This section is an overview of key issues in the psychiatric management of patients with schizophrenia. It highlights areas that research has shown to be important in affecting the course of illness and success of treatment. These issues arise in the management of all psychiatric illnesses. This section notes the particular ways in which they occur in the treatment of patients with schizophrenia.

1. Assessing symptoms and establishing a diagnosis

Effective and appropriate treatments are based on accurate, relevant diagnostic and clinical assessments. In the case of schizophrenia, the diagnosis has major implications for short- and long-term treatment planning. (See Part B, Section IV.A, "Clinical Features," for a description of the characteristic symptoms of schizophrenia and the DSM-IV-TR criteria for diagnosis of the illness.) It is beyond the scope of this guideline to discuss the differential diagnosis of psychotic disorders and their evaluation. However, it is important to note that diagnosis is a process rather than a one-time event. As new information becomes available about the patient and his or her symptoms, the patient's diagnosis should be reevaluated and, if necessary, the treatment plan changed.

Proper diagnosis, while essential, is insufficient to adequately guide treatment of schizophrenia. Treatments are directed at the manifestations and sequelae of schizophrenia. It is critical to identify the targets of each treatment, to have outcome measures that gauge the effect of treatment, and to have realistic expectations about the degrees of improvement that constitute successful treatment. Depression, suicide, homelessness, substance use disorders, medical comorbidities, social isolation, joblessness, criminal victimization, past sexual or physical abuse, and involvement in the criminal justice system are all far more common among persons with schizophrenia, particularly in the chronic stages of the illness, than in the general population. In addition to the core symptoms of schizophrenia, these areas need careful assessment and, as warranted, appropriate interventions.

A number of objective, quantitative rating scales to monitor clinical status in schizophrenia are available, as described in the American Psychiatric Association's (APA's) Handbook of Psychiatric Measures (1). They include the Structured Clinical Interview for DSM-IV (2) for establishing diagnosis, the Abnormal Involuntary Movement Scale (3) for monitoring tardive dyskinesia and other abnormal movements, and the Brief Psychiatric Rating Scale (BPRS) (4–6) and the Positive and Negative Syndrome Scale (PANSS) (7) for monitoring psychopathology. Other brief structured assessments are also available (8, 9). There are several reasons that use of rating scales is important. First, rating scales provide a record that documents the patient's response to treatment. This record is of particular value when the treatment is nonstandard (e.g., combination of antipsychotics) or expensive. Second, the ratings can be compared with the patient's, family members', and clinician's impressions of treatment effects and over time can clarify the longitudinal course of the patient's illness. This process can help temper excessive optimism when new treatments are begun and can provide useful information about the actual effects of prior treatments. Third, use of anchored scales with criteria to assess the severity and frequency of symptoms helps patients become more informed self-observers. Finally, use of the rating scales over time ensures that information about the same areas is collected at each administration and helps avoid omission of key elements of information needed to guide treatment.

2. Developing a plan of treatment

After the assessment of the patient's diagnosis and clinical and psychosocial circumstances, a treatment plan must be formulated and implemented. This process involves the selection of the treatment modalities, specific type(s) of treatment, and treatment setting. Depending on the acuity of the clinical situation and because information about the patient's history and from the clinical evaluation may only gradually become available, this process can be iterative and evolve over the course of the patient's association with the clinician. Indeed, formulation and periodic reevaluation of the treatment plan at different phases of implementation and stages of illness are essential to good clinical practice. This process is described in greater detail in the subsequent sections on the various phases of illness, treatment settings, and types of treatments.

3. Developing a therapeutic alliance and promoting treatment adherence

It is essential for the psychiatrist who is treating the patient to establish and maintain a supportive therapeutic alliance, which forms the foundation on which treatment is conducted (10). Such an alliance allows the psychiatrist to gain essential information about the patient and allows the patient to develop trust in the psychiatrist and a desire to collaborate in treatment. To facilitate this process, continuity of care with the same psychiatrist over time is recommended, allowing the psychiatrist to learn more about the patient as a person and the individual vicissitudes of the disorder over time. However, while continuity is desirable, it does not ensure quality, and continuity of inadequate treatment can be highly problematic.

Research indicates that specific attention in the therapeutic relationship to identifying the patient's goals and aspirations and relating them to treatment outcomes increases treatment adherence (11). Moreover, evidence supports the conclusion that the most effective medication adherence strategies focus on the patient's attitudes and behaviors with respect to medication rather than taking a general psychoeducational approach (12).

Not uncommonly, patients with schizophrenia stop taking medications, miss clinic appointments, fail to report essential information to their psychiatrists, and otherwise choose to not participate in recommended treatments. To address partial or full treatment nonadherence, the clinician should first assess contributing factors. Potential factors can be broadly conceptualized under the health belief model, which assumes adherence behavior is dynamic and influenced by a patient's beliefs about need for treatment, the potential risks and benefits of treatment, barriers to treatment, and social support for adhering to treatment (13). Frequent causes of poor adherence are lack of insight (14), breakdown of the therapeutic alliance, discrimination associated with the illness, cultural beliefs, failure to understand the need to take daily medication even in the stable phase, cognitive impairment (15, 16), and experience of unpleasant medication side effects such as akathisia (17, 18). Most patients have some ambivalence about taking antipsychotic medications, all of which can be associated with unpleasant and, rarely, dangerous side effects. Even patients with good insight into their symptoms or illness may not perceive their prescribed medication as potentially or actually helpful. Patients who do experience troublesome or serious side effects may decide that these effects outweigh the benefits of medication. Finally, people important to the patient, including family and friends, may discourage the patient from taking medication or participating in other aspects of treatment.

Once the reasons for incomplete adherence are understood, clinical interventions can be implemented to address them. For example, encouraging the patient to report side effects and attempting to diminish or eliminate them can significantly improve medication adherence. Also, it is important for patients who are relatively asymptomatic in the stable phase to understand that medication may be prophylactic in preventing relapse (19, 20). If a patient stops taking medication during the stable phase, he or she may feel better, with less sedation or other side effects. As a result, the patient may come to the false conclusion that the medication is not necessary or does not have benefits. As will be described in later sections, psychotherapeutic techniques based on motivational interviewing and cognitive behavior techniques may enhance insight and treatment adherence. In situations in which patients choose not to adhere to prescribed psychosocial interventions, a careful review of the patient's perceptions of the goals of the treatment and its likelihood for success is recommended.

The clinician may also help to identify practical barriers to adherence, such as cognitive impairments or disorganization that interferes with a willing patient's regular taking of medication or participation in treatment. Use of simple aids, such as a pillbox placed in a prominent location in the home and a watch with an alarm, can enhance adherence. Family members and significant others can also be involved, for example, by helping the patient fill the pillbox and by regularly monitoring adherence. Patients without health care insurance may have difficulty affording even generic antipsychotics or basic psychosocial services. The clinician may help with access to medications by suggesting and completing the physician's sections of the application for patients' assistance programs offered by most pharmaceutical companies. Some patients may not have transportation to the pharmacy or to physician appointments and other treatment services. For patients who are parents, lack of child care may also pose a barrier to attending appointments.

For some patients, medication with a longer elimination half-life or long-acting injectable medications are options that may improve treatment adherence or minimize nonadherence. It is also important to note that the half-lives of oral antipsychotic medications vary widely. For patients who are prone to forget doses or are intermittently nonadherent to treatment, drugs with slower rates of metabolism may be used preferentially.

When a patient does not appear for appointments or is nonadherent in other ways, assertive outreach, including telephone calls and home visits, when appropriate, may be very helpful in reengaging the patient in treatment. This outreach can be carried out by the psychiatrist or other designated team member (e.g., of an assertive community treatment team), when available, in consultation with the psychiatrist. For some patients, nonadherence with care is frequent and is associated with repeated cycles of decompensation and rehospitalization. Particularly for patients who pose ongoing risks to self or others as a result of nonadherence, many states now have programs available for mandatory outpatient treatment (sometimes referred to as outpatient commitment). Although some have questioned whether mandatory outpatient treatment increases patients' reluctance to seek help voluntarily (21–23), a growing body of evidence suggests that a number of benefits may occur with mandatory outpatient treatment for appropriately selected patients when it incorporates intensive individualized outpatient services for an extended period of time. In addition to enhanced adherence, most (24–27) but not all (28) studies show mandatory outpatient treatment to be associated with benefits, including reductions in substance use and abuse, decreases in violent incidents, reductions in the likelihood of being criminally victimized, and improvements in quality of life in appropriately targeted patients. Thus, for a small subgroup of patients with repeated relapses and rehospitalizations associated with nonadherence, mandatory outpatient treatment can be a useful approach to improved adherence and enhanced outcomes (29).

4. Providing patient and family education and therapies

Working with patients to recognize early symptoms of relapse can result in preventing full-blown illness exacerbations (30). Family education about the nature of the illness and coping strategies can markedly diminish relapses and improve quality of life for patients (31). For general educational purposes, a variety of useful written materials about schizophrenia is available. The interventions that have been shown to be effective, however, involve face-to-face interactions in individual or group sessions for a total of at least 9–12 months, with the availability of crisis intervention and problem-solving tasks as a central element of the therapy.

5. Treating comorbid conditions

As already noted, a number of psychiatric, social, and other medical conditions occur far more frequently in persons with schizophrenia than in the general population. Periodic assessment of these conditions by the treatment team is important. Commonly co-occurring major depression, substance use disorders, and PTSD are usually identifiable through clinical examinations and discussions with the patient and significant others, combined with longitudinal observation of the patient's behavior patterns. Each of these conditions deserves attention and possibly treatment in its own right, with such treatment concurrent with that for schizophrenia. Substance use disorders, in particular, complicate assessment and treatment of schizophrenia, but delaying treatment of the psychotic disorder until the substance use disorder is under control is not recommended, as untreated psychosis is likely to be associated with increased substance use (32).

Section II.F.3, "Concurrent General Medical Conditions", discusses nonpsychiatric medical conditions that are commonly comorbid with schizophrenia. Certain illnesses, such as diabetes, are more common in persons with schizophrenia and have also been associated with some second-generation antipsychotic medications. Nicotine dependence is also common among persons with schizophrenia and contributes to the increased risk of physical illnesses (33, 34). It is important that patients have access to primary care clinicians who can work with the psychiatrist to diagnose and treat concurrent general medical conditions and that the psychiatrist maintain competence in screening for common medical conditions and for providing ongoing monitoring and treatment of common medical conditions in conjunction with primary care clinicians.

6. Attending to the patient's social circumstances and functioning

The social circumstances and functioning of the patient can have profound effects on adherence and response to treatment. The patient's living situation, family involvement, sources and amount of income, legal status, and relationships with significant others (including children) can both produce stress and be protective; thus, all are areas where periodic exploration by mental health care clinicians is warranted. A frequently neglected aspect of social assessment is the parenting role of patients with children (35, 36). The patient's sexuality is also often not adequately assessed, not only from the standpoint of adverse medication effects, but in terms of sexual relations and practices.

Depending on the nature of the problem in the patient's social circumstances, other mental health professionals may need to be involved in achieving its resolution. The psychiatrist can work with team members, the patient, and the family to ensure that such services are coordinated and that referrals for additional services are made when appropriate. It is important that disability income support is secured when indicated.

7. Integrating treatments from multiple clinicians

Many patients with schizophrenia require a variety of treatments, often from multiple clinicians. This requirement creates the potential for fragmentation of treatment efforts for patients who frequently have problems with planning and organizing. In many settings integration of treatments is best accomplished through designation of treatment teams, led by a psychiatrist or other skilled mental health professional, that meet periodically to review progress and goals and to identify obstacles to improvement. So-called case management, which provides the patient assistance in gaining access to community services and resources, is often useful to facilitate integration of treatments. Either several members of a team or one person can be assigned to be the case manager, ensuring that the patient receives coordinated, continuous, and comprehensive services. For example, the case manager may accompany the patient to a welfare agency, visit the patient's home if a clinical appointment is missed, or convene a meeting of workers from different agencies serving the patient to formulate an overall treatment plan in conjunction with the psychiatrist. There are a variety of educational and organizational approaches to building teams and programs that facilitate the goal of integrated treatment (37, 38).

8. Documenting treatment

Whether treated in the private or public sector, most persons with schizophrenia will have many different practitioners over the course of their illness. These transitions result from changes in treatment venues (inpatient, outpatient, assertive community treatment, etc.), program availability, insurance, the patient's locale, and clinic personnel. Because an accurate history of past and current treatments and responses to them is a key ingredient to treatment planning, excellent documentation is paramount. Especially critical, for example, is information about prior medication trials, including doses, length of time at specific doses, side effects, and clinical response. Despite the importance of an accurate history, studies of the adequacy of documentation (39) and clinical experience illustrate the extraordinary difficulty encountered in efforts to piece together a coherent story from the medical records of most patients with schizophrenia. Although actual chart documentation is the responsibility of the individual practitioner, it is typically the employing or contracting organization that is in the best position to facilitate good documentation and to effect periodic overviews of treatment. Appropriate documentation of assessment of competency, informed consent for treatment, and release of information also deserve careful attention by the clinician and the treatment organization.

