Schizophrenia Treatment & Management

The use of antipsychotic medications, also known as neuroleptic medication or major tranquilizers, is the mainstay of treatment for schizophrenia. These medications have repeatedly been shown to diminish the positive symptoms of schizophrenia and prevent relapses. Approximately 80% of patients relapse within 1 year if antipsychotic medications are stopped, while only 20% relapse if treated.

The first antipsychotic medications were dopamine 2 antagonists, such as chlorpromazine and haloperidol. Medications that are similar to these are known as first-generation, typical, or conventional antipsychotics. Other antipsychotics, beginning with clozapine, are known as second-generation, atypical, or novel antipsychotics. 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.

The choice of which drug to use in schizophrenia depends on numerous issues, such as effectiveness, cost, side-effect burden, method of delivery, availability, and tolerability. Many studies are funded by pharmaceutical companies and compare antipsychotic drugs to one another. Little consensus has been reached.

For some years it was believed that the newer drugs were more effective, but that belief is now fading. The exception is clozapine, which consistently outperforms the other antipsychotic drugs. An influential study has been the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). This is a large study funded by the federal government to examine the effectiveness of several different antipsychotic drugs in more than 1400 patients. By multiple measures, perphenazine, a first-generation drug, was almost or about as good as the second-generation drugs.^[32]

In a study from the United Kingdom, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), more than 200 patients who were about to change antipsychotic medication were randomly assigned to either a first-generation or second-generation agent. In this study, the first-generation drugs seemed to perform slightly better than the newer ones. Clozapine was the exception, in that it outperformed all of the other drugs.^[33]

In a large study from Finland, researchers used a database to review the effectiveness of antipsychotic agents in the treatment of 2600 people after their first episode of schizophrenia.^[34] The study found that slightly less than half of patients continued treatment for longer than 30 days after discharge. With respect to rehospitalization, patients treated with depot haloperidol did the best, followed by those treated with clozapine. Patients treated with depot haloperidol, perphenazine, or risperidone stayed on these medications longer than those treated with the oral equivalents and had a lower rehospitalization rate.

These findings are difficult to translate to practice in the United States for a few reasons. Medical care is delivered differently in Finland, with the cost of antipsychotic medication fully reimbursed, according to the authors. The average age at admission was 38 years, which is much older than is expected for the first episode. Finally, depot perphenazine and zuclopenthixol are not available in the United States. Depot olanzapine was not used. However, the authors’ findings that patients who had their first episode did best in terms of avoiding more hospitalizations when treated with depot haloperidol or clozapine are noteworthy.

The following adverse effects are those typically associated with conventional antipsychotic agents or with risperidone, a novel antipsychotic agent, at doses greater than 6 mg/d.

• Akathisia is a subjective sense of inner restlessness, mental unease, irritability, and dysphoria.
• Dystonia is the occurrence of painful and frightening muscle cramps that usually occur within 12-48 hours of the beginning of treatment or an increase in dose. This typically occurs in young muscular men. It affects the head and neck, but it may extend to the trunk and limbs.
• Hyperprolactinemia (high levels of prolactin) is associated with galactorrhea, amenorrhea, gynecomastia, impotence, and osteoporosis.
• Neuroleptic malignant syndrome is marked by fever, muscular rigidity, altered mental state, and autonomic instability. Laboratory findings include increased creatine kinase and myoglobinuria. Acute renal failure may be present. A significant mortality rate exists. Rarely, neuroleptic malignant syndrome associated with clozapine and other atypical antipsychotic agents has been reported.
• Parkinsonism presents with tremor, bradykinesia, akinesia, and, sometimes, rigidity or bradyphrenia (slowed thinking). This occurs particularly in women and elderly patients.
• The incidence of tardive dyskinesia (TD) is as high as 70% in elderly patients. It presents as 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 and/or "jerky" speech. The patient is often not aware of these movements. Risk factors for TD include age, female sex, and negative symptoms. Duration of therapy and dose seem to be logical risk factors, but this has not been demonstrated conclusively. TD is probably less common with the use of novel antipsychotic drugs but, until many patients have been exposed to these drugs for several years, this will not be known with certainty.

The following adverse effects may occur with all antipsychotic agents, except as noted.

