CHAPTER 9

Schizophrenia Spectrum and Other Psychotic Disorders

T. Scott Stroup, M.D., M.P.H.

Ryan E. Lawrence, M.D.

Atheir Ibrahim Abbas, M.D., Ph.D.

Bradley Ress Miller, M.D., Ph.D.

Diana O. Perkins, M.D., M.P.H.

Jeffrey A. Lieberman, M.D.

Schizophrenia is a brain disorder that generally affects mental functions and behavior. It is associated with a variable course, and outcomes range from complete recovery to severe disability. The most prominent characteristics of schizophrenia are hallucinations, delusions, and disorganization, which may lead to dangerous or bizarre behaviors. More insidious are so-called negative symptoms, such as social withdrawal and diminished emotional engagement, and cognitive impairments that can significantly impair social and occupational functioning. Because onset is usually in late adolescence or early adulthood, schizophrenia and related disorders are a leading cause of disability. Globally, schizophrenia is the fifth leading cause of years lost to disability for men and the sixth leading cause for women (World Health Organization 2008). Adverse consequences include unemployment, violence, hospitalization, medical comorbidities, homelessness, and premature mortality.

The often-cited 1% worldwide prevalence of schizophrenia is a reasonable approximation but is somewhat higher than that supported by a systematic review of 46 epidemiological studies, which reported a lifetime morbid risk of schizophrenia of 0.7% for all persons in a birth cohort (Saha et al. 2005). This review found that the median point prevalence of schizophrenia was 4.6 per 1,000 persons, or 0.5%. Studies of the incidence of schizophrenia have found fivefold variation across different populations. In a systematic review of more than 100 epidemiological studies in 32 countries, the median incidence rate was 15.2 per 100,000 persons per year (McGrath et al. 2004).

Treatments for schizophrenia include antipsychotic medications, which reduce hallucinations, delusions, and disorganized behaviors, and psychosocial interventions that improve illness management and promote recovery. Epidemiological evidence from the United States suggests, however, that many individuals with schizophrenia do not receive treatment (Regier et al. 1993).

Studies of the course of schizophrenia find a range of disability and illness chronicity. Most patients who experience a first episode of psychosis will experience symptomatic remission, but almost all will later have a relapse. However, as many as one of every five people who develop a schizophrenic disorder will have a sustained recovery, and a small proportion will completely recover and may never have a relapse. Ultimately, about one-third of patients achieve a relatively good outcome with only mild symptoms and functional impairments, with the remainder having moderate to severe symptoms and functional impairments. About 10% of patients will have persistent, unremitting psychosis (Wiersma et al. 1998). Clinicians who treat individuals with schizophrenia typically see patients with persistent or recurrent symptoms and functional disability and thus do not have much opportunity to see recovered patients, who commonly do not seek treatment.

Despite the heterogeneous course of schizophrenia, several factors are known to increase the likelihood of sustained recovery. Therapeutic interventions including antipsychotic medications should occur as close to the onset of psychosis as possible. Long-term maintenance treatment is associated with sustained recovery. Because it is not possible to determine prospectively who will have a severe and who will have a benign course, most experts currently recommend maintenance antipsychotic treatment. Efforts to prevent recurrent episodes and to promote family and social support are also likely to improve prognosis.

In this chapter, we describe the clinical presentation of schizophrenia and recommended diagnostic assessment. We discuss the natural history of schizophrenia and provide current recommendations for clinical management. Also included is a section on etiology and pathophysiology and a conclusion that focuses on future directions.

Clinical Presentation

Schizophrenia broadly affects mental activity and is associated with varying but marked functional impairment. The core psychopathology of schizophrenia, according to DSM-5 (American Psychiatric Association 2013) nosology, includes positive symptoms (delusions and hallucinations), disorganization (disorganized speech or grossly abnormal behavior), and negative symptoms (e.g., avolition and decreased emotional expression) (American Psychiatric Association 2013). Natural history data suggest that the pervasiveness and severity of these symptoms are highly variable (Fenton and McGlashan 1991).