Within the organization there are at least two major issues in information management. From the standpoint of information collection, the organization and its practitioners need to agree on the critical elements of information to obtain and the frequency with which they should be obtained. Recording of information may occur contemporaneously with collection or immediately thereafter. Labor-saving forms (paper or computer-based) may help in prompting data collection and easing its recording. Once information is collected, the ability to gain access to the information is essential. Thus, the organization will want to develop plans so that medical records will be available whenever and wherever the patient is seen. In addition, if the patient's care is transferred from one practitioner to another (e.g., outpatient to inpatient), necessary information will need to be transferred to the new practitioner ahead of or along with the patient. Release of a patient's information will generally require the patient's consent and should conform to applicable regulations and policies (e.g., state law, the Health Insurance Portability and Accountability Act, and Principles of Medical Ethics: With Annotations Especially Applicable to Psychiatry[40]).

The goals of treatment during the acute phase of a psychotic exacerbation are to prevent harm, control disturbed behavior, reduce the severity of psychosis and associated symptoms (e.g., agitation, aggression, negative symptoms, affective symptoms), determine and address the factors that led to the occurrence of the acute episode, effect a rapid return to the best level of functioning, develop an alliance with the patient and family, formulate short- and long-term treatment plans, and connect the patient with appropriate aftercare in the community. It is especially important to address the anxiety, fear, and dysphoria commonly associated with an acute episode. Efforts to engage and collaborate with family members and other natural caregivers are often successful during the crisis of an acute psychotic episode, whether it is the first episode or a relapse. Also, family members and other caregivers are often needed to provide support to the patient while he or she is recovering from an acute episode. The main therapeutic challenge for the clinician is to select and "titrate" the doses of both pharmacological and psychosocial interventions in accordance with the symptoms and sociobehavioral functioning of the patient (41). It is important to emphasize that acute-phase treatment is often but no longer necessarily associated with hospitalization. With the growth of managed care restricting the use of hospitalization and the development of alternative community-based programs, acute-phase treatment frequently occurs outside of the hospital.

1. Assessment in the acute phase

A thorough initial workup, including complete psychiatric and general medical histories and physical and mental status examinations, is recommended for all patients, as allowed by the patient's clinical status. Interviews of family members or other persons knowledgeable about the patient should be conducted routinely unless the patient refuses to grant permission, especially since many patients are unable to provide a reliable history at the first interview. In emergency circumstances, as when a patient's safety is at risk, it may be necessary and permissible to speak with others without the patient's consent.

When a patient is in an acute psychotic state, acutely agitated, or both, it may be impossible to perform an adequate evaluation at the time of the initial contact. With the patient's consent, the psychiatrist may begin treatment with an appropriate medication and perform the necessary evaluations as the patient's condition improves and permits. For acutely psychotic or agitated patients who lack the capacity or are unwilling to agree to receive medication, state regulations on involuntary treatment should be followed.

Some of the most common contributors to symptom relapse are antipsychotic medication nonadherence, substance use, and stressful life events (42–47). Medication adherence may be assessed by the patient's report, the reports of family members or other caregivers, pill counts, prescription refill counts, and, for some medications, antipsychotic blood levels. Attention needs to be given to potential drug-drug interactions that may affect blood levels and hence toxicity and adherence. Useful guides for determining potential adverse drug interactions related to the cytochrome P450 enzyme system are now available (48, 49). The reason for nonadherence should also be evaluated and considered in the treatment plan.

General medical health as well as medical conditions that could contribute to symptom exacerbation can be evaluated by medical history; physical and neurological examination; and appropriate laboratory, electrophysiological, and radiological assessments. Substance use should be routinely evaluated as part of the medical history and with a urine toxicology screen. It is important to realize that many drugs of abuse, including most designer drugs and hallucinogens, are not detected by urine toxicology screens; if use of such substances is suspected, a blood toxicology screen can detect some of them. Withdrawal from alcohol or some other substances can present as worsening psychosis, and the possibility of withdrawal should be evaluated by medical history and vital sign monitoring in all patients with acute exacerbation of symptoms. (The results of toxicology screens will usually be negative, since risk of withdrawal is often highest several days after abstinence from chronic abuse.) Body weight and vital signs (heart rate, blood pressure, temperature) should be measured. A CT or MRI scan may provide helpful information, particularly in assessing patients with a new onset of psychosis or with an atypical clinical presentation. Although imaging studies cannot establish a diagnosis of schizophrenia, specific findings from a CT or MRI scan (e.g., ventricular enlargement, diminished cortical volume) may enhance the confidence of the diagnosis and provide information that is relevant to treatment planning and prognosis. Given the subtle nature of the neuropathological findings in schizophrenia, MRI is preferred over CT.

Table 1 delineates suggested laboratory tests for evaluating health status, including studies that may be indicated when the clinical picture is unclear or when there are abnormal findings on routine examination, as well as suggested methods to monitor for side effects of treatment.

These tests may detect occult disease that is contributing to psychosis and also determine if there are comorbid medical conditions that might affect medication selection, such as impaired liver or renal function. Tests to assess other general medical needs of patients should also be considered (e.g., gynecological examination, mammogram, and rectal examination) (54). The U.S. Preventive Services Task Force has reviewed the evidence of effectiveness and developed recommendations for clinical preventive services (http://www.ahcpr.gov/clinic/uspstfix.htm).

It is also important that special precautions be taken in the presence of suicidal ideation or intent or a suicide plan, including an assessment of risk factors such as prior attempts, depressed mood, and suicidal ideation, which are the best predictors of a subsequent suicide attempt in schizophrenia (55, 56). Other predictors of suicide that also warrant close attention include the presence of command hallucinations, hopelessness, anxiety, extrapyramidal side effects, and an alcohol or other substance use disorder. Similar evaluations are necessary in considering the likelihood of dangerous or aggressive behavior and whether the person will harm someone else or engage in other forms of violence (57). The coexistence of substance use (58) significantly increases the risk of violent behavior. Because past behavior best predicts future behavior, family members and friends are often helpful in determining the risk of a patient's harming self or others and in assessing the patient's ability for self-care.

2. Psychiatric management in the acute phase

Psychosocial interventions in the acute phase are aimed at reducing overstimulating or stressful relationships, environments, or life events and at promoting relaxation or reduced arousal through simple, clear, coherent communication and expectations; a structured and predictable environment; low performance requirements; and tolerant, nondemanding, supportive relationships with the psychiatrist and other members of the treatment team.

The patient should be provided information on the nature and management of the illness that is appropriate to his or her ability to assimilate information. The patient should also be encouraged to collaborate with the psychiatrist in selecting and adjusting the medication and other treatments provided. Ordinarily, a hospitalized patient should be provided with some information about the disorder and the medications being used to treat it, including their benefits and side effects. As described in Section II.A.3, "Developing a Therapeutic Alliance and Promoting Treatment Adherence", the psychiatrist must realize that the degree of acceptance of medication and information about it will vary according to the patient's cognitive capacity, the extent of the patient's insight, and efforts made by the psychiatrist to engage the patient and the patient's family members in a collaborative treatment relationship.

The acute phase is also the best time for the psychiatrist to initiate a relationship with family members, who tend to be particularly concerned about the patient's disorder, disability, and prognosis during this phase and during hospitalization. Educational meetings, "survival workshops" that teach the family how to cope with schizophrenia, and referrals to the local chapter of NAMI may be helpful. The NAMI web site (http://www.nami.org) offers a wealth of useful information. Manuals, workbooks, and videotapes are also available to aid families in this process (59–64). Active efforts to involve relatives in treatment planning and implementation are often a critical component of treatment.

3. Use of antipsychotic medications in the acute phase

Treatment with antipsychotic medication is indicated for nearly all episodes of acute psychosis in patients with schizophrenia. In this guideline the term "antipsychotic" refers to several classes of medications (Table 2). These include the first-generation antipsychotic medications and the second-generation (sometimes referred to as "atypical") agents clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Pharmacological treatment should be initiated as soon as is clinically feasible, because acute psychotic exacerbations are associated with emotional distress, disruption to the patient's life, and a substantial risk of behaviors that are dangerous to self, others, or property (57, 68, 69). There are limited circumstances where it may be appropriate to delay treatment, for example, for patients who require more extensive or prolonged diagnostic evaluation, who refuse medications, or who may experience a rapid recovery because substance use or acute stress reactions are thought to be the potential cause of the symptom exacerbation.

Before treatment with antipsychotic medication is begun, baseline laboratory studies may be indicated, if they have not already been obtained as a part of the initial assessment (Table 1). In addition, the treating physician should, as is feasible, discuss the potential risks and benefits of the medication with the patient. The depth of this discussion will, of course, be determined by the patient's condition. Even with agitated patients and patients with thought disorder, however, the therapeutic alliance will be enhanced if the patient and physician can identify target symptoms (e.g., anxiety, poor sleep, and, for patients with insight, hallucinations and delusions) that are subjectively distressing and that antipsychotics can ameliorate. Acute side effects such as orthostatic hypotension, dizziness, and extrapyramidal side effects, including dystonic reactions, insomnia, or sedation, should be discussed at this stage, leaving discussion of long-term side effects to when the acute episode is resolving. Mentioning the possibility of acute side effects helps patients to identify and report their occurrence and also may help maintain a therapeutic alliance. To the extent possible, it is important to minimize acute side effects of antipsychotic medications, such as dystonia, that can significantly influence a patient's willingness to accept and continue pharmacological treatment. Patients with schizophrenia often have attentional and other cognitive impairments that may be more severe during an acute illness exacerbation, and so it is often helpful to return to the topic of identifying target symptoms and risk of acute side effects multiple times during the course of hospitalization.

Rapid initiation of emergency treatment is needed when an acutely psychotic patient is exhibiting aggressive behaviors toward self, others, or objects. When the patient is in an emergency department, inpatient unit, or other acute treatment facility, existing therapeutic protocols usually define the appropriate response. Most of these protocols recognize that the patient is usually frightened and confused and that the first intervention involves staff members talking to the patient in an attempt to calm him or her. Attempts to restrain the patient should be done only by a team trained in safe restraint procedures to minimize risk of harm to patients or staff (70). Antipsychotics and benzodiazepines are often helpful in reducing the patient's level of agitation (71). If the patient will take oral medication, rapidly dissolving forms of olanzapine and risperidone can be used for quicker effect and to reduce nonadherence. If a patient refuses oral medication, most states allow for emergency administration despite the patient's objection. Short-acting parenteral formulations of first- and second-generation antipsychotic agents (e.g., haloperidol, ziprasidone, and olanzapine), with or without a parenteral benzodiazepine (e.g., lorazepam), are available for emergency administration in acutely agitated patients (72–79). Use of rapidly dissolving oral formulations of second-generation agents (e.g., olanzapine, risperidone) or oral concentrate formulations (e.g., risperidone, haloperidol) may also be useful for acute agitation. Other medications, such as droperidol, can be used in selected clinical situations of extreme emergency or in highly agitated patients (80). However, if droperidol is used, its potential for cardiac rhythm disturbances must be considered, as indicated in its labeling by a black-box warning for QTc prolongation.

In nonemergency circumstances in which the patient is refusing medication, the physician may have limited options. When a patient refuses medication, it is often helpful to enlist family members as allies in helping the patient to accept medication. Often, patients can be helped to accept pharmacological treatment over time and with psychotherapeutic interactions that are aimed toward identifying subjectively distressing symptoms that have previously responded to treatment (12). Clinicians are encouraged to make greater use of the option of advance directives by patients in states where this option is available. Advance directives allow competent patients to state their preferences about treatment choices in the event of future decompensation and acute incapacity to make decisions. Depending on prevailing state laws, when treatment measures instituted on the basis of an advance directive fail, pharmacological treatment may be administered involuntarily even in the absence of acute dangerousness (81). In other instances, depending on state laws, a judicial hearing may need to be sought for permission to treat a patient who lacks capacity.

The process for determining pharmacological treatment in the acute phase is shown in Table 3 and Figure 1.

The selection of an antipsychotic medication is frequently guided by the patient's previous experience with antipsychotics, including the degree of symptom response, the side effect profile (including past experience of side effects such as dysphoria), and the patient's preferences for a particular medication, including the route of administration. The second-generation antipsychotics should be considered as first-line medications for patients in the acute phase of schizophrenia, mainly because of the decreased risk of extrapyramidal side effects and tardive dyskinesia (82–85), with the understanding that there continues to be debate over the relative advantages, disadvantages, and cost-effectiveness of first- and second-generation agents (86–89). For patients who have been treated successfully in the past or who prefer first-generation agents, these medications are clinically useful and for specific patients may be the first choice. With the possible exception of clozapine for patients with treatment-resistant symptoms, antipsychotics generally have similar efficacy in treating the positive symptoms of schizophrenia, although there is emerging evidence and ongoing debate that second-generation antipsychotics may have superior efficacy in treating global psychopathology and cognitive, negative, and mood symptoms. To date, there is no definitive evidence that one second-generation antipsychotic will have superior efficacy compared with another, although in an individual patient there may be clinically meaningful differences in response (89). A patient's past history of side effects can guide antipsychotic drug selection, since there is considerable difference in side effect profiles among the available antipsychotics. Table 4 lists the relative frequency of some adverse effects associated with selected antipsychotic medications. Strategies for the monitoring and clinical management of selected side effects of antipsychotic medications are outlined in Table 1 and discussed in detail in Part B, Section V.A.1, "Antipsychotic Medications."

