):348-54. [Medline]. 70. Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open. 2012;2(1):e000850. [Medline]. [Full Text]. 71. Tiihonen J, Suokas JT, Suvisaari JM, Haukka J, Korhonen P. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry. May 2012;69(5):476-83. [Medline]. 72. Bennett DJ, Ogloff JR, Mullen PE, et al. Schizophrenia disorders, substance abuse and prior offending in a sequential series of 435 homicides. Acta Psychiatr Scand. Sep 2011;124(3):226-33. [Medline]. 73. Fazel S, Långström N, Hjern A, Grann M, Lichtenstein P. Schizophrenia, substance abuse, and violent crime. JAMA. May 20 2009;301(19):2016-23. [Medline]. 74. Cummings JL, Gosenfeld LF, Houlihan JP, McCaffrey T. Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia. Biol Psychiatry. May 1983;18(5):591-601. [Medline]. 75. Rosebush PI, MacQueen GM, Clarke JT, et al. Late-onset Tay-Sachs disease presenting as catatonic schizophrenia: diagnostic and treatment issues. J Clin Psychiatry. Aug 1995;56(8):347-53. [Medline]. 76. Pope HG Jr, Katz DL. Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry. May 1994;51(5):375-82. [Medline]. 77. Reuler JB, Girard DE, Cooney TG. Current concepts. Wernicke's encephalopathy. N Engl J Med. Apr 18 1985;312(16):1035-9. [Medline]. 78. Salokangas RK. Medical problems in schizophrenia patients living in the community (alternative facilities). Curr Opin Psychiatry. Jul 2007;20(4):402-5. [Medline]. 79. Brauser D. Long-term Injectable Drug Effective for Schizophrenia. Medscape Medical News [serial online]. May 11 2012;Accessed Apr 5 2013. Available at http://www.medscape.com/viewarticle/763689. 80. Cassels C. FDA Approves Once-Monthly Treatment for Schizophrenia. Medscape Medical News [serial online]. Mar 1 2013;Accessed Apr 5 2013. Available at http://www.medscape.com/viewarticle/780106. 81. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. May 2012;73(5):617-24. [Medline]. [Full Text]. 82. Citrome L. New second-generation long-acting injectable antipsychotics for the treatment of schizophrenia. Expert Rev Neurother. Jul 2013;13(7):767-83. [Medline]. 83. Lieberman JA, Stroup TS. The NIMH-CATIE Schizophrenia Study: what did we learn?. Am J Psychiatry. Aug 2011;168(8):770-5. [Medline]. 84. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. Oct 2006;63(10):1079-87. [Medline]. 85. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. Mar 29 2008;371(9618):1085-97. [Medline]. 86. McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. Jul 2007;164(7):1050-60. [Medline]. 87. [Guideline] Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. Jan 2010;36(1):71-93. [Medline]. [Full Text]. 88. Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. 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. Sep 2013;70(9):913-20. [Medline]. 89. Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. May 2003;28(5):995-1003. [Medline]. 90. Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM. Clozapine as a first treatment for schizophrenia. Am J Psychiatry. Aug 2003;160(8):1514-6. [Medline]. 91. Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. Nov 2007;68(11):1751-62. [Medline]. 92. Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. Nov 2011;72(11):1439-44. [Medline]. 93. Essock SM, Schooler NR, Stroup TS, McEvoy JP, Rojas I, Jackson C, et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry. Jul 2011;168(7):702-8. [Medline]. 94. Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. Mar 2009;35(2):443-57. [Medline]. [Full Text]. 95. Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. Jan 2012;73(1):13-20. [Medline]. 96. Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S. Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. Nov 18 2013;11:CD006625. [Medline]. 97. Rosenheck RA, Krystal JH, Lew R, Barnett PG, Fiore L, Valley D, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med. Mar 3 2011;364(9):842-51. [Medline]. 98. Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, et al. Long-Acting Injectable vs Oral Antipsychotics for Relapse Prevention in Schizophrenia: A Meta-Analysis of Randomized Trials. Schizophr Bull. Jan 2 2013;[Medline]. 99. Subotnik KL, Nuechterlein KH, Ventura J, et al. Risperidone nonadherence and return of positive symptoms in the early course of schizophrenia. Am J Psychiatry. Mar 2011;168(3):286-92. [Medline]. 