Positive Symptoms

Positive symptoms can manifest in many forms, including hallucinations, hyperactivity and hypervigilance, mood lability, grandiosity, suspiciousness, and hostility. Historical evidence (from before the antipsychotic era) showed that 91% of hospitalized patients had delusions (47% marked/severe), 87% had bizarre behavior (40% marked/severe), 66% had hallucinations (28% marked/severe), and 66% had thought disorder (8% marked/severe) (Fenton and Mc-Glashan 1991).

Psychological studies trace positive symptoms to errors in cognitive processing; altered perceptions, misattribution of environmental cues, attentional deficits, bias toward threatening information, and an overreliance on internal states have all been implicated. For example, when given cognitive tasks, delusional patients tend to be overconfident in their responses, and they require less information before jumping to conclusions (Ventura et al. 2010).

Disorganization

Although disorganization is considered by many to be a positive symptom, factor analyses suggest that disorganization is distinct from delusions and hallucinations. Disorganization encompasses conceptual disorganization, disorientation, posturing and mannerisms, bizarre behavior, stereotyped thinking, difficulties with abstract thinking, poor attention, and inappropriate affect (Ventura et al. 2010).

Disorganization is more socially impairing than hallucinations or delusions and is associated with a worse prognosis. Although individuals may learn to ignore hallucinations or to avoid talking about or acting on delusions, disorganization is harder to mask. Disorganization also correlates with deficits in attention/vigilance, reasoning and problem solving, processing speed, and IQ (Ventura et al. 2010).

Negative Symptoms

Negative symptoms include blunted affect, emotional withdrawal, social withdrawal, poor rapport with other persons, difficulty with abstract thinking, loss of spontaneous conversation, and stereotyped thinking (rigid, repetitious, or barren thought content). Historical evidence (from before the antipsychotic era) showed that among hospitalized patients, 76% had anhedonia (23% marked/severe), 72% had flattened affect (17% marked/severe), 71% had avolition or apathy (25% marked/severe), 48% had alogia (16% marked/severe), and 46% had attentional impairment (17% marked/severe) (Fenton and McGlashan 1991).

Severe negative symptoms are associated with worse premorbid function (fewer vocational skills, fewer avocational interests, lower mean IQ, lower likelihood of marriage). Negative symptoms are also associated with insidious onset of disease, fewer remissions, and poorer long-term functioning. Negative symptoms tend to worsen over time (Fenton and McGlashan 1991).

Cognition

Schizophrenia is associated with significant cognitive impairment, in some cases along with disorganization. Cognitive impairment is increasingly considered a core feature of the illness and not the result of other symptoms, treatments, or measurement issues. A striking aspect of the cognitive deficits of individuals with schizophrenia is the broad dissimilarity to healthy control subjects. Individuals who develop schizophrenia have a lower premorbid IQ than normal controls (a mean of 94.7 vs. 100), and longitudinal studies have shown a decline in IQ over time. In some cognitive domains, the average impairment approaches two standard deviations below the mean of healthy control subjects (Saykin et al. 1994).

Complications

Suicide

Individuals with schizophrenia are at increased risk of suicide, with approximately 5% dying by suicide and 20% or more making at least one suicide attempt at some point. Significant suicidal ideation is also common. Until recently, the lifetime risk of suicide in schizophrenia was held to be 10%-15% because estimates arose from estimates of proportionate mortality (the percentage of fatalities due to suicide), which likely overestimate suicide risk in a population in which the suicide risk goes down over time as in schizophrenia (Palmer et al. 2005).

Several risk factors for suicide among people with schizophrenia have been identified. Suicide risk is increased near illness onset and remains elevated for many years after initial treatment, but declines somewhat over time (Nielssen et al. 2012). Other specific risk factors include younger age, younger age at symptom onset, high premorbid functioning, high personal expectations, awareness that life's expectations are unlikely to be met, awareness of symptoms (especially if aware of delusions, anhedonia, asociality, blunted affect), and a negative attitude toward or noncompliance with treatment. As in the general population, male gender, unmarried status, living alone, unemployment, and access to lethal means are risk factors for suicide among individuals with schizophrenia (Siris 2001).