While many patients prefer oral medication, patients with recurrent relapses related to partial or full nonadherence are candidates for a long-acting injectable antipsychotic medication, as are patients who prefer the injectable formulation (91). If a long-acting injectable medication is indicated, the oral form of the same medication (i.e., fluphenazine, haloperidol, and risperidone in the United States) is the logical choice for initial treatment during the acute phase. The transition from oral to long-acting injectable medication can begin during the acute phase; however, the long-acting injectable agents are not usually prescribed for acute psychotic episodes because these medications can take months to reach a stable steady state and are eliminated very slowly (92). As a result, the psychiatrist has relatively little control over the amount of medication the patient is receiving, and it is difficult to titrate the dose to control side effects and therapeutic effects. There may, however, be circumstances when it is useful to prescribe long-acting medications during acute treatment. For example, if a patient experiences an exacerbation of psychotic symptoms while receiving long-acting injectable medications, it may be useful to continue the long-acting injectable medication while temporarily supplementing it with oral medication (92).

Determining the optimal dose of antipsychotic medication in the acute phase is complicated by the fact that there is usually a delay between initiation of treatment and full therapeutic response. Patients may take between 2 and 4 weeks to show an initial response (93) and up to 6 months or longer to show full or optimal response. It is important to select a dose that is both effective and not likely to cause side effects that are subjectively difficult to tolerate, since the experience of unpleasant side effects may affect long-term adherence (see Section II.A.3, "Developing a Therapeutic Alliance and Promoting Treatment Adherence"). Some common early side effects such as sedation, postural hypotension, acute dystonia, or nausea will typically improve or resolve after the first several days or weeks of treatment, and patients can be encouraged to tolerate or temporarily manage these short-term effects. Other side effects, notably akathisia and parkinsonism, are likely to persist with long-term treatment. In general, the optimal dose (range) of medication is that which produces maximal therapeutic effects and minimal side effects. The optimal dose of first-generation antipsychotics (Table 2) is, for most patients, at the "EPS threshold," the dose that will induce extrapyramidal side effects and where a physical examination of the patient shows minimal rigidity (94). Evidence suggests that doses above this threshold increase risk of extrapyramidal and other side effects without enhancing efficacy (95–97). Second-generation antipsychotics can generally be administered at doses that are therapeutic yet well below the "EPS threshold." The target dose (Table 2) usually falls within the therapeutic dose range specified by the manufacturer and in the package labeling approved by the U.S. Food and Drug Administration (FDA). In clinical practice, however, doses of several second-generation drugs, including olanzapine, quetiapine, and ziprasidone, have extended above their recommended ranges. In determining the target dose, the psychiatrist should consider the patient's past history of response and dose needs, clinical condition, and severity of symptoms. Doses should be titrated as quickly as tolerated to the target therapeutic dose (generally sedation, orthostatic hypotension, and tachycardia are the side effects that limit the rate of increase), and unless there is evidence that the patient is having uncomfortable side effects, the patient's clinical status ideally should then be monitored for 2–4 weeks before increasing the dose or changing medications. During these weeks it is often important for the physician to be patient and avoid the temptation to prematurely escalate the dose for patients who are responding slowly. Rapid escalation can create the false impression of enhanced efficacy when time is often an important factor, and higher doses may actually be detrimental.

If the patient is not improving, consider whether the lack of response can be explained by medication nonadherence, rapid medication metabolism, or poor absorption. If the patient has been treated with one of the medications for which there are adequate data on blood level relationships with clinical response (e.g., clozapine, haloperidol), determination of the plasma concentration may be helpful. If nonadherence is a problem, behavioral tailoring (i.e., fitting taking medication into one's daily routine) (30), motivational interviewing, and other psychotherapeutic techniques may be useful in helping the patient develop an understanding of the potential benefits of medication (12, 98). In addition, surreptitious nonadherence (i.e., "cheeking") may be addressed by use of a liquid (e.g., risperidone, haloperidol), a quick-dissolving tablet (e.g., olanzapine, risperidone), or a short-acting intramuscular form (e.g., ziprasidone, haloperidol).

If the patient is adhering to treatment and has an adequate plasma concentration of medication but is not responding to the treatment, alternative treatments should be considered. If the patient is able to tolerate a higher dose of antipsychotic medication without significant side effects, raising the dose for a finite period, such as 2–4 weeks, can be tried, although the incremental efficacy of higher doses has not been well established. If dose adjustment does not result in an adequate response, a different antipsychotic medication should be considered.

4. Use of adjunctive medications in the acute phase

Other psychoactive medications are commonly added to antipsychotic medications in the acute phase to treat comorbid conditions or associated symptoms (e.g., agitation, aggression, affective symptoms), to address sleep disturbances, and to treat antipsychotic drug side effects. Therapeutic approaches to treatment resistance and residual symptoms are discussed in Section II.E, "Special Issues in Caring for Patients With Treatment-Resistant Illness".

Adjunctive medications are also commonly prescribed for residual symptoms and comorbid conditions during the acute phase. For example, benzodiazepines may be helpful in treating catatonia as well as in managing both anxiety and agitation. The most agitated patients may benefit from addition of an oral or a parenteral benzodiazepine to the antipsychotic medication. Lorazepam has the advantage of reliable absorption when it is administered either orally or parenterally (99). There is some evidence that mood stabilizers and beta-blockers may be effective in reducing the severity of recurrent hostility and aggression (100–102). Major depression and obsessive-compulsive disorder are common comorbid conditions in patients with schizophrenia and may respond to an antidepressant. However, some antidepressants (those that inhibit catecholamine reuptake) can potentially sustain or exacerbate psychotic symptoms in some patients (103). Careful attention must be paid to potential drug-drug interactions, especially those related to the cytochrome P450 enzymes (48, 49).

Sleep disturbances are common in the acute phase, and while controlled studies are lacking, there is anecdotal evidence that a sedating antidepressant (e.g., trazodone, mirtazapine) or a benzodiazepine sedative-hypnotic may be helpful.

Medications can be used to treat extrapyramidal side effects (Table 5) and other side effects of antipsychotic medications that are described in detail in Part B, Section V.A.1, "Antipsychotic Medications." Decisions to use medications to treat side effects are driven by the severity and degree of distress associated with the side effect and by consideration of other potential strategies, including lowering the dose of the antipsychotic medication or switching to a different antipsychotic medication. The following factors should be considered in decisions regarding the prophylactic use of antiparkinsonian medications in acute-phase treatment: the propensity of the antipsychotic medication to cause extrapyramidal side effects, the patient's preferences, the patient's prior history of extrapyramidal side effects, other risk factors for extrapyramidal side effects (especially dystonia), and risk factors for and potential consequences of anticholinergic side effects.

5. Use of ECT and other somatic therapies in the acute phase

ECT in combination with antipsychotic medications may be considered for patients with schizophrenia or schizoaffective disorder with severe psychotic symptoms that have not responded to treatment with antipsychotic agents. The efficacy of acute treatment with ECT in patients with schizophrenia has been described in a number of controlled trials as well as in multiple case series and uncontrolled studies (106–108). The greatest therapeutic benefits appear to occur when ECT is administered concomitantly with antipsychotic medications. The majority of studies, including several randomized studies, have shown benefit from ECT combined with first-generation antipsychotic agents (109–126). More recent findings also suggest benefit from combined treatment with ECT and second-generation antipsychotic medications (127–135). However, given the clear benefits of clozapine in patients with treatment-resistant psychotic symptoms, a trial of clozapine will generally be indicated before acute treatment with ECT.

Clinical experience, as well as evidence from case series and open prospective trials, suggests that ECT should also be considered for patients with prominent catatonic features that have not responded to an acute trial of lorazepam (136–143). For patients with schizophrenia and comorbid depression, ECT may also be beneficial if depressive symptoms are resistant to treatment or if features such as suicidal ideation and behaviors or inanition, which necessitate a rapid therapeutic response, are present.

For additional details on the assessment of patients before ECT, the informed consent process, the technical aspects of ECT administration, and the side effects associated with treatment, the reader is referred to APA's The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association (107).

Although it has been suggested that repetitive transcranial magnetic stimulation (rTMS) may share beneficial features of ECT (144, 145) and several recent studies with rTMS have shown promising results in decreasing auditory hallucinations (146–148), rTMS does not have an FDA indication for the treatment of psychosis, and additional research is needed before recommending its use in clinical practice.

During the stabilization phase, the aims of treatment are to sustain symptom remission or control, minimize stress on the patient, provide support to minimize the likelihood of relapse, enhance the patient's adaptation to life in the community, facilitate the continued reduction in symptoms and consolidation of remission, and promote the process of recovery.

Controlled trials provide relatively little guidance for medication treatment during this phase. If the patient has achieved an adequate therapeutic response with minimal side effects or toxicity with a particular medication regimen, he or she should be monitored while taking the same medication and dose for the next 6 months. Premature lowering of dose or discontinuation of medication during this phase may lead to a relatively rapid relapse. However, it is also critical to assess continuing side effects that may have been present in the acute phase and to adjust pharmacotherapy accordingly to minimize adverse side effects that may otherwise lead to medication nonadherence and relapse. Moreover, any adjunctive medications that have been used in the acute phase should be evaluated for continuation.

Psychotherapeutic interventions remain supportive but may be less structured and directive than in the acute phase. Education about the course and outcome of the illness and about factors that influence the course and outcome, including treatment adherence, can begin in this phase for patients and continue for family members. Educational programs during this phase have been effective in teaching a wide range of patients with schizophrenia the skills of medication self-management (e.g., the benefits of maintenance antipsychotic medication, how to cope with side effects) and symptom self-management (e.g., how to identify early warning signs of relapse, develop a relapse prevention plan, and refuse illicit drugs and alcohol), as well as strategies for interacting with health care providers (149–152).

It is important that there be no gaps in service delivery, because patients are vulnerable to relapse and need support in adjusting to community life. Not uncommonly, problems in continuity of care arise when patients are discharged from hospitals to community care. It is imperative to arrange for linkage of services between hospital and community treatment before the patient is discharged from the hospital. Short lengths of hospital stay create challenges for adequately linking inpatient to outpatient care, but to the extent possible, patients should have input into selecting their postdischarge follow-up residential and treatment plans. It is frequently beneficial to arrange an appointment with an outpatient psychiatrist and, for patients who will reside in a community residence, to arrange a visit before discharge (153, 154). After discharge, patients should be helped to adjust to life in the community through realistic goal setting without undue pressure to perform at high levels vocationally and socially, since unduly ambitious expectations on the part of therapists (20), family members (155), or others, as well as an overly stimulating treatment environment (156), can be stressful to patients and can increase the risk of relapse. These principles also apply in the stable phase. Efforts should be made to actively involve family members in the treatment process. Other psychosocial treatments, discussed in Section II.D, "Stable Phase"), may be initiated during this phase depending on the patient's level of recovery and motivation. While it is critical not to place premature demands on the patient regarding engagement in community-based activities and rehabilitation services, it is equally critical to maintain a level of momentum aimed at improving community functioning in order to instill a sense of hope and progress for the patient and family. These efforts set the stage for continuing treatments during the stable phase.

Treatment during the stable phase is designed to sustain symptom remission or control, minimize the risk and consequences of relapse, and optimize functioning and the process of recovery.

1. Assessment in the stable phase

Ongoing monitoring and assessment during the stable phase are necessary to determine whether the patient might benefit from alterations in the treatment program. Ongoing assessment allows patients and those who interact with them to describe any changes in symptoms or functioning and raise questions about specific symptoms and side effects.

Monitoring for adverse effects should be done regularly (Table 1). Clinicians should inquire about the course of any side effects that developed in the acute or stabilization phases (e.g., sexual side effects, sedation). Monitoring for other potential adverse effects should be guided by the particular medications chosen (see Part B, Section V.A.1, "Antipsychotic Medications,"

If the patient agrees, it is helpful to maintain strong ties with persons who interact with the patient frequently and would therefore be most likely to notice any resurgence of symptoms and the occurrence of life stresses and events that may increase the risk of relapse or impede continuing functional recovery. However, the frequency of assessments by the psychiatrist or other members of the treatment team depends on the specific nature of the treatment and expected fluctuations of the illness. Frequency of contacts may range from every few weeks for patients who are doing well and are stabilized to as often as every day for those who are going through highly stressful changes in their lives.

2. Psychosocial treatments in the stable phase

For most persons with schizophrenia in the stable phase, treatment programs that combine medications with a range of psychosocial services are associated with improved outcomes. Knowledge and research regarding how best to combine treatments to optimize outcome are scarce. Nonetheless, provision of such packages of services likely reduces the need for crisis-oriented care hospitalizations and emergency department visits and enables greater recovery.