100. Takeuchi H, Suzuki T, Remington G, et al. Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. Schizophr Bull. Sep 2013;39(5):993-8. [Medline]. [Full Text]. 101. Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. Nov 2001;158(11):1774-82. [Medline]. 102. Strom BL, Eng SM, Faich G, Reynolds RF, D'Agostino RB, Ruskin J, et al. Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). Am J Psychiatry. Feb 2011;168(2):193-201. [Medline]. 103. Vieweg WV. New Generation Antipsychotic Drugs and QTc Interval Prolongation. Prim Care Companion J Clin Psychiatry. Oct 2003;5(5):205-215. [Medline]. [Full Text]. 104. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68 Suppl 1:20-7. [Medline]. 105. [Best Evidence] Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. Oct 2010;197(4):266-71. [Medline]. 106. Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry. Sep 2011;168(9):947-56. [Medline]. 107. Wang M, Tong JH, Zhu G, Liang GM, Yan HF, Wang XZ. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. Jun 2012;138(1):54-7. [Medline]. 108. Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine. Lancet. Apr 1 2000;355(9210):1155-6. [Medline]. 109. Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic drugs and venous thromboembolism. Lancet. Jul 15 2000;356(9225):252. [Medline]. 110. Lowry F. Psychotropic Drugs Can Reduce Bone Mass in Kids. Medscape Medical News [serial online]. Jun 24 2014;Accessed Jul 2 2014. Available at http://www.medscape.com/viewarticle/827275. 111. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. Feb 2011;68(2):128-37. [Medline]. 112. Kern RS, Glynn SM, Horan WP, Marder SR. Psychosocial treatments to promote functional recovery in schizophrenia. Schizophr Bull. Mar 2009;35(2):347-61. [Medline]. [Full Text]. 113. [Guideline] Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW, et al. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull. Jan 2010;36(1):48-70. [Medline]. [Full Text]. 114. Guo X, Zhai J, Liu Z, Fang M, Wang B, Wang C, et al. Effect of antipsychotic medication alone vs combined with psychosocial intervention on outcomes of early-stage schizophrenia: A randomized, 1-year study. Arch Gen Psychiatry. Sep 2010;67(9):895-904. [Medline]. 115. Wexler BE, Bell MD. Cognitive remediation and vocational rehabilitation for schizophrenia. Schizophr Bull. Oct 2005;31(4):931-41. [Medline]. 116. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. May 2011;168(5):472-85. [Medline]. 117. Grant PM, Huh GA, Perivoliotis D, Stolar NM, Beck AT. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry. Feb 2012;69(2):121-7. [Medline]. 118. Puig O, Penadés R, Baeza I, De la Serna E, Sánchez-Gistau V, Bernardo M, et al. Cognitive remediation therapy in adolescents with early-onset schizophrenia: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. Aug 2014;53(8):859-68. [Medline]. 119. Brooks, M. Cognitive Therapy a Viable Monotherapy for Schizophrenia?. Medscape Medical News. Available at http://www.medscape.com/viewarticle/820258. Accessed February 19, 2014. 120. Morrison, Anthony P., Turkington, D., Pyle, M., et al. Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial. The Lancet. February 2014;[Full Text]. 121. Bond GR, Drake RE. Making the Case for IPS Supported Employment. Adm Policy Ment Health. Nov 17 2012;[Medline]. 122. McHugo GJ, Drake RE, Xie H, Bond GR. A 10-year study of steady employment and non-vocational outcomes among people with serious mental illness and co-occurring substance use disorders. Schizophr Res. Jul 2012;138(2-3):233-9. [Medline]. 123. Pharoah F, Mari J, Rathbone J, Wong W. Family intervention for schizophrenia. Cochrane Database Syst Rev. Dec 8 2010;CD000088. [Medline]. 124. Hegelstad WT, Larsen TK, Auestad B, Evensen J, Haahr U, Joa I, et al. Long-term follow-up of the TIPS early detection in psychosis study: effects on 10-year outcome. Am J Psychiatry. Apr 2012;169(4):374-80. [Medline]. 125. Weiser M. Early intervention for schizophrenia: the risk-benefit ratio of antipsychotic treatment in the prodromal phase. Am J Psychiatry. Aug 2011;168(8):761-3. [Medline]. 