Clinical factors that increase risk include depressive symptoms, florid psychosis, panic symptoms, alcohol or substance abuse, prior suicide attempts, and few negative symptoms. Clinicians should also be aware that risk is higher when the patient is out of the hospital on pass, was recently discharged from the hospital, had only a brief hospitalization, or has had multiple recent admissions (Siris 2001).

Clozapine appears to reduce suicide risk. When patients with treatment-resistant schizophrenia received clozapine, the suicide attempt rate fell from 25% to 3.5%. Subsequent research showed that clozapine reduced suicidal behaviors in a high-risk group of patients who did not meet criteria for treatment-resistant schizophrenia. Possible explanations include the following: psychotic symptoms were better controlled, clozapine may have antidepressant properties, or patients taking clozapine are seen more frequently (due to blood draws) and this clinical contact is protective (Siris 2001).

Substance Abuse

Among individuals diagnosed with schizophrenia, co-occurring substance abuse and dependence are common, with lifetime prevalence rates approaching 50% (not including nicotine) (Regier et al. 1990). Substance use disorders are associated with a worse course of illness and treatment complications, including increased risk of treatment nonadherence, suicidal and violent behaviors, hospitalization, homelessness, victimization, and infection with HIV, hepatitis B, and hepatitis C (Drake and Mueser 1996; Rosenberg et al. 2001).

Nicotine is the most commonly used substance; smoking rates among individuals diagnosed with schizophrenia are much higher than those in the general population (de Leon and Diaz 2005). Multiple factors have been hypothesized to contribute to the high prevalence of smoking. Biologically, a7 nicotinic receptors have been implicated in the diminished auditory sensory gating that has been found in people with schizophrenia. That the nicotinic system may be involved in the pathophysiology of schizophrenia suggests possible biological underpinnings to the high smoking rates (Leonard et al. 2007). In addition, smoking increases the metabolism of many antipsychotic drugs and may reduce side effects by reducing blood levels or by directly reducing drug-induced parkinsonism. Psychologically, studies have suggested that individuals with schizophrenia may smoke to self-medicate illness symptoms (Lucksted et al. 2004). Social factors that may affect smoking rates among people with schizophrenia include the high prevalence of smokers in the social networks of people with schizophrenia.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which included 1,460 patients with schizophrenia from 57 sites in the United States, 60.3% reported some substance use (other than nicotine). Of these subjects, 37% met criteria for abuse or dependence, and another 23% used substances without evidence of impairment (Lieber-man et al. 2005a; Swartz et al. 2006). Alcohol was the most common substance used (48%), followed by marijuana (23%) and cocaine (19%). Additional CATIE analyses found that the greater severity of use was associated with greater impairment (Kerfoot et al. 2011).

Substance abuse is associated with an earlier age at schizophrenia onset (17.7 vs. 25.7 years) and a worse clinical outcome. Patients with comorbid substance problems have higher relapse rates, more treatment noncompliance, poorer overall response to pharmacotherapy, more hospitalizations, and an increased risk of violence (Green 2006). A growing body of evidence suggests that marijuana use is a risk factor for developing schizophrenia.

Treating comorbid substance abuse may improve outcomes. Among anti-psychotics, clozapine has been associated with decreased cocaine craving, decreased smoking rates, decreased alcohol use, decreased overall substance use, and increased abstinence. Disulfiram has been used with some success but carries concern about worsening psychotic symptoms. Naltrexone can help patients with alcohol problems. Acamprosate and topiramate are not well studied in schizophrenia.

Depression

Approximately 25% of patients with schizophrenia suffer from comorbid depression. It is associated with more impaired functioning, more personal suffering, higher relapse rates, more hospitalizations, and suicide (Siris 2000).

Comorbid depression can be difficult to diagnose, because its symptoms overlap with the negative symptoms of schizophrenia, especially anhedonia, anergia, and blunted affect. However, true depression is marked by the subjective experience of sad mood or guilty thoughts. Recognizing depression is challenging when patients have impaired communication skills; however, distinguishing between depression and negative symptoms is important, because depression is a risk factor for suicide, whereas negative symptoms are relatively protective (Siris 2000).