A number of psychosocial treatments have demonstrated effectiveness. These treatments include family interventions (31, 157, 158), supported employment (159–162), assertive community treatment (163–166), social skills training (167–169), and cognitive behaviorally oriented psychotherapy (158, 170). An evidence-based practices project sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA) is developing resource kits on family interventions, assertive community treatment, and supported employment (draft versions available at http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/family/; http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/community/; http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/employment/).

In the same way that psychopharmacological management must be individually tailored to the needs and preferences of the patient, so too should the selection of psychosocial treatments. The selection of appropriate and effective psychosocial treatments needs to be driven by the circumstances of the individual patient's needs and his or her social context. At the very least, all persons with schizophrenia should be provided with education about their illness. Beyond needing illness education, most patients will also benefit from at least some of the recommended psychosocial interventions. However, since patients' clinical and social needs will vary at different points in their illness course and since some psychosocial treatments share treatment components, it would be rare for all of these psychosocial interventions to be utilized during any one phase of illness for an individual patient.

a) Prevention of relapse and reduction of symptom severity

A major goal during the stable phase is to prevent relapse and reduce the severity of residual symptoms. Certain psychosocial interventions have demonstrated effectiveness in this regard. They include family education and support, assertive community treatment, and cognitive therapy.

Interventions that educate families about schizophrenia, provide support, and offer training in effective problem solving and communication have been subjected to numerous randomized clinical trials (171, 172). The data strongly and consistently support the value of such interventions in reducing symptom relapse, and there is some evidence that these interventions contribute to improved patient functioning and family well-being. Randomized clinical trials have reported 2-year relapse rates for patients receiving family "psychoeducation" programs in combination with medication that are 50% lower than those for patients receiving medication alone (173–180). Further, a recent study found psychoeducational programs using multiple family groups to be more effective and less expensive than individual family psychoeducational interventions for Caucasians, though not for African Americans (178). On the basis of the evidence, persons with schizophrenia and their families who have ongoing contact with each other should be offered a family intervention, the key elements of which include a duration of at least 9 months, illness education, crisis intervention, emotional support, and training in how to cope with illness symptoms and related problems.

PACT is a specific model of community-based care. Its origin is an experiment in Madison, Wisconsin, in the 1970s in which the multidisciplinary inpatient team of the state hospital was moved into the community (181, 182). The team took with it all of the functions of an inpatient team: interdisciplinary teamwork, 24-hour/7-days-per-week coverage, comprehensive treatment planning, ongoing responsibility, staff continuity, and small caseloads. PACT is designed to treat patients who are at high risk for hospital readmission and who cannot be maintained by more usual community-based treatment as well as for patients with severe psychosocial impairment who need extensive assistance to live in the community. Randomized trials comparing PACT to other community-based care have consistently shown that PACT substantially reduces utilization of inpatient services and promotes continuity of outpatient care (183, 184). Patients' satisfaction with this model is generally high, and family advocacy groups, such as NAMI in the United States, strongly support its use and dissemination.

Results are less consistent regarding the effect of PACT on other outcomes, although at least some studies have shown enhancement of clinical status, functioning, and quality of life. Cost-effectiveness studies support its value in the treatment of high-risk patients. Studies also indicate that a particular PACT program's effectiveness is related to the fidelity with which it is implemented, that is, the degree to which the program adheres to the original PACT model.

Controlled studies of cognitive behavior psychotherapy have reported benefits in reducing the severity of persistent psychotic symptoms (170). Most of the studies have been performed with individual cognitive behavior therapy of at least several months' duration; in some studies, group cognitive behavior therapy and/or therapy of a shorter duration has been used. In all of the studies clinicians who provided cognitive behavior therapy received specialized training in the approach. In addition, the key elements of this intervention include a shared understanding of the illness between the patient and therapist, identification of target symptoms, and the development of specific cognitive and behavioral strategies to cope with these symptoms. Therefore, based on the available evidence, persons with schizophrenia who have residual psychotic symptoms while receiving adequate pharmacotherapy may benefit from cognitive behaviorally oriented psychotherapy.

A variety of other approaches to counseling individual patients to help them cope better with their illness are used, although research in this area remains limited. In general, counseling that emphasizes illness education, support, and problem solving is most appropriate. A notable prototype of this approach is personal therapy, as developed by Hogarty and colleagues (185–187). Personal therapy is an individualized long-term psychosocial intervention provided to patients on a weekly to biweekly frequency within the larger framework of a treatment program that provides pharmacotherapy, family work (when a family is available), and multiple levels of support, both material and psychological. The approach is carefully tailored to the patient's phase of recovery from an acute episode and the patient's residual level of severity, disability, and vulnerability to relapse.

b) Negative symptoms

During the stable phase, negative symptoms (e.g., affective flattening, alogia, avolition) may be primary and represent a core feature of schizophrenia, or they may be secondary to psychotic symptoms, a depressive syndrome, medication side effects (e.g., dysphoria), or environmental deprivation. The effectiveness of psychosocial treatments for reducing negative symptoms is not well studied. Furthermore, most research (for both psychosocial and pharmacological treatments) does not distinguish between primary and secondary negative symptoms. Thus, the generic term "negative symptoms" is used to summarize these findings. Some studies of cognitive behavior therapy report improvements in residual negative symptoms. In a review of three studies, Rector and Beck (188) reported a large aggregated effect size favoring cognitive behavior therapy over supportive therapy for reducing negative symptoms. Also, one study of family psychoeducation reported an improvement in negative symptoms with this intervention (189).

c) Improving functional status and quality of life

A primary treatment goal during the stable phase is to enable the patient to continue the recovery process and to achieve the goals of improved functioning and quality of life. To the degree to which active positive symptoms impair functional capacity, medications that reduce positive symptoms may improve functioning. However, research indicates consistently that positive symptoms show a low correspondence with functional impairments among patients with schizophrenia (190). Rather, it is the negative symptoms and cognitive impairments that are more predictive of functional impairment (191). Because available medications have at best only modest effects on these illness dimensions, it is not surprising that there is scant evidence that medications improve functional status beyond that achieved through reduction of impairing positive symptoms. Consequently, certain psychosocial and rehabilitative interventions are essential to consider in the stable phase to enhance functional status.

Supported employment is an approach to improve vocational functioning among persons with various types of disabilities, including schizophrenia (192). The evidence-based supported employment programs that have been found effective include the key elements of individualized job development, rapid placement emphasizing competitive employment, ongoing job supports, and integration of vocational and mental health services. Randomized trials have consistently demonstrated the effectiveness of supported employment in helping persons with schizophrenia to achieve competitive employment (193, 194). Employment outcomes related to the duration of employment and to the amount of earnings also favor supported employment over traditional vocational services. Further, there is no evidence that engagement in supported employment leads to stress, increased symptoms, or other negative outcome (159). Evidence is inconsistent about the relationship between clinical and demographic variables and successful vocational performance; therefore, it is recommended that any person with schizophrenia who expresses an interest in work should be offered supported employment. Promoting job retention is a continuing challenge even for supported employment. Studies have found that persons with schizophrenia experience considerable difficulties retaining jobs achieved through supported employment (162, 194). This problem appears to be related to neurocognitive impairments (195), among other factors.

Social skills training has been found helpful in addressing functional impairments in social skills or activities of daily living. The key elements of this intervention include behaviorally based instruction, modeling, corrective feedback, and contingent social reinforcement. Clinic-based skills training should be supplemented with practice and training in the patient's day-to-day environment. The results of controlled trials indicate the benefit of skills training in improving illness knowledge, social skills, and symptom and medication management when offered with adequate pharmacotherapy (167). Evidence is strongest for the benefit of skills training in increasing the acquisition of skills assessed by situationally specific measures.

d) Patient and self-help treatment organizations

Peer support is social-emotional and sometimes instrumental support that is mutually offered or provided by persons having a mental health condition, i.e., mental health consumers, to others sharing a similar mental health condition to bring about a desired social or personal change (196). The oldest and most widely available type of peer support is self-help groups. Based largely on uncontrolled studies of self-help groups for persons with severe mental illness, Davidson et al. (197) concluded that self-help groups seem to improve symptoms and increase participants' social networks and quality of life. Additional studies of self-help groups have demonstrated other positive outcomes, including reductions in hospitalizations, improved coping, greater acceptance of the illness, improved medication adherence and illness management, improved daily functioning, lower levels of worry, and higher satisfaction with health (198–200, unpublished 1989 manuscript of M. Kennedy).

Within the realm of consumer-provided or -delivered services are consumer-run or -operated services, consumer partnership services, and consumer employees. Consumer-run or -operated services are services that are planned, operated, administered, and evaluated by consumers (201, 202). Those service programs that are not freestanding legal entities but share control of the operation of the program with nonconsumers are categorized as consumer partnerships. Consumer employees are persons who fill positions designated for consumers as well as consumers who are hired into traditional mental health positions. Reviews of peer support/consumer-provided services specifically for persons with severe mental illness have generated positive results, but the findings are somewhat tentative, given the infancy of the research area (197, 203, 204). Such services have been associated with reduced hospitalizations, reduced use of crisis services, improved social functioning, reduced substance use, and improved quality of life (205–209).

3. Use of antipsychotic medications in the stable phase

Once a patient reaches the stable or maintenance phase of treatment, it is important for the physician to develop a long-term treatment management plan that minimizes the risk of relapse, monitors for and minimizes the severity of side effects, and to the extent possible addresses residual symptoms.

Antipsychotics can reduce the risk of relapse in the stable phase of illness to less than 30% per year (210–215). Without maintenance treatment, 60%–70% of patients relapse within 1 year, and almost 90% relapse within 2 years. Strategies can be used to increase the likelihood that patients will adhere to prescribed medication regimens. Such strategies are described in Section II.A.3, "Developing a Therapeutic Alliance and Promoting Treatment Adherence".

Deciding on the dose of an antipsychotic medication during the stable phase is complicated by the fact that there is no reliable strategy available to identify the minimum effective dose to prevent relapse. Although higher doses are often more effective at reducing relapse risk than lower doses, higher doses often cause greater side effects and lessen subjective tolerability; therefore, clinicians should attempt to treat at a dose that minimizes side effects but is still in the effective range of a particular drug (refer to Table 2). For most patients treated with first-generation antipsychotics, clinicians should use a dose around the "EPS threshold" (94), since studies indicate that higher doses are usually not more efficacious and increase risk of subjectively intolerable side effects (95–97). Lower doses of first-generation antipsychotic medications may be associated with improved adherence and better subjective state and perhaps ultimately better functioning. Second-generation antipsychotics can generally be administered at doses that are therapeutic but will not induce extrapyramidal side effects. The advantages of decreasing antipsychotics to the "minimal effective dose" should be weighed against a somewhat greater risk of relapse and more frequent exacerbations of schizophrenic symptoms (216). Recent evidence suggests potentially greater efficacy in relapse prevention for the second-generation antipsychotic drugs (215, 217); however, whether this result is due to better efficacy or some other factor such as greater treatment adherence or reduced side effects is unclear.

The available antipsychotics are associated with differential risk of a variety of adverse effects, including neurological, metabolic, sexual, endocrine, sedative, and cardiovascular effects (Table 4). A suggested approach to monitoring of side effects is detailed in Table 1 and should be based on the side effect profile of the prescribed antipsychotic as detailed in Part B, Section V.A.1, "Antipsychotic Medications."

Antipsychotic treatment often results in substantial improvement or even remission of positive symptoms. However, most patients remain functionally impaired because of negative symptoms, cognitive deficits, and impaired social function. It is important to evaluate whether residual negative symptoms are in fact secondary to a parkinsonian syndrome or an untreated major depressive syndrome, since interventions are available to address these negative symptoms. There are few proven treatment options for residual positive symptoms, primary negative symptoms, cognitive deficits, or social impairments (see Section II.E, "Special Issues in Caring for Patients With Treatment-Resistant Illness").

Most patients who develop schizophrenia and related psychotic disorders (schizoaffective disorder and schizophreniform disorder) are at very high risk of relapse in the absence of antipsychotic treatment. Emerging evidence suggests this may even be true for first-episode patients; some studies (46, 218) have shown that more than 80% of such patients who do not receive antipsychotic treatment experience some recurrence of symptoms in the 5 years after remission. Unfortunately, there is no reliable indicator to differentiate the minority who will not relapse from the majority who will relapse. Antipsychotics are highly effective in the prevention of relapse in remitted first-episode patients. One-year relapse risk varies from 0% to 46% of patients who are prescribed antipsychotics (210–213). Adherence to maintenance antipsychotic medication likely has an influence on effectiveness and may contribute to varying relapse rates. The most prudent treatment options that clinicians may discuss with remitted first- or multi-episode patients include either 1) indefinite antipsychotic maintenance medication or 2) medication discontinuation (after at least 1 year of symptom remission or optimal response while taking medication) with close follow-up and with a plan to reinstitute antipsychotic treatment on symptom recurrence. However, evidence indicates that sustained treatment is associated with fewer relapses than is targeted intermittent treatment (219). In addition, intermittent treatment strategies appear to increase rather than decrease the risk of tardive dyskinesia. Clinicians should engage patients in a discussion of the long-term potential risks of maintenance treatment with the prescribed antipsychotic (see Part B, Section V.A.1, "Antipsychotic Medications") versus the risks of relapse (e.g., the effect of relapse on social and vocational functioning, the risk of dangerous behaviors with relapse, and the risk of developing chronic treatment-resistant symptoms). If a decision is made to discontinue antipsychotic medication, the discontinuation should be gradual (e.g., reducing the dose by 10% per month). Additional precautions should be taken to minimize the risk of a psychotic relapse. The physician should educate the patient and the family about early signs of relapse, advise them to develop plans for action should these signs appear, and suggest that the patient continue to be seen by a physician on a regular basis.