• Anticholinergic side effects include dry mouth, exacerbation of glaucoma, confusion, decreased memory, agitation, visual hallucinations, and constipation. Risperidone, aripiprazole, and ziprasidone are relatively free of anticholinergic adverse effects.
• The QT interval is the electrocardiogram interval between the beginning of the QRS complex and the end of the T wave. It reflects the time required for the ventricles to depolarize and repolarize. When the QT interval is corrected for heart rate, it is called QTc. A prolonged QTc interval puts a person at risk for torsade 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. Risk is increased by individual susceptibility, heart failure, bradycardias, electrolyte imbalance (especially hypokalemia), hypomagnesemia, and female gender.^[35]
• As of 2003, no novel antipsychotic agents had been reported to lead to torsade de pointes.
• In a large simple trial, more than 18,000 patients in 18 countries were randomly assigned to receive either ziprasidone or olanzapine. No cases of torsade de pointes were reported, although this event is so rare that this finding is not entirely surprising. No increase in nonsuicide mortality was reported. In particular, no increase in cardiac mortality was found, which is somewhat reassuring in terms of the cardiac safety of ziprasidone.^[36]
• Haloperidol has only a small influence on the ECG but it has been implicated, although very rarely, in causing torsades de pointes.^[37]
• All antipsychotic agents may be associated with esophageal dysmotility, aspiration, and the subsequent risk of pneumonia.
• Orthostatic hypotension can be problematic at the beginning of therapy, with dose increases, and in elderly patients. This is related to alpha1-blockade and is 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. The reasons for this possible association are not understood.^{[38, 39]}
• Altered glucose and lipid metabolism, with or without weight gain, may occur with most antipsychotic agents, as can weight gain itself.^[40] Aripiprazole and ziprasidone are the antipsychotic drugs least likely, and olanzapine and clozapine the most likely, to lead to these adverse effects. 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. Weight gain is associated both with psychological problems (eg, decreased self-esteem) and with medical problems (eg, diabetes, coronary artery disease, arthritis). Some approaches to the problem of weight gain include educational programs on nutrition and exercise, and cognitive behavioral therapy. Various medications have been tried but with little success.
• Kessing et al examined nearly 346,000 patient records where individuals purchased antipsychotics and nearly 1.5 million unexposed individuals registered in Denmark to compare risk for diabetes.^[41] Treatment with antipsychotics has been associated with an increased risk for diabetes. The rate ratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the rate ratio varied widely for second-generation antipsychotics (RR = 1.32; range, 1.17-1.57).

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 preparations. Most importantly, they are also available as depot preparations. In other countries, several different antipsychotic depot preparations exist, but, in the United States, only haloperidol and fluphenazine are available in depot forms. With respect to the newer agents, risperidone is now available as a long-acting injection (Risperdal Consta) that uses biodegradable polymers, and a long-acting olanzapine intramuscular injection also is available.

Therapeutic drug monitoring is the measurement of medication levels in the blood to ensure that the levels are in the therapeutic range. This is important in schizophrenia for several reasons.

• Patients may not always take their medications; checking the level can detect this.
• Patients may not always be the best reporters of their side effects, and medication levels can occasionally detect clinically silent toxicity.
• Smoking tobacco products induces the liver enzyme CYP1A2, which metabolizes a number of antipsychotic drugs. For example, patients who stop smoking while being treated with clozapine or olanzapine often experience an increase in their antipsychotic levels. (Nicotine patches and nicotine inhalers and chewing tobacco do not induce this enzyme.)

However, many medications do not have clear dose-response curves established. Plasma concentrations of haloperidol are somewhat correlated with clinical effects. levels of about 15-25 ng/mL are thought to be optimal. Plasma concentrations of clozapine of around 300-400 ng/mL may be optimal.

• Anticholinergic agents (eg, benztropine, procyclidine, trihexyphenidyl, diphenhydramine) or 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.
• Clozapine is the oldest atypical antipsychotic agent and probably the most effective.^[42] It is associated with about a 1% risk of agranulocytosis, so patients must have weekly white blood cell count monitoring for the first 6 months^[43] (the period of greatest risk) and then monitoring every 2 weeks for 6 months, and then every 4 weeks, as long as the absolute neutrophil count (ANC) is normal. (If the ANC drops, then a strict protocol of monitoring and possibly medication cessation must be followed). Clozapine is also associated with anticholinergic adverse effects, sedation, and drooling.^[43] Constipation and cardiac side effects (cardiomyopathy and myocarditis) can be life threatening. However, approximately one third of patients who have not responded to conventional antipsychotic agents do better on clozapine. Violence, substance abuse, smoking, and suicidality are diminished with the use of clozapine.

Many patients with schizophrenia are treated with other psychotropic medications in addition to antipsychotic agents. Very little rigorous evidence for the use of polypharmacy in schizophrenia exists, but it is widely practiced. Medications often used include the antidepressants, mood stabilizers, and anxiolytic agents. Note that carbamazepine and clozapine should not be used together.