Common organic etiologies must first be ruled out (e.g., thyroid dysfunction, anemia, substance abuse, medication side effects). Akinesia associated with antipsychotic drugs can resemble depression. Reducing the antipsychotic dosage, or adding an anticholinergic agent to treat parkinsonism can improve symptoms. Sometimes, depressive symptoms emerge prior to a psychotic relapse, but these typically last only a few days or weeks before they are surpassed by more prominent and definitive psychotic symptoms (Siris 2000).

Treatments for comorbid depression in schizophrenia are not well established, and studies that established the efficacy of antidepressants for regulatory approval systematically excluded people diagnosed with schizophrenia. However, some evidence suggests that adding an antidepressant to an antipsychotic regimen can be helpful. Most trials to date combined a tricyclic antidepressant with a typical antipsychotic. Combining a serotonin reuptake inhibitor with an antipsychotic does not have a strong evidence base but is common practice.

Patients who do best taking combinations of antipsychotics and antidepressants are those who are not floridly psychotic and who fully meet criteria for a major depressive episode when the antidepressant is added. Psychosocial interventions are always appropriate (Siris 2000). A recent pharmacoepidemiological study from Finland found that use of antidepressants in combination with antipsychotics was associated with decreased all-cause and suicide mortality (Tiihonen et al. 2012).

Violence

Most patients with schizophrenia are not violent, and most episodes of violence do not result in any significant injury. However, schizophrenia—especially untreated psychosis—is a risk factor for violence. A review of violence during a first episode of psychosis found that one-third of persons in their first episode of psychosis commit an act of violence before entering treatment (Nielssen et al. 2012). One in six patients experiencing a first psychotic episode commits an act of serious violence (i.e., assault causing any degree of injury, sexual assault, or assault with a weapon). Less than 1% of first-episode patients commit an act of severe violence resulting in severe or permanent injury.

In the CATIE study, 19% of patients exhibited violent behavior at some point prior to the study. Predictors of violence were childhood conduct problems, substance misuse, a history of victimization, economic deprivation, and living with other people (rather than living alone). Patients with a history of violence were more likely to discontinue their medication. A history of violence was a predictor of violence over the next 6 months (Swanson et al. 2008). Increased positive symptoms were associated with increased rates of violent behaviors, whereas negative symptoms were protective.

Antipsychotic medications reduce the rate of violent behaviors. However, persons with a history of violence continue to be at risk for further violence, according to longitudinal studies (Nielssen et al. 2012). In the CATIE study, all antipsychotics tested (perphenazine, quetiapine, risperidone, ziprasidone, olanzapine) reduced the incidence of violence (Swanson et al. 2008). Clozapine has also been shown to reduce violence and is considered the treatment of choice for persistently violent individuals in inpatient units. To reduce violent behaviors, antipsychotics are commonly augmented with lithium, valproic acid or other anticonvulsants, or benzodiazepines, but the evidence supporting these treatments is limited (Buckley et al. 2011).

In hospital settings, aggression is ideally managed by employing verbal de-escalation techniques, clearing the room of potential stimuli or potential victims, recruiting adequate staff to manage the aggression, and medicating with rapid-onset medicines (intramuscular injections). The combination of intramuscular haloperidol 5 mg and lorazepam 2 mg leads to more rapid tranquilization than either medication alone, but medically complicated individuals should receive haloperidol alone. Intramuscular olanzapine 10 mg is superior to haloperidol in some trials. Lower dosages should be given to individuals who are medically ill and older patients, and intramuscular olanzapine should not be given with intramuscular benzodiazepines because it can cause orthostatic hypotension (Buck-ley et al. 2011).

Medical Comorbidity

Mortality rates in patients with schizophrenia are two to four times higher than in the general population, and the average lifespan is up to 25 years shorter than in the general population. Although some of this variation is attributable to the increased suicide rate and a higher rate of traumatic injuries, medical comorbidity also plays a major role. Cardiovascular disease accounts for a large share of the premature mortality. In comparison with control populations, patients with schizophrenia have higher rates of cardiovascular disease, die more frequently from cardiovascular disease, and experience more sudden death. Risk factors for cardiovascular disease that are common among individuals with schizophrenia include smoking, obesity, diabetes, dyslipidemia, lack of exercise, and the cardiac side effects of antipsychotic drugs (Leucht et al. 2007).