Indefinite maintenance antipsychotic medication is recommended for patients who have had multiple prior episodes or two episodes within 5 years. Patients taking antipsychotic medication should also be monitored for signs and symptoms of impending or actual relapse, since even in adherent patients the risk of relapse in chronic schizophrenia is about 30% per year. The treatment program should be organized to respond quickly when a patient, family member, or friend reports any symptoms that could indicate an impending or actual relapse. Early intervention using supportive therapeutic techniques and increasing medication as indicated can be very helpful in reducing the likelihood of relapse and hospitalization (220). During prodromal episodes, patients and family members should be seen more frequently for treatment, monitoring, and support, and assertive outreach, including home visits, should be used when indicated.

4. Use of adjunctive medications in the stable phase

Other psychoactive medications are commonly added to antipsychotic medications in the stable phase to treat comorbid conditions, aggression, anxiety, or other mood symptoms; to augment the antipsychotic effects of the primary drug; and to treat side effects. Other medications that may address treatment-resistant and residual psychotic symptoms are discussed in Section II.E, "Special Issues in Caring for Patients With Treatment-Resistant Illness".

Adjunctive medications are commonly prescribed for comorbid conditions. For example, major depression and obsessive-compulsive disorder are common comorbid conditions in patients with schizophrenia and may respond to antidepressant medications (221–223). However, some antidepressants (those that inhibit catecholamine reuptake) can potentially sustain or exacerbate psychotic symptoms in some patients (103). Benzodiazepines may be helpful for managing anxiety during the stable phase of treatment (224), although risk of dependence and abuse exists with chronic use of this class of medication. There is some evidence that mood stabilizers and beta-blockers (100–102) may be effective in reducing the severity of recurrent hostility and aggression. Mood stabilizers may also address prominent mood lability. As mentioned previously, attention must be given to potential drug interactions, especially related to metabolism by the cytochrome P450 enzymes (48, 49).

Patients treated with first-generation antipsychotics may require the long-term use of medications for treatment of extrapyramidal side effects (Table 5). Although the study findings are not consistent, there is some evidence that vitamin E may reduce the risk of development of tardive dyskinesia (225, 226). Given the low risk of side effects associated with vitamin E, patients may be advised to take 400–800 I.U. daily as prophylaxis.

Many other medications may be used to treat or reduce the risk of various antipsychotic side effects. These medications are discussed with each specific antipsychotic in Part B, Section V.A.1, "Antipsychotic Medications."

5. Use of ECT in the stable phase

Clinical observations (227, 228) and a single randomized clinical trial (229) suggest that maintenance ECT may be helpful for some patients who have responded to acute treatment with ECT but for whom pharmacological prophylaxis alone has been ineffective or cannot be tolerated. The frequency of treatments varies from patient to patient and depends on the degree of clinical response and side effects of treatment (107). As with acute treatment with ECT, available evidence suggests that treatment with antipsychotics should continue during the maintenance ECT course (229).

About 10%–30% of patients have little or no response to antipsychotic medications, and up to an additional 30% of patients have partial responses to treatment, meaning that they exhibit improvement in psychopathology but continue to have mild to severe residual hallucinations or delusions. Even if a patient's positive symptoms respond or remit with antipsychotic treatment, other residual symptoms, including negative symptoms and cognitive impairment, often persist. Treatment resistance is defined as little or no symptomatic response to multiple (at least two) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range).

Treatment may be completely or partially unsuccessful for a variety of reasons. The patient may receive a suboptimal dose of antipsychotic, either because an inadequate dose has been prescribed or because the patient does not take some or all of the prescribed antipsychotic. The prescribed antipsychotic may be partially or fully ineffective in treating acute symptoms or in preventing relapse. Substance use may also cause or contribute to treatment resistance.

In assessing treatment resistance, clinicians should carefully evaluate whether the patient has had an adequate trial of an antipsychotic, including whether the dose is adequate and whether the patient has been taking the medication as prescribed. Strategies for improving adherence are described in Section II.A.3, "Developing a Therapeutic Alliance and Promoting Treatment Adherence".

Even when patients are taking antipsychotics, suboptimal treatment response and residual symptoms are common. There are considerable differences between patients in responsiveness to available antipsychotics. However, currently there is no reliable strategy to predict response or risk of side effects with one agent compared with another. Thus, adequate trials of multiple antipsychotics are often needed before antipsychotic treatment is optimized. Complicating the evaluation of treatment response is the fact that there is some time delay between initiation of treatment and full clinical response. An initial trial of 2–4 weeks generally is needed to determine if the patient will have any symptomatic response, and symptoms can continue to improve for up to 6 months (230, 231).

Because of clozapine's superior efficacy, a trial of clozapine should be considered for a patient with a clinically inadequate response to antipsychotic treatment or for a patient with suicidal ideation or behavior (55). Besides clozapine, there are limited options for the many patients who have severe and significant residual symptoms even after antipsychotic monotherapy has been optimized, and none have proven benefits. Various augmentation strategies that have limited or no evidence supporting their efficacy are often used. However, clinicians may consider a time-limited trial of an agent to determine if it offers any benefit to an individual patient. To avoid risking side effects and potential drug interactions, it is important that the actual efficacy of adjunctive medications is carefully evaluated and that adjunctive medications that do not produce clinical benefits are discontinued. Depending on the type of residual symptom (e.g., positive, negative, cognitive, or mood symptoms; aggressive behavior), augmentation strategies include adding another antipsychotic (232–234), anticonvulsants (102, 235–237), benzodiazepines (224), N-methyl-d-aspartate (NMDA) receptor allosteric agonists (e.g., d-serine [238], glycine [239–242], d-cycloserine [243–246]), and cholinergic agonists (247–249). ECT has demonstrated benefits in patients with treatment-resistant symptoms (106–108). Cognitive behavior therapy techniques may have value in improving positive symptoms with low risk of side effects (98). In addition, cognitive remediation is under investigation as a therapeutic strategy to reduce the severity of cognitive deficits (250).

1. Psychiatric features

a) First episode

Active psychosis is dangerous to a person's safety; disrupts capacity to function, life, and reputation; and if persistent for too long can negatively affect prognosis (251). In contrast, early treatment may result in a significant reduction in morbidity and better quality of life for patients and families (252–256). Approximately 25 studies have examined this phenomenon; about two-thirds have shown a significant association between earlier treatment and better outcome on one or more measures, and none has shown a significant association between delayed treatment and better outcome on any measure (257). Despite the benefits of early treatment, there is usually a delay of 1–2 years between the onset of psychotic symptoms and the time the patient first receives adequate psychiatric treatment (252, 258–261). Thus, once psychosis is evident, it should be treated immediately.

In some persons, particularly those with a family history of schizophrenia or other factors influencing risk, prodromal symptoms may be apparent before the development of a full schizophrenia syndrome. Although empirical evidence on long-term outcome is limited, antipsychotic medication treatment may also be helpful in some persons with prodromal symptoms (262–264).

When a patient presents with a first episode of psychosis, close observation and documentation of the signs and symptoms over time are important because initial psychotic episodes can be polymorphic and evolve into a variety of specific disorders (e.g., schizophreniform disorder, bipolar disorder, schizoaffective disorder). There is controversy over whether first-episode patients should be treated as outpatients or in the hospital. Inpatient care offers both risks and protections. On the one hand, the experience of a first psychiatric hospitalization, especially in a closed setting with many chronically ill patients, can be frightening and produce its own trauma (265). On the other hand, the nature and severity of a first episode are often unknown, unpredictable, and require more than "usual" surveillance. A hospital setting also allows for careful monitoring of the psychotic symptoms as well as any side effects, including acute dystonia, akathisia, or neuroleptic malignant syndrome (266), that may arise from treatment with antipsychotic medications.

Patients with first-episode psychosis are comparatively more treatment responsive than patients with multiple episodes of psychosis but, at the same time, are quite sensitive to side effects (267–270). Up to the early 1990s, drug treatment for a first episode of psychosis was limited to first-generation antipsychotic medications that could cause severe sedation and extrapyramidal side effects. The second-generation antipsychotic medications have less propensity to cause extrapyramidal side effects, and patients are hence less likely to need concomitant anticholinergic agents (271–273).

More than 70% of first-episode patients achieve a full remission of psychotic signs and symptoms within 3–4 months, with 83% achieving stable remission at the end of 1 year (274). Studies also reveal that first-episode patients often respond to low doses of antipsychotic medications (275–279). However, predictors of poor treatment response include male gender, pre- or perinatal injury, more severe hallucinations and delusions, attentional impairments, poor premorbid function, longer duration of untreated psychosis (280), the development of extrapyramidal side effects (281), and high levels of expressed emotion in the patient's family (282–289).

Not uncommonly, symptoms of schizophrenia have their onset before adulthood, and aspects of treatment may differ in children and adolescents. For more information on treating children and adolescents, readers are referred to the American Academy of Child and Adolescent Psychiatry's Practice Parameter for the Assessment and Treatment of Children and Adolescents With Schizophrenia (290).

Once remission of psychotic symptoms is achieved, a high priority should be placed on minimizing risk of relapse, given its potential clinical, social, and vocational costs. In particular, recurrent episodes are associated with increasing risk of chronic residual symptoms and evidence of anatomical neuroprogression (257, 280, 291–293). Patients, their families, and treating clinicians often hope that symptom remission indicates that the disease will not become chronic, although this is true only for a minority (about 10%–20%) of patients (46, 218, 294). Thus, clinicians should candidly discuss the high risk of relapse and factors that may minimize relapse risk. Although there is very little study of factors that act to maintain recovery in remitted first-episode patients, evidence suggests that antipsychotics are highly effective in prevention of relapse. In patients for whom antipsychotics are prescribed, 1-year relapse risk varies from 0% to 46%, with relapse rates of patients who discontinue taking medication being up to five times higher than rates for those who continue treatment (46, 210–213). Since adherence to maintenance medication treatment likely influences effectiveness, it may contribute to the varying relapse rates found in these studies.

In arriving at a plan of treatment with remitted first-episode patients, clinicians should engage patients in discussion of the long-term potential risks of maintenance treatment with the prescribed antipsychotic versus risks of relapse (e.g., effect of relapse on social and vocational function, risk of dangerous behaviors with relapse, and risk of developing chronic treatment-resistant symptoms). Prudent treatment options that clinicians may discuss with remitted patients include either 1) indefinite antipsychotic maintenance medication (295) or 2) medication discontinuation with close follow-up and a plan of antipsychotic reinstitution with symptom recurrence. Medications should never be stopped abruptly, as rebound psychosis may result and may be misinterpreted as a reoccurrence. In addition to maintenance antipsychotic medication, other potential strategies to maintain recovery in remitted first-episode patients include enhancing stress management and eliminating exposure to cannabinoids and psychostimulants (296).

b) Subtypes and deficit symptoms

According to DSM-IV-TR, the classic subtypes of schizophrenia are paranoid, disorganized, catatonic, undifferentiated, and residual. There are at present no treatment strategies specific to the various subtypes, with the exception of the use of benzodiazepines for catatonia. The deficit/nondeficit categorization, or the deficit syndrome, is also important to recognize, although there are also no specific treatments (297). The negative symptoms of schizophrenia may be classified as primary or secondary. Negative symptoms may be primary and represent a core feature of schizophrenia, or they may be secondary to positive psychotic symptoms (e.g., paranoid withdrawal), medication side effects (e.g., dysphoria), depressive symptoms (e.g., anhedonia), anxiety symptoms (e.g., social phobia), demoralization, or environmental deprivation (e.g., in chronic institutionalization). Deficit schizophrenia is heavily loaded with enduring primary negative symptoms such as affective flattening, alogia, and avolition.

The prevalence of deficit states in first-episode schizophrenia has been estimated to be between 4% and 10% (298). Negative symptoms are already present in the prodromal phase (299–301), and the prevalence increases with the length of the schizophrenic illness (302–306). Male patients have been found to experience more negative symptoms than female patients (307–309). Patients with deficit schizophrenia are also found to have poorer premorbid adjustment during childhood and early adolescence. They exhibit more impairment in general cognitive abilities and have problems in sequencing of complex motor acts, which suggests frontoparietal dysfunction (310).

Treatment of negative symptoms begins with assessing the patient for factors that can cause the appearance of secondary negative symptoms (311). The treatment of such secondary negative symptoms consists of treating their cause, e.g., antipsychotics for primary positive symptoms, antidepressants for depression, anxiolytics for anxiety disorders, or antiparkinsonian agents or antipsychotic dose reduction for extrapyramidal side effects. If negative symptoms persist after such treatment, they are presumed to be primary negative symptoms of the deficit state (312).

