Sections

Treatment

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.^[79] A meta-analysis of 16 case-control studies comprising 15 samples (731 patients and 614 controls) found that individuals with first-episode schizophrenia had elevated fasting plasma glucose levels. Additionally, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, and insulin resistance (homeostatic model assessment of insulin resistance) were all significantly elevated in patients compared with controls. The results demonstrate that altered glucose homeostasis is present from illness onset, showing a direct link between schizophrenia and the development of diabetes.^[80]

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]

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, intramuscular (IM), and transdermal 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. Another second-generation agent, asenapine is available for transdermal use.^{[81, 82, 83, 84, 85]}

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.^[86]

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.^[87]

First-episode schizophrenia

According to the results of a year-long randomized controlled trial, starting a long-acting injectable (LAI) antipsychotic after a first episode of schizophrenia is more effective than starting an oral antipsychotic. The study included 86 patients with a recent first episode of schizophrenia who were randomly assigned to receive LAI risperidone (n = 43) or oral risperidone (n = 43) for 12 months. Study data showed that the LAI formulation of risperidone proved superior to oral risperidone on measures of relapse and symptom control. The psychotic exacerbation and/or relapse rate was 5% in the LAI risperidone group vs 33% in the oral risperidone group. Treatment with LAI risperidone also provided better control of hallucinations and delusions.^[88]

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.^[89]

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.^[90]

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.^[91]

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.^[91]

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.^[91]

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.^[92]

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.^{[93, 94]}

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.^[95]

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.^[96]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.^[96]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.^[97]A meta-analysis of 19 studies involving more than 1200 subjects found a modest advantage for antipsychotic polypharmacy.^[98]

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.^[99]

In a recent Cochrane review, authors studied quetiapine compared with other antipsychotics.^[100]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.^[91]

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. In the United States, several drugs have been approved for every 4-6 week dosing (eg, aripiprazole [Abilify Maintena, Aristada], paliperidone [Invega Sustenna]), every 2 month dosing (aripiprazole [Aristada 1064 mg dose]), and every 3 month dosing (eg, paliperidone [Invega Trinza]). 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.^[101]

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.^[102]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.^[103]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.^[104]

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.^[105]

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.^[106]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, typically at high doses and when given intravenously.^[107]

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.^[108]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).^[109]

Stroup et al studied 215 patients whose psychotic symptoms were stabilized on olanzapine, quetiapine, or risperidone.^[110]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.

In May 2021, the FDA approved a fixed-dose combination of olanzapine with samidorphan (Lybalvi). It is indicated for treatment of schizophrenia in adults. It is also approved for bipolar I disorder as monotherapy or as an adjunct to lithium or valproate. Olanzapine acts through a combination of dopamine and serotonin type 2 antagonism. Samidorphan is an opioid antagonist and mitigates weight gain associated with olanzapine.

Approval was based on the ENLIGHTEN clinical trials. Olanzapine is associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. The ENLIGHTEN trials showed the combination provided sustained antipsychotic efficacy with minimal effects on weight, waist circumference, and metabolic parameters.^[111]

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.^[112]

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 alpha₁ -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.^{[113, 114]}

Results from a prospective study indicated that in children and adolescents, long-term use of risperidone can negatively affect bone mass.^[115]

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.^[116]

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.

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.^[71]

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.^[117]PORT (see Antipsychotic Pharmacotherapy) also provides a detailed review of psychosocial interventions.^[118]

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.^[119]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.^[120]These effects are durable, lasting even after the training has stopped.^[121]

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.^[122]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.^[123]

Cognitive therapy may be effective as a standalone treatment for schizophrenia.^{[124, 125]}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.^{[124, 125]}

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.^{[124, 125]}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.^{[124, 125]}

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.^[126]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.^[127]

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.^[128]

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.

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.

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.^[129]

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.^[130]

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.^[131]

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^[132]and negative symptoms^[133]in schizophrenia.

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Media Gallery

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.