Related to cardiovascular disease is the constellation of risk factors labeled metabolic syndrome (weight gain, insulin resistance, hypertension, elevated triglycerides, and decreased high-density lipoprotein cholesterol levels). A metaanalysis estimated a point prevalence of 32.5% for metabolic syndrome in adults with schizophrenia, with variation according to individual factors, behaviors, and medications taken (Mitchell et al. 2013). Some antipsychotic medications, in particular olanzapine and clozapine, are associated with high levels of weight gain and metabolic problems. When risk factors are considered individually, half of patients with schizophrenia are overweight, one in five has hyperglycemia, and two in five have lipid abnormalities (Mitchell et al. 2013).

Of the infectious diseases, HIV and hepatitis are more common among patients with schizophrenia than in the general population (Leucht et al. 2007). Increased rates of osteoporosis have been noted among patients with schizophrenia. Possible explanations include elevated prolactin levels from antipsychotic medication, sedentary lifestyle and lack of exercise, smoking, other substance use, dietary and vitamin deficiencies, decreased sun exposure, and polydipsia-induced electrolyte imbalances (Leucht et al. 2007).

Polydipsia is a poorly understood complication of schizophrenia that can cause (potentially fatal) hyponatremia. Risk factors include younger age at schizophrenia onset, male sex, white race, heavy smoking, poor antipsychotic response, and tardive dyskinesia (Jeste et al. 1996).

Other complications have been described. High prolactin levels can cause galactorrhea and amenorrhea (Leucht et al. 2007). Sexual dysfunction and urinary incontinence have also been described. The pregnancies of women diagnosed with schizophrenia have higher rates of complications compared with those of other women, possibly due to cigarette smoking and illicit drug and alcohol use. Most antipsychotic medications have unknown effects on human fetuses, but possible risks to the fetus must be weighed against maternal benefits.

Much medical comorbidity among psychiatric patients goes unrecognized, by both patients and caregivers. Some evidence suggests that patients with schizophrenia have a higher pain tolerance or that neuroleptics may reduce pain sensitivity, resulting in fewer complaints to the physician. Additionally, patients with known somatic delusions may not be fully evaluated for their complaints (Jeste et al. 1996). Current efforts to create medical or behavioral health homes are intended to improve the integration of medical and psychiatric care and have the potential to improve the recognition of medical illnesses and thus improve outcomes.

Case Examples

Case 1

A 19-year-old man with no psychiatric history leaves home to attend a university. Early in his first semester, he stops attending class and instead spends all of his time in the library collecting newspaper articles about international espionage. In his second semester, he is brought to the emergency room after campus safety officers found him breaking into the biology building. On psychiatric interview he insists that researchers in the university laboratory are inventing viruses and deliberately poisoning the campus water supply, as evidenced by the fact that the plant in his dorm room is dying. The patient begins taking an antipsychotic medication and has a good response, showing reduced preoccupation with his delusions. He returns home to live with his parents, remains stable on his medication, and is able to complete his undergraduate degree at the local university. Upon graduation he obtains a full-time job in a small business owned by a family friend. He continues to have periods of symptom exacerbation, requiring temporary increases in his medication and an occasional hospitalization, but each time he is able to return to work afterward.

Case 2

A 27-year-old woman is brought to the emergency room by her parents. For the past year, she has been increasingly socially withdrawn. She was fired from her job for missing work without calling. She stopped socializing with friends, and currently spends all of her time in her bedroom. She leaves her room only to get food from the kitchen. On presentation she is malodorous, disheveled, and wearing wrinkled clothing with stains on it. During the interview she gives only brief answers to questions and often appears distracted, frequently looking over her shoulder even though nobody else is in the room. She endorses occasionally hearing voices of two people saying she is a bad person. She begins taking an antipsychotic, which reduces the auditory hallucinations. However, she continues to live with her parents, does not return to work, and spends most of her time watching television.