There are no treatments with proven efficacy for primary negative symptoms. Clozapine was reported to be effective for negative symptoms in earlier short-term trials (313), but subsequent longer-term studies challenged such claims (314, 315), although clozapine treatment was associated with significant improvement in social and occupational functioning (314). The second-generation antipsychotic medications have been reported to be useful against negative symptoms (316–322), but this improvement may be accounted for by their having less propensity to cause extrapyramidal side effects (323).

c) Substance use disorders

More than one-third of patients with schizophrenia spectrum disorders also have a substance use disorder, and people with schizophrenia show six times the risk of developing a substance use disorder than do persons in the general population (324). Other research finds that between 20% and 65% of people with schizophrenia experience comorbid substance use disorders (325–328). A recent Australian study found the 6-month and lifetime prevalence of substance abuse or dependence among people with schizophrenia to be 26.8% and 59.8%, respectively (329).

Substance abuse in schizophrenia has been associated with male gender, single marital status, less education, earlier age at onset of schizophrenia and at first hospital admission, frequent and longer periods of hospitalization, more pronounced psychotic symptoms, more severe cerebral gray matter volume deficits, and negative consequences such as poor treatment adherence, depressive symptoms, suicide, violence, legal problems, incarceration, severe financial problems, family burden, housing instability, and increased risk of HIV infection (327, 330–332) and hepatitis infection, particularly hepatitis C infection (333). Substance abuse has been associated with precipitation of schizophrenia at an earlier age (334–340), and in some studies amphetamine abuse has been associated with an earlier age of onset (341). Alcohol and a variety of other substances have also been associated with symptom relapses in schizophrenia (342). Nicotine, alcohol, cannabis, and cocaine have been found to be the most commonly abused substances. Patients may also abuse prescribed medications such as benzodiazepines and antiparkinsonian agents.

The goals of treatment for patients with schizophrenia who also have a substance use disorder are the same as those for treatment of schizophrenia without comorbidity but with the addition of the goals for treatment of substance use disorders, e.g., harm reduction, abstinence, relapse prevention, and rehabilitation (343).

Evaluation of the patient with schizophrenia should always include a comprehensive inquiry into possible substance use. Self-report is often unreliable; corroborating evidence from all sources such as family members, friends, community-based case managers, and treatment personnel should be sought (330, 344). Screening instruments for substance use disorders developed for the general population, such as the Alcohol Use Disorders Identification Test (AUDIT) (345), can be used, but screening instruments specifically for patients with severe mental illnesses, such as the Dartmouth Assessment of Lifestyle Instrument (346), have been developed and may have greater sensitivity for detecting substance use disorders in people with schizophrenia. Laboratory investigations such as urine and blood toxicology for abused substances and liver function tests should be carried out. Many patients with schizophrenia do not develop the full physiological dependence syndrome associated with dependence on alcohol or other substances (330). However, even use of low levels of alcohol or other substances by patients with schizophrenia can have untoward consequences. Psychiatrists should therefore attend carefully to the presence of alcohol or other substance use and be familiar with the potential negative consequences described earlier. The rates of current substance use will likely be higher in acute settings such as the emergency department, and thus the index of suspicion and effort devoted to assessment of substance use should be especially high in such settings.

Traditionally, patients with schizophrenia and comorbid substance use disorders were treated in separate programs, either sequentially or in parallel, for the two types of disorder. Since the mid-1980s, a comprehensive integrated treatment model has been adopted to provide continuous outpatient treatment interventions and support over long periods of time (months to years), enabling patients to acquire the skills they need to manage both illnesses and to pursue functional goals. In this model, the same clinicians or teams of clinicians provide treatment both for substance use disorders and for other mental disorders. This form of treatment features assertive outreach, case management, family interventions, housing, rehabilitation, and pharmacotherapy. It also includes a stage-wise motivational approach for patients who do not recognize the need for treatment of substance use disorders and behavioral interventions for those who are trying to attain or maintain abstinence. The interventions have been associated with reduced substance use and attainment of remission (347–350).

Initially, many patients need interventions to build motivation rather than to achieve abstinence. Special efforts are made to help them recognize that their substance use is interfering with their ability to pursue personal goals and to nurture their desire to reduce and eliminate their substance use (161, 349). Such efforts represent examples of interventions during the second (persuasion) stage in a four-stage dual-diagnosis treatment model based on readiness for change; the other treatment stages are engagement, active treatment, and relapse prevention (351). Studies show that treatment programs with these characteristics can be effective in reducing substance use and in decreasing the frequency and severity of psychotic decompensations (332, 352–354). Collaboration with family members is often helpful for both the patients and the family members (64, 171, 355, 356).

In practice, treatment of substance use disorders is commonly conducted by means of a group therapy approach, usually after patients have achieved stabilization of their schizophrenic symptoms. The therapeutic approach should be an integrated one that takes into account patients' cognitive deficits and limited tolerance for stress. Generally, groups should emphasize support, psychoeducation, and skills training (344, 352, 357). The length and frequency of group sessions should be regulated according to the attention span and interactive tolerance of the patients. Therapists should be active in keeping the group structured and focused and should limit the amount of stress by avoiding the direct confrontation of patients that is common to traditional treatment programs for persons with substance use disorders. Patients should understand that they have two complex chronic disorders that together lead to a poorer prognosis than each would have separately. Patients who have not yet attained complete abstinence should be accepted into treatment, with abstinence as a treatment goal (344, 352, 358). Patients who do not view abstinence as a treatment goal may still be successfully engaged in treatment that is aimed at achieving abstinence (359). Community-based self-help and support groups such as Alcoholics Anonymous or Narcotics Anonymous can be important in the recovery of patients with substance use disorders. Such connections are, however, more effective once patients are actively pursuing abstinence (349).

Antipsychotic medications remain the mainstay of pharmacological treatment for patients with comorbid substance use disorders. They are used in the usual doses, but patients should be informed that side effects such as sedation and incoordination can be aggravated when combining antipsychotic medication with alcohol or other substances. First-generation antipsychotic medications and clozapine also have the potential to lower the seizure threshold and infrequently may precipitate seizures during alcohol or benzodiazepine withdrawal. Dysphoria associated with first-generation antipsychotic medications may precipitate or worsen the substance use (360). On the other hand, studies have demonstrated that clozapine use is associated with reductions in the use of nicotine, alcohol, cannabis, and cocaine (361–363). In some clinical trials, second-generation antipsychotics such as risperidone and olanzapine have also been shown to be effective for reducing craving in cocaine dependence (364).

There is suggestive evidence from a case series of 30 patients with schizophrenia and other severe mental illnesses and alcoholism that disulfiram in moderate doses can be used safely and is associated with clinical benefits in alcohol outcomes over 1–3 years (365). However, for patients with schizophrenia who abuse alcohol, disulfiram may pose some risk since it can precipitate psychosis at high doses (358, 366). It also has harmful physical effects when taken with alcohol, and thus it is recommended only for patients who are motivated and who have previously shown good judgment, treatment adherence, and reality testing.

d) Depressive symptoms

Depressive symptoms are common in all phases of schizophrenia (367). The proportion of patients with schizophrenia who also manifest depression ranges from 7% to 75% (368). Depression may occur in the prodromal phase (300, 301), in the first episode (369–371), during the early course (372, 373), and after remission, and it may be superimposed on the symptoms of residual schizophrenia ("postpsychotic depression") (374) or may occur in a prodrome to a psychotic relapse (375–379).

When patients with schizophrenia present with depressive features, important differential diagnostic possibilities need to be considered (368, 380). These include side effects of antipsychotic medications (including medication-induced dysphoria, akinesia, and akathisia), demoralization, and the primary negative symptoms of schizophrenia. Concurrent abuse or the sudden withdrawal of substances such as cannabis, cocaine, narcotics, alcohol, nicotine, and caffeine can also lead to depression. When the depressive symptoms are present at a syndromal level during the acute phase of the schizophrenic illness, the possibility of schizoaffective disorder should be considered.

Depressive symptoms that occur during the acute psychotic phase usually improve as the patient recovers from the psychosis. There is also evidence to suggest that depressive symptoms are reduced by antipsychotic treatment, with comparison trials finding that second-generation antipsychotics may have greater efficacy for depressive symptoms than first-generation antipsychotics (381, 382). However, there is also evidence to suggest that this apparent antidepressant effect may be related to the lower likelihood of neurological side effects with second-generation antipsychotics (222, 368, 383, 384). The approach hence is first to treat the psychosis.

If antipsychotic medication-induced dysphoria is suspected, then antipsychotic dose reduction may be effective. Alternatively, the clinician may switch the patient's medication to an antipsychotic with a lower risk of inducing extrapyramidal symptoms (Table 4). There is no evidence that medications that treat the motor symptoms of extrapyramidal side effects (e.g., benztropine, amantadine) (Table 5) are effective for the treatment of neuroleptic-induced dysphoria.

Antidepressants are added as an adjunct to antipsychotics when the depressive symptoms meet the syndromal criteria for major depressive disorder, are severe and causing significant distress (e.g., when accompanied by suicidal ideation), or are interfering with function. Tricyclic antidepressants have been extensively studied in the treatment of postpsychotic depression (103, 385). Antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and dual reuptake inhibitors, have also been found to be useful in the treatment of depression in schizophrenia (368, 384). However, very few studies have examined the effects of antidepressants in patients treated with second-generation antipsychotic medications, making it difficult to evaluate the current utility of adjunctive antidepressant agents. When prescribed, antidepressants are used in the same doses that are used for treatment of major depressive disorder. There are, however, potential pharmacokinetic interactions with certain antipsychotic medications; for example, the SSRIs (such as fluoxetine, paroxetine, and fluvoxamine) are inhibitors of cytochrome P450 enzymes and thereby increase antipsychotic plasma levels. Similarly, the blood levels of some antidepressants may be elevated by the concomitant administration of antipsychotic medications.

e) Risk of suicide

Suicide is the leading cause of premature death among persons with schizophrenia (386, 387). Compared to the general population, persons with schizophrenia are nine times more likely to die by suicide (388). Up to 30% of patients with schizophrenia attempt suicide (389), and between 4% and 10% die by suicide (390–394). The estimated rate of suicidal behavior among persons with schizophrenia is between 20% and 40% (395, 396).

Some risk factors for suicide in schizophrenia are the same as those for the general population, including being male, white, single, socially isolated, and unemployed; having a positive family history of suicide; previous suicide attempts; having a substance use disorder; being depressed or hopeless; and having a significant recent adverse life event. Specific risk factors for suicide among persons with schizophrenia are young age, high socioeconomic status background, high IQ with a high level of premorbid scholastic achievement, high aspirations and expectations, an early age at onset of illness/first hospitalization, a chronic and deteriorating course with many relapses, and greater insight into the illness (391, 397–401). A change in the environment, such as a hospital admission and discharge, may trigger suicidal behavior (402, 403). Suicide is more common within the first 6 years of the initial hospitalization and also during periods of remission after 5–10 years of illness. Other risk factors include severe depressive and psychotic symptoms, with an increase in the patient's paranoid behavior (395, 404–406). Suicidal ideation has also been shown to be predictive of suicide over the subsequent 2–4 weeks (407). As patients do not often report suicidal ideation spontaneously, clinicians are encouraged to ask patients about suicidal ideas whenever there is suggestion that they could be present (e.g., in the presence of depression or severe stress). Treatment-related factors associated with suicide include inadequate antipsychotic treatment, nonadherence to the medication regimen, and lack of response to medication (408). In several case reports, suicide has also been noted among patients with akathisia (409, 410).

Despite identification of these risk factors, it is not possible to predict whether an individual patient will attempt suicide or will die by suicide. Suicide thus must be considered at all stages of the illness, and suicide risk must be assessed initially and regularly as part of each patient's psychiatric evaluation. The patient's desire to die may be more important than the lethality of the methods used (403). Additional information may be obtained from close family members and treating therapists. Patients should be admitted to a secure inpatient unit if they are judged to be at substantial risk for suicide.

It is important to maximize the treatment of both psychosis and depression. There is suggestive evidence that both first- and second-generation antipsychotic medications may reduce the risk of suicide (411). However, clozapine is the most extensively studied and has been shown to have the greatest therapeutic effect on suicidal behavior, possibly reducing the suicide rate by as much as 75%–85% (55, 398, 399, 412). For these reasons, clozapine should be preferentially considered for patients with a history of chronic and persistent suicidal ideation or behaviors.

During the initial hospitalization, suicide precautions should be instituted, and the patient must be closely monitored to prevent escape. There should also be minimal use of ward transfers. Suicide risk should be examined carefully before a patient is granted any privileges and again before the patient is finally discharged from the hospital. The patient and the patient's family members should be advised to look for warning signs and to initiate specific contingency plans if suicidal ideation recurs. In outpatients, the frequency of visits should be higher after a recent discharge from the hospital and may need to be increased in times of personal crisis, significant environmental changes, heightened distress, or deepening depression during the course of illness.