126. Bechdolf A, Wagner M, Ruhrmann S, Harrigan S, Putzfeld V, Pukrop R, et al. Preventing progression to first-episode psychosis in early initial prodromal states. Br J Psychiatry. Jan 2012;200(1):22-9. [Medline]. 127. Rosenberg O, Gersner R, Klein LD, Kotler M, Zangen A, Dannon P. Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. Ann Gen Psychiatry. May 6 2012;11:13. [Medline]. [Full Text]. 128. Levkovitz Y, Rabany L, Harel EV, Zangen A. Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study. Int J Neuropsychopharmacol. Aug 2011;14(7):991-6. [Medline]. 129. Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med. Mar 14 1991;324(11):746-54. [Medline]. 130. Brauser D. Psychosocial Interventions May Help Nip Psychosis in the Bud. Medscape Medical News. Available at http://www.medscape.com/viewarticle/829526. Accessed August 9, 2014. 131. Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic Risk in Patients With First-Episode Schizophrenia Spectrum Disorders: Baseline Results From the RAISE-ETP Study. JAMA Psychiatry. Oct 8 2014. 132. [Best Evidence] Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. Jan 21 2009;CD000059. [Medline]. 133. Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. Nov 2014;75(11):1254-60. [Medline]. [Full Text]. 134. Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. Nov 2014;75(11):1254-60. [Medline]. 135. Keller DM. Parkinsonism a major mortality risk factor in schizophrenia. Medscape Medical News [serial online]. March 5, 2014;Accessed March 7, 2014. Available at http://www.medscape.com/viewarticle/821492. 136. Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. Feb 2012;14(1):31-40. [Medline]. 137. Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. Jan 2011;198(1):51-8. [Medline]. [Full Text]. 138. Lowry F. Rapid Rise in Cardiometabolic Risk in Early Schizophrenia. Medscape Medical News [serial online]. Oct 14 2014;Accessed Oct 15 2014. Available at http://www.medscape.com/viewarticle/833223. 139. Miklowitz DJ, O'Brien MP, Schlosser DA, Addington J, Candan KA, Marshall C, et al. Family-focused treatment for adolescents and young adults at high risk for psychosis: results of a randomized trial. J Am Acad Child Adolesc Psychiatry. Aug 2014;53(8):848-58. [Medline]. [Full Text]. 140. Schoepf D, Uppal H, Potluri R, Heun R. Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. Presented at: The 22nd European Congress of Psychiatry (EPA); March 3, 2014; Munich, Germany. Abstract FC07. Eur Arch Psychiatry Clin Neurosci. Feb 2014;264(1):3-28. [Medline]. [Full Text]. Previous Next Cortical activation patterns during verbal working memory maintenance. Healthy controls (A), patients with schizophrenia (B), and significantly different activation between groups (subtraction of SZ-CO) (C) are shown. The time series plots in the middle column show activation associated with true memory maintenance (red lines) relative to the baseline activities (blue line). Bright parts in the middle of each plot represent 1-volume (1.5 s) after onset, and offset of the maintenance phase (4.5 secs). All p-values are corrected with false discovery rate of q< 0.005. Image courtesy of Kim J, Matthews NL, and Park S. An event-related fMRI study of phonological verbal working memory in schizophrenia. PLoS One. 2010; 5(8): e12068. Cortical activation patterns during false memory trials. (A) False memory, baseline in controls (CO). (B) False memory, baseline in schizophrenia (SZ). (C) SZ – CO. All p-values are corrected with a false discovery rate of q< 0.005. The time course plots show false memory-related activities (yellow) and true memory-related activities (red) relative to the baseline (blue). Image courtesy of Kim J, Matthews NL, and Park S. An event-related fMRI study of phonological verbal working memory in schizophrenia. PLoS One. 2010; 5(8): e12068. Magnetic resonance imaging showing differences in brain ventricle size in twins. The twin on the right has schizophrenia, whereas the twin on the left does not. Image courtesy of Dr. Daniel Weinberger, Clinical Brain Disorders Branch, National Institutes of Health. Previous Next View Table List Read more about Schizophrenia on Medscape Related Reference Topics * Emergent Treatment of Schizophrenia * Childhood-Onset Schizophrenia * Schizophreniform