Diagnostic Assessment

Diagnostic Criteria tor Schizophrenia

A DSM-5 diagnosis of schizophrenia (Box 9-1) requires two or more core symptoms, one of which must be hallucinations, delusions, or disorganized speech. Core symptoms must persist for a significant portion of 1 month, with continuous signs of disturbance lasting at least 6 months. There must be evidence of markedly impaired functioning for a significant proportion of the illness, and competing diagnoses must have been ruled out. DSM-5 has eliminated the prior exception to the requirement for two characteristic symptoms if the one symptom is bizarre delusions or hallucinations involving running commentary or voices conversing with each other. DSM-IV and DSM-IV-TR (American Psychiatric Association 1994, 2000) included paranoid, disorganized, catatonic, undifferentiated, and residual subtypes, but also warned that subtyping had limited value in predicting disease course, treatment response, or disease correlates. All schizophrenia subtypes have been eliminated from DSM-5.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Initial Assessment

As with any change in mental status, a presentation consistent with schizophrenia warrants a medical evaluation to look for alternate diagnoses and reversible causes. The history and physical examination should pay special attention to any family history of neurological disease, mental illness, personal exposure to drugs or chemicals, and exposure to infectious agents. Routine laboratory testing, especially for newly diagnosed patients, should include a complete blood count, serum electrolytes (including calcium), blood urea nitrogen and creatinine, liver function tests, thyroid function tests, vitamin B₁₂ level, HIV and syphilis tests, drug screen, and brain imaging (MRI provides better images, but CT is significantly cheaper and faster). If clinically indicated, the following may be done: electroencephalography, ceruloplasmin test, chest radiography, or lumbar puncture (Viron et al. 2012).

Although schizophrenia has long been known to have a genetic component, genetic testing is not currently part of the standard evaluation for psychosis, unless family history or clinical evidence points to a known genetic disorder (e.g., Huntington's disease, velocardiofacial syndrome). Genetic testing remains an active area of research.

Differential Diagnosis

Table 9-1 provides examples of medical conditions that commonly or sometimes present with psychotic symptoms and should be considered in the differential diagnosis of schizophrenia.

Acute psychotic symptoms may occur in the context of delirium along with disturbances in attention and other cognitive problems when the disturbance is caused by another medical condition, substance abuse or withdrawal, exposure to a toxin, or a combination of causes. If psychosis is not present only in the context of delirium and is demonstrated by evidence (from the history, physical examination, or laboratory findings) to be the direct physiological consequence of a general medical condition, then the diagnosis is psychotic disorder due to another medical condition. When hallucinations or delusions develop in the context of exposure to or intoxication or withdrawal from a drug, medication, or toxin and do not occur exclusively during the course of a delirium, then the diagnosis is substance/medication-induced psychotic disorder. Hallucinations that occur only when going to sleep or when waking up (called, respectively, hypnogogic or hypnopompic hallucinations) are not considered a psychiatric disorder.

When medical etiologies have been ruled out and the symptoms are attributed to a primary psychiatric disorder, careful attention is paid to the timing, the nature of the symptoms, and associated features before arriving at a diagnosis. According to DSM-5 nosology, a diagnosis of schizophrenia means that signs of the illness have persisted for at least 6 months.