For additional information, readers are directed to APA's Practice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors (56) (included in this volume).

f) Aggressive behavior

Although only a minority of patients with schizophrenia are violent, evidence does suggest that schizophrenia is associated with an increase in the risk of aggressive behavior (413–419). Sociodemographic risk factors for aggression in schizophrenia are male gender; being poor, unskilled, uneducated, or unmarried; and having a history of prior arrests or a prior history of violence (420). The risk for aggressive behavior increases with comorbid alcohol abuse, substance abuse, antisocial personality, or neurological impairment (421–427). Violent patients with schizophrenia have more positive symptoms and bizarre behaviors and may act on their delusions, especially if the delusions are distressing and the patient can find evidence to support them (428–430). Patients who experience command hallucinations to harm others are also more likely to be violent (431).

Identifying risk factors for violence and assessment of dangerousness are parts of a standard psychiatric evaluation, which should be conducted in an environment that is safe for both the patient and clinician (432). It is important to determine if use of alcohol or other substances, including use of amphetamines or other stimulants, is causing or contributing to aggressive behavior. Severe akathisia associated with prescribed medications may also cause or contribute to aggressive behavior. It is important to inquire about thoughts of violence and determine the persons to whom these thoughts are directed. Parents, for example, are frequent targets of violence when it occurs (433). When a patient is found to pose a serious threat to others (e.g., having homicidal ideation with imminent plans), the psychiatrist should consider hospitalizing the patient and must exercise his or her own best judgment, in accord with the legal requirements of the jurisdiction, to protect those people from foreseeable harm (54, 434).

If the patient is acutely aggressive, the clinician can try to calm the patient by distraction or "talking down" techniques. If restraint or seclusion is needed, it should be done with adequate numbers of well-trained professional staff (70). When sedation is indicated and the patient is unwilling to accept oral medication, intramuscular injection of a first-generation antipsychotic agent (5 mg of haloperidol) (75) or second-generation agent (e.g., ziprasidone) (76–79) can be given, with or without a concomitant dose of 1–2 mg of oral or intramuscular lorazepam (72–74). Other medications, such as 5 mg i.m. of droperidol, can be used in selected clinical situations of extreme emergency or in highly agitated patients (80, 435). However, if droperidol is used, its potential for cardiac rhythm disturbances must be considered, as indicated in its labeling by a black-box warning for QTc prolongation. After seclusion, restraint, or sedation, the mental status and vital signs of the patient should be monitored regularly. Release from seclusion or restraint can proceed in a graded fashion, as risk of harm to self or others diminishes (432).

Limit setting and behavioral approaches have been employed for the management of persistently violent patients (432, 436). Antipsychotic medications remain the mainstay of management (421, 437), with good evidence for clozapine in particular (438–440). Other agents have been used, including mood stabilizers (lithium, valproate), SSRIs (such as citalopram), benzodiazepines, and -adrenergic blocking agents (propranolol, nadolol), but empirical evidence is lacking.

It is common for patients with schizophrenia in the community to stop taking their medications. Patients who are more likely to be violent with psychotic relapses are of particular concern and may be primary candidates for mandatory outpatient treatment programs (441) (see Section II.A.3, "Developing a Therapeutic Alliance and Promoting Treatment Adherence").

g) Psychosis-induced polydipsia

Polydipsia is compulsive water drinking, usually in excess of 3 liters per day. It can be complicated by water intoxication, i.e., severe hyponatremia (serum sodium <120 mmol/liter), which is potentially fatal, as the associated cerebral edema can result in delirium, seizures, coma, and death. About 20%–25% of chronically ill inpatients have primary polydipsia, and as many as 10% have a history of water intoxication (442–445).

The pathophysiology of the water imbalance is still unclear. It occurs most commonly in the most severely ill patients with schizophrenia and thus has been termed "psychosis-induced polydipsia." Polydipsia and water intoxication are associated with long hospitalization, high doses of antipsychotic medications, moderate doses of anticholinergic medications, and heavy smoking (442, 444). Development of hyponatremia has also been associated with use of diuretics, SSRIs and venlafaxine (446, 447), tricyclic antidepressants, and calcium antagonists (448). Polydipsia has also been known to occur prior to the introduction of antipsychotic medications (449).

The approach to psychosis-induced polydipsia is to control both the psychosis and water intake after excluding possible underlying medical causes of polydipsia, such as diabetes mellitus, diabetes insipidus, chronic renal failure, malignancy, pulmonary disease, hypocalcemia, and hypokalemia. Acute management involves water restriction and sodium replacement to prevent seizures. Clozapine appears to be effective, albeit in studies with small sample sizes (450–452). The second-generation antipsychotics have also been examined for their role in the long-term management of the condition (453, 454). Various other medications, including demeclocycline (455, 456), naltrexone (457), enalapril (458), clonidine (458, 459), and propranolol (460), have also been used in some case studies.

2. Demographic and psychosocial variables

a) Homelessness

By current estimates, as many as 800,000 Americans are homeless on any given night; an estimated one-fourth of these people have serious mental illnesses, and more than one-half have an alcohol and/or drug problem (461). Schizophrenia is a risk factor for homelessness, as is infectious disease, alcohol and other substance use, depression, and social isolation (462, 463). Comprehensive reviews have suggested that the rate of schizophrenia in homeless persons has ranged from 2% to 45%. Methodologically superior studies have produced estimates of 4%–16%, with a weighted average prevalence of 11% (464). Factors that have been noted to contribute to the magnitude of homelessness among patients with schizophrenia include deinstitutionalization (465), limitations of public funding, problems in service integration, and lack of low-cost housing (466). Substance use disorders contribute substantially to homelessness among patients with schizophrenia. Many housing programs do not accept patients with schizophrenia who use alcohol or other substances, and treatment for substance use disorders is often lacking for these individuals (466). In addition, the illness of schizophrenia may directly predispose persons to housing difficulties through withdrawal, disorganization, and disruptive behaviors (467).

Homeless mentally ill persons are likely to have multiple impairments. Most lack basic health care, income, and any social support network. Only slightly more than one-half of the homeless persons with schizophrenia have been found to be currently receiving psychiatric treatment (464). Homeless persons with schizophrenia have been found to have elevated rates of victimization (468) and to have mortality rates that are three to four times higher than the expected rate (469). Further, a large study of mentally ill homeless veterans found that a majority of homeless veterans contacted through a national outreach program did not receive medical services within 6 months of program entry (470). Medical treatment is thus a great challenge for this population.

Given the level of need of this population, services should include provision of appropriate housing, access to medical services, treatment of substance use disorders, income support and benefits, and rehabilitation and employment assistance (466). Such services must be comprehensive, continuous, accessible, and individualized (467). A number of controlled studies have demonstrated the effectiveness of such treatment models for reducing homelessness and improving psychiatric outcomes (164, 471). The Center for Mental Health Services conducted a multisite 5-year demonstration program called Access to Community Care and Effective Services and Supports (ACCESS) to test the effect of the integration of fragmented services in treating homeless persons with serious mental illness. This study involved 18 sites in nine states from 1993 to 1998, and treatment outcomes were studied at both the system and patient levels. All project sites conducted extensive outreach efforts to engage homeless persons and provided a comprehensive range of services, including mental health treatment, medications, substance use disorder treatment or referral, job placement, housing support, social support, and primary health care. Patients served in the ACCESS program showed improved housing stability and reductions in substance use and minor criminal incidents, as well as increased use of psychiatric outpatient care, although integration of treatment did not influence these outcomes. The provision of direct community services and outreach appeared to be most important.

Clinical care of homeless mentally ill patients involves three basic stages: 1) engagement, 2) intensive care, and 3) ongoing rehabilitation (472). In introducing services into the community, psychiatrists must be prepared to work with homeless patients in nonclinical environments, including streets, shelters, subways, bus terminals, and other public spaces. In discussing outreach to homeless patients with schizophrenia, Goldfinger (467) stressed the importance of engagement. Homeless patients with schizophrenia are often fearful and distrustful of the mental health system, and they can require a combination of patience, persistence, and understanding. Depending on the needs and wants of a particular patient, the provision of food, clothing, medical attention, or simply company can be indispensable in developing a therapeutic relationship. As noted by Goldfinger (467), such provisions document one's concern, demonstrate one's reliability, and acknowledge the importance of the needs of the homeless person with schizophrenia. To engage the homeless person with schizophrenia, active outreach is usually necessary and is often performed by case managers. In particular, street outreach to homeless persons with serious mental illness is justified, as they have been found to be more severely impaired, to have more basic service needs, to be less motivated to seek treatment, and to take longer to engage than those contacted in other settings. The ACCESS program found that patients engaged from the street showed improvement on nearly all outcome measures that was equivalent to that of enrolled patients who were contacted in shelters and other service agencies (473).

Despite appropriate outreach efforts, some homeless persons with mental illness are so impaired that they remain unable to recognize their basic needs or avoid personal dangers. One program developed to address the treatment needs of this population was the Homeless Emergency Liaison Project (Project HELP), in which a mobile treatment team arranged for involuntary psychiatric emergency department evaluation of high-risk homeless patients (474). Involuntary hospitalization resulted from 93% of such evaluations, and 80% of all patients received the diagnosis of schizophrenia. At 2-year follow-up of 298 patients initially evaluated during the project, only 12% were found to be back living on the streets.

b) Cultural factors

Cultural factors are known to affect the course, diagnosis, and treatment of schizophrenia (475). There is a robust pattern of evidence that race has a substantial effect on whether persons with substantively similar symptoms receive a diagnosis of an affective disorder or a schizophrenia spectrum psychotic disorder. Compared with Caucasians, African Americans, especially men, are less likely to receive a diagnosis of a mood disorder and more likely to receive a diagnosis of schizophrenia (476–479). African Americans with schizophrenia are also less likely to receive a diagnosis of a comorbid affective or anxiety disorder (480, 481). While it is possible that such differences may reflect actual illness variation among racial/ethnic groups, there is growing evidence that cultural differences in symptom and personal presentation, help seeking, interpretation of symptoms and clinical judgments by (usually Caucasian) clinicians, and treatment referral are likely causing race-linked biases in diagnosis and therefore in treatment (e.g., see references 482–486). Additional possible causes or contributors to this pattern of disparity include low levels of cultural competence among clinicians, unbalanced research samples, inaccurate or biased pathology assessment tools, and the failure of researchers to control for socioeconomic status, education, and urbanicity (487, 488). These remarkably consistent findings suggest that clinicians should be mindful of the extent to which cultural factors influence their diagnostic approach.

c) Race

Once patients receive a diagnosis, substantial data suggest that race affects the type of pharmacological treatment they receive. For example, the Schizophrenia Patient Outcomes Research Team (PORT) (65) showed that among patients for whom psychotropic medications at doses outside the recommended range were prescribed, patients from racial/ethnic minority groups (especially African Americans) were much more likely than Caucasian patients to receive doses above recommended levels. The same patients were also more likely to receive prophylactic antiparkinsonian agents, suggesting increased rates of adverse side effects related to higher doses. Prescription of higher doses of antipsychotic medications to African American patients has also been noted in several other reports (489–493).

However, in another PORT study, among patients with schizophrenia who were also experiencing significant depression, Caucasian patients were significantly more likely to receive adjunctive medications (494). In addition, there is growing evidence that racial/ethnic minority patients with psychotic disorders are less likely than Caucasian patients to receive second-generation antipsychotics and more likely to receive long-acting injectable agents (495–498). Other research suggests that these gaps may be decreasing over time but are still persistent and may be related to differential prescribing patterns in private versus managed health care (496, 499).

There is clearly a need for more research to describe and understand the differences in patterns of treatment by race and ethnicity. Most of the published research focuses on African Americans; the needs and treatments of other cultural groups also require attention. The observed phenomena provide little guidance about whether the care delivered is appropriate. In the meantime, the strength and consistency of these findings suggest that clinicians should consider the extent to which a patient's race and/or ethnicity are playing a role in the treatment and should ensure that care is being individualized and optimized.

To some extent, differences in drug dosing or side effect risk may be related to genetically based differences in drug metabolism. For example, the activity of the enzyme encoded by the CYP2D6 gene is very low or absent in 5%–8% of Caucasians but only 2%–5% of African Americans and Asians. Low activity of the enzyme encoded by the CYP2D6 gene may dramatically affect the metabolism of many drugs, increasing serum levels (500). There is also suggestive evidence that up to one-third of African Americans possess genetic polymorphisms of other enzymes that metabolize psychotropic agents, resulting in altered metabolism and potential for enhanced medication side effects. Ethnic factors may also confer a susceptibility to medication side effects in certain persons. For example, patients of Jewish descent have been noted to be at greater risk for clozapine-induced agranulocytosis than other patients with schizophrenia (501) and therefore may require close monitoring during clozapine treatment.

d) Gender

There are numerous gender differences in the presentation and course of schizophrenia (502–505). Men with schizophrenia have been noted to have a younger age at onset, a poorer premorbid history, more negative symptoms, a greater likelihood of having the deficit syndrome (306, 309), and a poorer overall course than women with schizophrenia (503, 506). Compared with men, women are more likely to have affective symptoms, auditory hallucinations, and persecutory delusions, but they have a better overall course and better outcomes than men, as evidenced by better social and occupational functioning, fewer hospitalizations, and less substance use and antisocial behavior (504, 505, 507). While such differences may be biologically mediated, psychosocial factors, including family and societal expectations, may also affect outcome. Haas and colleagues (507) noted that social and occupational role demands may result in unrealistic family expectations of men with schizophrenia, and this issue should be dealt with in treatment.