Disorder Related News and Articles * Feasibility, Acceptability, and Preliminary Efficacy of a Smartphone Intervention for Schizophrenia * Brain Structure Correlates of Urban Upbringing, an Environmental Risk Factor for Schizophrenia * Positive Topline Phase 2 Results for Novel Schizophrenia Drug Medscape Reference © 2011 WebMD, LLC * print Print * Share Share Email Twitter Facebook About Medscape Drugs & Diseases [ CLOSE WINDOW ] About Medscape Drugs & Diseases Medscape's clinical reference is the most authoritative and accessible point-of-care medical reference for physicians and healthcare professionals, available online and via all major mobile devices. All content is free. The clinical information represents the expertise and practical knowledge of top physicians and pharmacists from leading academic medical centers in the United States and worldwide. The topics provided are comprehensive and span more than 30 medical specialties, covering: Diseases and Conditions More than 6000 evidence-based and physician-reviewed disease and condition articles are organized to rapidly and comprehensively answer clinical questions and to provide in-depth information in support of diagnosis, treatment, and other clinical decision-making. Topics are richly illustrated with more than 40,000 clinical photos, videos, diagrams, and radiographic images. Procedures More than 1000 clinical procedure articles provide clear, step-by-step instructions and include instructional videos and images to allow clinicians to master the newest techniques or to improve their skills in procedures they have performed previously. Anatomy More than 100 anatomy articles feature clinical images and diagrams of the human body's major systems and organs. The articles assist in the understanding of the anatomy involved in treating specific conditions and performing procedures. They can also facilitate physician-patient discussions. Drug Monographs More than 7100 monographs are provided for prescription and over-the-counter drugs, as well as for corresponding brand-name drugs, herbals, and supplements. Drug images are also included. Drug Interaction Checker Our Drug Interaction Checker provides rapid access to tens of thousands of interactions between brand and generic drugs, over-the-counter drugs, and supplements. Check mild interactions to serious contraindications for up to 30 drugs, herbals, and supplements at a time. Formulary Information Access health plan drug formulary information when looking up a particular drug, and save time and effort for you and your patient. Choose from our complete list of over 1800 insurance plans across all 50 US states. Customize your Medscape account with the health plans you accept, so that the information you need is saved and ready every time you look up a drug on our site or in the Medscape app. Easily compare tier status for drugs in the same class when considering an alternative drug for your patient. Medical Calculators Medscape Reference features 129 medical calculators covering formulas, scales, and classifications. Plus, more than 600 drug monographs in our drug reference include integrated dosing calculators. Image Collections Hundreds of image-rich slideshow presentations visually engage and challenge readers while expanding their knowledge of both common and uncommon diseases, case presentations, and current controversies in medicine. MEDLINE Click on citations within drug and disease topics in our clinical reference to review the clinical evidence on MEDLINE. Plus, search the MEDLINE database for journal articles. Medscape is the leading online destination for healthcare professionals seeking clinical information. In addition to clinical reference tools, Medscape offers: Medical News Learn more Continuing Medical Education Learn more [060214_usAcq_ref_v1_300x140.jpg] * About Medscape * Privacy Policy * Terms of Use * WebMD * MedicineNet * eMedicineHealth * RxList * WebMD Corporate * Help All material on this website is protected by copyright, Copyright © 1994-2015 by WebMD LLC. This website also contains material copyrighted by 3rd parties. DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill. * * * * * more (Close) Close IFRAME: VPTrackFrame