In brief psychotic disorder (Box 9-2), delusions, hallucinations, or disorganized speech last for more than 1 day but resolve within 1 month. Characteristically, people experiencing a brief psychotic disorder will change from a nonpsychotic state to a psychotic state suddenly ( e.g., within 2 weeks) without a prodrome. A full return to the premorbid level of functioning is required by DSM-5. Ruling out psychoses due to medications or abused substances is key to making the diagnosis of brief psychotic disorder.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Schizophreniform disorder (Box 9-3), like schizophrenia, is characterized by two or more of the following core symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and negative symptoms. The overall disturbance lasts from 1 to 6 months. Unlike schizophrenia, schizophreniform disorder does not have impaired social and occupational functioning as a diagnostic criterion. According to DSM-5, a "provisional" qualifier should be used if a schizophreniform diagnosis is made before 6 months have elapsed and it is unclear whether symptoms will resolve within 6 months. If the psychotic symptoms resolve in less than 6 months and do not return, the diagnosis remains schizophreniform disorder. If the symptoms last longer than 6 months, then the diagnosis is likely schizophrenia or schizoaffective disorder.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Delusional disorder (Box 9-4) is characterized by one or more delusions that are present for longer than 1 month. If hallucinations are present, they are not prominent and are related to the content of the delusions. For a diagnosis of delusional disorder, functioning should not be markedly impaired and behavior not obviously odd (apart from the impact of the delusions). Individuals with delusional disorder tend to behave and appear appropriately when their delusions are not being discussed or acted upon. However, social, marital, work, or legal problems can result from delusional beliefs or actions taken in response to delusions.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Psychosis can also occur during the manic phase of bipolar I disorder or during major depressive disorder with psychotic features. If delusions or other psychotic symptoms occur exclusively during manic or depressive episodes, then the diagnosis is bipolar or major depressive disorder with psychotic features. Schizoaffective disorder (Box 9-5) is diagnosed when the core symptom criteria for schizophrenia co-occur with a manic or major depressive episode but are preceded or followed by at least 2 weeks of delusions or hallucinations without a major mood episode. To meet DSM-5 criteria for schizoaffective disorder, major mood episodes must be present for at least half the total duration of the illness. Some individuals who initially receive a diagnosis of schizoaffective disorder may no longer fulfill this condition if mood symptoms become less prominent over time. Impaired social or occupational functioning is not a diagnostic criterion, reflecting a belief that schizoaffective disorder has a somewhat better prognosis than schizophrenia.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Other specified or unspecified schizophrenia spectrum and other psychotic disorder is diagnosed when a patient's presentation does not fit any of the categories described above. The "other specified" designation is used when the clinician wishes to indicate the reasons that full criteria for a specific psychotic disorder are not met. Examples of presentations that could qualify for this designation include attenuated psychosis syndrome (see discussion in "Prodromal Stage" under "Natural History of Schizophrenia" section below) and persistent auditory hallucinations without other psychotic features. The "unspecified" designation requires no assignment of the specific reason(s) that a patient's presentation does not meet full criteria; this category may be used when additional information is needed to make a definitive diagnosis.

Natural History of Schizophrenia

The natural history of schizophrenia is characterized by four stages of illness: the premorbid, prodromal, progressive, and chronic-residual stages (Figure 9-1). All stages are characterized by specific symptoms and functional deficits that progress as patients move through the illness stages and worsen in severity.

Premorbid Stage

In the premorbid stage of illness, individuals who will eventually develop schizophrenia do not yet exhibit significant signs or symptoms of the illness. Although function in the premorbid stage is not typically concerning enough to bring individuals to the attention of mental health practitioners, a number of studies have identified subtle differences in various domains between those individuals who later develop schizophrenia and those who do not, including physical and motor abnormalities and deficits in intellectual and social functioning. In two large cohort studies, children who would subsequently develop schizophrenia reached gross motor milestones later than other children, and they were almost five times less likely at health care-related visits to have reached all their milestones (Jones 1997). School doctors more frequently noted nonstructural speech defects that persisted to at least age 11, and health professionals were three times more likely to note any speech problem in these children. At age 7 years, children who went on to develop schizophrenia were differentiable as a group from other children with respect to motor coordination and incontinence. Similar deficits persisted when children were reexamined at age 11 years. Finally, a number of subtle physical abnormalities have been noted in children in the premorbid stage, including variations in limb length and fingerprint patterns.

Ample evidence indicates that children who go on to develop schizophrenia exhibit deficits in intellectual and behavioral function in a broad range of categories, including measures of both verbal and nonverbal intelligence, as well as ratings of behaviors that include, for example, conduct, orderliness, and motivation. Notably, the aforementioned abnormalities are mild in severity and have low predictive validity. Also of note, the pre-morbid abnormalities that have been measured in children who would later develop schizophrenia are in most cases either not present in children who go on to develop affective illness such as bipolar disorder or who are significantly attenuated in severity in comparison to the children who would subsequently develop schizophrenia.

Figure 9-1. Natural history of schizophrenia.