There are also gender differences in both response to and adverse effects of treatments for schizophrenia. Most of this research has been conducted with first-generation antipsychotic medications. Women exhibit more rapid responses to antipsychotic medications and a greater degree of improvement in both first-episode and multi-episode schizophrenia (504). It has also been observed that even after body weight is considered, women require lower antipsychotic doses (508, 509) than men, although there is suggestive evidence that postmenopausal women may require higher doses (504). Although women may show greater responsivity to antipsychotics, they also experience more neurological side effects, including acute dystonia, parkinsonism, akathisia, and tardive dyskinesia (504). Women also develop higher serum prolactin levels in response to both first-generation antipsychotics and risperidone, compared with men (504), and therefore women may be more prone to the sexual side effects of the medications. Finally, although studies of gender differences in response to psychosocial treatments are sparse, there is some evidence to suggest that social skills training may be more effective for male patients, whereas inpatient family interventions have shown greater success in families of female patients (504, 505).

e) Pregnancy

Treatment of the pregnant or lactating patient with schizophrenia must consider two issues: 1) risks of various psychotropic medications to the fetus, newborn, and breast-fed infant, and 2) adequacy of prenatal care. A general reference on medications in pregnancy and lactation is the text by Briggs et al. (510).

Controlled studies of psychotropic drug risks during pregnancy are, for obvious ethical reasons, not done. Knowledge of the risks of these agents comes from animal studies and from uncontrolled exposures in humans. Nonetheless, there is a body of information that can help guide clinicians' and patients' decision making about the use of psychotropic agents during pregnancy and lactation. Risks do vary from drug to drug and from drug class to drug class. In addition, two periods of high risk to the fetus or newborn are identifiable: teratogenic risk is highest in the first trimester, and withdrawal risk is highest at the time of birth. Only with planned pregnancies is management of first trimester psychotropic drug exposure under full control of the doctor and patient. Drug withdrawal risk at the time of parturition may be more predictable and manageable, depending on the drug(s) involved and the circumstances of delivery.

There are substantial data on fetal exposure to first-generation antipsychotic medications, with relatively little evidence of harmful effects, especially with high-potency agents (511–513). Much less information is available regarding fetal exposure to second-generation antipsychotic medications. Koren et al. (514) found that pregnant women with schizophrenia taking second-generation antipsychotic medications were frequently obese and had inadequate intake of folic acid, putting their offspring at increased risk for neural tube defects. Such an outcome would be an indirect rather than a direct effect of these medications. A limited number of reports of treatment with olanzapine during pregnancy and lactation showed that olanzapine did not appear to increase the risk of harm (515). A case report of clozapine treatment during pregnancy described development of gestational diabetes, possibly exacerbated by clozapine, but no fetal abnormalities (516). Pregnancy can be a period of decreased symptoms for women with schizophrenia, but relapses are frequent in the postpartum period (517). Thus, the clinical risks of not using antipsychotic medications may be somewhat less during pregnancy but are greater thereafter.

Compared with antipsychotic medications, mood stabilizers and benzodiazepines are much more closely associated with fetal malformations and behavioral effects (511, 513, 518). Thus, their risk/benefit ratio is different, and the need for their continuation during pregnancy and breast-feeding requires strong clinical justification.

A number of studies have shown that pregnant women with schizophrenia receive relatively poor prenatal care. These women have more obstetric complications, and their offspring are more likely to have adverse outcomes, such as low birth weight and stillbirth (519–522). There are many contributing factors to the relatively poor prenatal care and outcomes, such as low socioeconomic status, high rates of smoking and substance use disorders, and obesity. For the clinician treating a pregnant woman with schizophrenia, it is particularly important to insist on early involvement of an obstetrician who can help reduce the risks of the pregnancy and with whom risks and benefits of pharmacological treatment options can be discussed.

f) Psychosocial stressors

A variety of psychosocial stressors can precipitate the initial development or recurrence of symptoms in a vulnerable person (304, 523–526). Stressors include stressful life events (e.g., interpersonal loss, leaving home, military service), sociocultural stress (e.g., poverty, homelessness, fragmented social network), or a distressing emotional climate (e.g., hostile and critical attitudes and overprotection by others in one's living situation or high levels of expressed emotion) (282–289). While schizophrenia can emerge or worsen in the absence of environmental influences, attention to stressors frequently helps to prevent relapse and/or maximize healthy functioning. Sometimes the stress is internal, and knowledge of developmental vulnerabilities can assist in identifying and assisting with this variety of stress. Treatment strategies include preventing the development or accumulation of stressors and helping the patient develop coping strategies that keep tension levels within manageable bounds.

g) Schizophrenia in later life

With the overall increase in longevity, the number of older patients with schizophrenia is expected to increase rapidly over the next three decades (527). Among middle-aged and elderly persons with schizophrenia, approximately 80% have early-onset schizophrenia (528), with the remaining 20% including persons with late-onset schizophrenia (onset after age 40) and very-late-onset schizophrenia-like psychosis (onset after age 60) (DSM-IV, 529). The rate of aging-associated cognitive decline in older patients with schizophrenia is similar to that in age-comparable normal persons, although, as with younger patients, they have greater overall cognitive impairment (530, 531). The approach to the treatment of older persons with schizophrenia is similar to that of younger patients (532) and involves combining pharmacotherapies with psychosocial interventions.

Several age-related physiological changes may influence the approach to pharmacotherapy. These physiological changes include reduced cardiac output (and concomitant reduction in renal and hepatic blood flow, relative to younger persons), reduced glomerular filtration rate, possible reduction in hepatic metabolism, and increased fat content. These changes may alter the absorption, distribution, metabolism, and excretion of medications and may result in prolonged drug effects and greater sensitivity to medications, in terms of both therapeutic response and side effects (533). Age-related changes in receptor-site activity may further influence response to drugs in elderly patients. In general, recommended starting doses in older patients are one-quarter to one-half of the usual adult starting dose (529) (see Table 2).

The presence of concomitant medical illness or the use of multiple medications frequently complicates the treatment of older patients. In addition, age-related sensory deficits and cognitive impairment may interfere with patients' adherence to prescribed medication regimens. Elderly patients may unintentionally take incorrect doses of medications or follow erroneous dosing schedules.

Several important considerations bear on the use of antipsychotics in elderly patients. The cumulative annual incidence of tardive dyskinesia with first-generation antipsychotic medications has been found to be sixfold higher in later life than in younger adults (i.e., about 30% in later life) (534). Other side effects of particular concern in elderly patients include sedation, anticholinergic effects, and postural hypotension. Second-generation antipsychotics are generally recommended over first-generation agents because of their significantly lower risk of inducing extrapyramidal symptoms and tardive dyskinesia in older persons (534–538). However, the second-generation agents have other clinically significant and common side effects (Table 4), most notably sedation and orthostatic hypotension. Elderly patients with low cardiac output are especially vulnerable to hypotension and cardiac arrhythmia. The anticholinergic side effects of antipsychotic drugs in the presence of the age-related decrease in cholinergic function can contribute to problems such as urinary retention, confusion, and constipation or fecal impaction in the elderly patient. In some cases, elderly patients who are frail or poorly nourished may benefit from medication-induced weight gain; however, weight gain may also aggravate preexisting cardiovascular disease or osteoarthritis in this population. Elevated prolactin levels may also compromise bone-mineral density and increase osteoporosis.

Depression is not only common but also functionally disruptive in older persons with schizophrenia (539). In such instances, an antidepressant may need to be added to the treatment regimen. A wide variety of antidepressants are commonly used, although no comprehensive comparative trials in this population have been published. One small study found citalopram to be both useful and relatively safe in older patients with psychosis (540).

Psychosocial treatments are also recommended for a majority of individuals. Psychosocial evaluation may reveal a precipitating stress, such as a death in the family or a move to unfamiliar surroundings, that may explain a sudden change in the elderly person's behavior. Recent work has evaluated the benefits of integrated cognitive behavioral and social skills training (CBSST) in groups of older patients with schizophrenia (541). Results of a small randomized, controlled pilot study comparing CBSST plus pharmacotherapy to pharmacotherapy alone demonstrated the feasibility and acceptability by patients of CBSST and some improvement in psychopathology with CBSST in older patients with schizophrenia (541). Another pilot study showed the usefulness of functional adaptation skills training (542) in improving daily functioning in older patients with schizophrenia.

3. Concurrent general medical conditions

Patients with schizophrenia and related severe and persistent mental illness suffer disproportionately from a variety of comorbidities, including cardiovascular disease, respiratory disease, diabetes, infectious diseases (e.g., HIV), and substance use disorders (including nicotine, alcohol, and other substances) (543–554). A consequence of this excess comorbidity is an increased non-suicide-related mortality rate in this population (34, 388, 555). The increased frequencies of the various comorbid conditions are determined by multiple factors, including associations with schizophrenia itself (e.g., diabetes, smoking), life style (e.g., smoking, substance use, obesity, lack of exercise), environment (e.g., poverty, institutionalization), and medications (e.g., extrapyramidal syndromes, tardive dyskinesia, hyperprolactinemia, weight gain, hyperglycemia, hyperlipidemia, and cardiac arrhythmias). Thus, treatment selection and clinical management of patients with schizophrenia must consider the patient's past medical history and general medical status of the patient in determining the treatment plan. Patients should be evaluated in terms of their medical history and baseline assessments and then monitored with the relevant measures at appropriate intervals or when the patient's medical condition warrants or when a change in medication that could affect their medical condition is made, as indicated in Table 1. In the event that the patient's comorbid medical condition is affected adversely by a therapeutic agent (including an antipsychotic drug), management strategies may include helping the patient tolerate the adverse effect, treating the comorbid condition, or considering a change in the psychotropic medication to an alternative with less potential to induce side effects.

Patients with dementia and elderly patients are at very high risk of tardive dyskinesia. In addition, patients with dementia, Parkinson's disease, or other disorders associated with structural brain pathology are at increased risk of worsening of extrapyramidal side effects. Similarly, patients with psychosis and mental retardation are at increased risk for extrapyramidal side effects and tardive dyskinesia (556, 557). Thus, in these groups of patients, second-generation antipsychotics and particularly those with minimal or no risk of extrapyramidal effects (e.g., quetiapine) are recommended (558, 559). Furthermore, when such patients are treated with antipsychotic drugs, they must be monitored for side effects, and the increased risk of extrapyramidal side effects and tardive dyskinesia must be weighed against potential therapeutic benefits.

For patients with preexisting osteopenia or osteoporosis, an antipsychotic with minimal to no effects on prolactin should be prescribed. If a drug that increases prolactin is clinically indicated, then the relative safety of the antipsychotic should be discussed with the physician treating the bone demineralization. Female patients with menstrual or fertility problems should be evaluated for abnormalities in prolactin secretion, and non-prolactin-elevating medications should be considered as indicated. In addition, for women with breast cancer, antipsychotics with prolactin-elevating effects should be avoided or prescribed only after consultation with the patient's oncologist. In such instances, aripiprazole, which partially suppresses prolactin release, may be specifically indicated. However, in lactating mothers, suppression of prolactin may be detrimental, and the potential for this effect should be considered.

Obese patients and patients who have or may be at risk for diabetes and cardiovascular disease should be assessed before beginning treatment with antipsychotic drugs. Additional assessments are indicated at appropriate intervals thereafter or when warranted by a change in the patient's medical condition or medication regimen (see Table 1). Treatment selection should weigh the expected benefits of antipsychotic therapy against its potential to exacerbate or contribute to the development of specific medical conditions.

Patients with prolonged QT syndrome, bradycardia, certain electrolyte disturbances, heart failure, or recent myocardial infarction and patients who are taking drugs that prolong the QT interval should not be treated with an antipsychotic that could further prolong the QT interval or increase the risk of the arrhythmia torsades de pointes. These antipsychotics include thioridazine, droperidol, and ziprasidone. Pimozide also may prolong the QT interval.

Medications with low affinity for -adrenergic receptors should be prescribed for patients who are vulnerable to orthostatic hypotension, including elderly patients, patients with peripheral vascular disease or compromised cardiovascular status, and other severely debilitated patients.

For patients with acute angle-closure glaucoma, severe constipation (or at risk for fecal obstruction), history of a paralytic ileus, urinary retention, prostate hypertrophy, or delirium/dementia, antipsychotics with little or no antagonism for cholinergic receptors should be prescribed.

Patients with severe dementia may be at increased risk of stroke when treated with risperidone. Clinicians treating psychosis in patients with dementia should refer to up-to-date FDA guidelines when considering the safety of risperidone in this population.

Clozapine should not be prescribed for patients with neutropenia (<1500/mm³) or low white blood cell (WBC) count (<3000/mm³) or a history of such sensitivities to prior medications.