Using 2 or even 3 different antipsychotic agents together is also common. Recent reports suggest that patients prefer this.^[44]

A recent meta-analysis of 19 studies involving more than 1200 subiects also found an advantage for antipsychotic polypharmacy.^[45]

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. Those patients treated with higher doses of antipsychotic medications seemed to lose gray matter throughout their brain (except the cerebellum); those treated with lower doses of antipsychotic medications seemed to have a small increase in white matter of the brain.^[46]

The clinical significance of these findings is unclear. Whether these changes are associated with any clinical symptoms directly or if the changes are reversible is unknown. Whether higher doses of medication were in response to the gray matter loss or the other way around is unclear.

No choice of antipsychotic medication in schizophrenia is clear. Clozapine is the most effective medication but is rarely initially used because it is so burdensome. It has not outperformed other medications in first-episode patients.^{[47, 48]}

Numerous guidelines or algorithms for the treatment of schizophrenia are available. Treatment guidelines are recommendations that need clinical judgment in their application and regular updating based on new evidence.^[49]

Few studies have examined the outcome of trials using these algorithms. In a study from Canada, Agid et al described the outcome of treatment among 244 patients with first-episode schizophrenia using a 2003 algorithm. If no response to the first antipsychotic trial 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. The patients who did not respond to either trial were offered clozapine, and 75% responded. Unanswered questions from this study include the role of first-generation antipsychotic medications, newer second-generation antipsychotic medications, and when clozapine should be used.^[50]

Psychological interventions

Psychosocial treatment for the person with schizophrenia is essential, since medications alone are insufficient. Psychosocial treatments are currently oriented according to the recovery model. The goal of treatment, according to this model, is for the person with schizophrenia to have few or stable symptoms, not be hospitalized, manage his or her own funds and medications, and either be in work or school at least half-time. Hope, empowerment, choice, and community integration are emphasized in this treatment approach.

The best studied psychosocial treatments are social skills training, cognitive behavioral therapy, cognitive remediation, and social cognition training.^[51]

In one study from China, the authors randomly assigned over a thousand patients with schizophrenia to either antipsychotic medication alone or medication with a psychosocial intervention. The authors chose an interesting way of delivering a psychosocial intervention. Each month, the patients and their families received a day of 4 types of evidence-based interventions: psychoeducation, family intervention, skills training, and cognitive behavior therapy. After a year, the patients in the group receiving the extra interventions were more compliant with their medications and had fewer rehospitalizations and greater quality of life.^[52]

Cognitive impairment, a core feature of schizophrenia, is less dramatic than other symptoms (eg, hallucinations, delusions) but can be more problematic with respect to work, social relationships, and independent living. Cognitive impairment responds poorly to medication. Cognitive remediation is a treatment modality that is based on principles of neuropsychological rehabilitation. It is based, in part, on the idea 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 emphasize drill practice of isolated cognitive skills with the aid of computers, whereas others help people to develop strategies to overcome 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. People improve across numerous cognitive functions, and changes are found on brain imaging that reflect these changes in brain functioning. These techniques are time-intensive and labor-intensive and seem to work best when individualized to the particular person. This is because cognitive deficits are multiple and vary from person to person. When combined with other therapies, such as supported employment, cognitive remediation leads to clinically relevant improvements.^[53] These effects are durable; the effects last even after the training has stopped.^[54]

In a study by Grant et al, low-functioning patients with prominent negative symptoms were assigned to recovery-oriented cognitive behavioral therapy or standard treatment. After 18 months, the authors found that both negative and positive symptoms had decreased. The study was not blind, and the treatment was delivered by enthusiastic doctoral level therapists, which may limit the generalizability of these findings.^[55]

Social work

Social work: 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 over involvement 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.^[56]

Vocational rehabilitation

Few patients with schizophrenia are able to maintain competitive employment. Supported employment programs are associated with higher rates of employment but not with increases in global functioning, self-esteem, time out of the hospital, or quality of life.

Many psychotropic medications are associated with weight gain and changes in glucose or lipid metabolism. Occasionally the person with schizophrenia develops odd food preferences. 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, persons with schizophrenia should be encouraged to be as physically active as possible.

• Most patients with schizophrenia smoke. This may be a result of previous conventional antipsychotic treatment because 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. The health risks from smoking are well known, and patients should be encouraged to stop smoking. Cessation of tobacco smoking, however, may result in the unexpected increase of clozapine levels.
• Involving people outside the usual medical settings is also helpful. 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. Patients with schizophrenia often have difficulty finding housing; therefore, working with associations that may provide housing assistance is important.