Source. Adapted from Lieberman JA, Perkins D, Belger A, et al: "The Early Stages of Schizophrenia: Speculations on Pathogenesis, Pathophysiology, and Therapeutic Approaches." Biological Psychiatry 50:884-897, 2001.

In the context of the genetic model of schizophrenia, the premorbid stage can be viewed as one in which the phenotype is expressed only mildly or not at all. It also should be emphasized that although mean differences can be detected between the subjects who go on to develop schizophrenia and their peers, the distributions of the two groups overlap substantially and do not permit individual prediction of who will develop schizophrenia.

Prodromal Stage

Despite the fact that children who subsequently develop schizophrenia exhibit abnormalities in motor, intellectual, and behavioral function, there is little to no evidence of any progression of deficits until they reach the so-called prodromal stage. This stage of illness is characterized by the onset of signs and symptoms that herald impending psychosis. The prodromal stage is a particularly active area of research and program development in the United States, Europe, and Australia, with the intention of developing methods for early detection and intervention to prevent the full manifestation of the psychotic syndrome.

The criteria used to identify individuals in the prodromal stage typically require one of three categories of symptoms: attenuated psychotic symptoms, transient psychotic symptoms that are brief in duration and remit spontaneously, or a significant decrease in functioning in conjunction with a genetic risk for schizophrenia or in conjunction with a schizophrenia spectrum personality disorder (Yung et al. 2003). In an analogous approach aimed at identified prodromal patients, a set of "basic symptoms" was identified that included five clusters: thought, language, perception, and motor disturbances; impaired bodily sensations; impaired tolerance to normal stress; disorders of emotion and affect; and increased emotional reactivity or impaired ability to maintain or initiate social contacts (Klosterkotter et al. 2001). In a recent meta-analysis of all studies that examine transition to psychosis of prodromal patients, the transition risk was shown to range from 22% within 1 year to 36% within 3 years of clinical presentation (Fusar-Poli et al. 2012a). Importantly, the criteria used to identify prodromal individuals are strongly biased toward identification of schizophrenic psychosis rather than affective psychosis.

As might be expected given the evidence of intellectual impairment in schizophrenia, individuals in the prodromal stage exhibit widespread cognitive deficits, including deficits in attention, executive function, general intelligence, processing speed, verbal fluency, visual memory, verbal memory, and working memory (Fusar-Poli et al. 2012b). Furthermore, adolescents who subsequently develop schizophrenia have a much higher rate of nonpsychotic psychiatric diagnoses, including schizophrenia-spectrum personality disorders, anxiety disorders, affective disorders, and attention-deficit/hyperactivity disorder prior to their first psychotic break. Finally, the prevalence of self-reported drug abuse is elevated in adolescents who go on to be diagnosed with schizophrenia. (Abuse of substances, particularly stimulants, hallucinogens, and cannabis, is also a known risk factor for schizophrenia.)

Much of the interest in better identifying patients in the prodromal phase has arisen in the hopes that early intervention may result in improved outcomes. In a meta-analysis of seven studies, five of which were randomized controlled trials, Preti and Celia (2010) reported that receiving any focused treatment was associated with a lowering of the risk of transitioning to psychosis (RR=0.36), although the effect of treatment was not stable after cessation. Overall, the data are limited, but this is an area of active investigation. As a result, a psychosis risk syndrome—essentially attenuated psychotic symptoms in conjunction with help-seeking behavior as a result of the distress caused by the symptoms—was proposed for DSM-5 to identify a subset of individuals at increased risk for developing schizophrenia. Substantial controversy ensued, and the decision was made to change the name of the category to attenuated psychosis syndrome (Box 9-6), focusing on current clinical need, and to include it under Conditions for Further Study in Section III of DSM-5.

Progressive Stage

The progressive stage of schizophrenia can be said to begin when overt psychotic symptoms develop. Earlier in the section "Clinical Presentation/' we detailed the characteristic symptoms of schizophrenia, which typically fall into the three major categories of positive, negative, and cognitive symptoms, and which result in significant social and occupational dysfunction. A key characteristic of the progressive stage of schizophrenia, which is typically conceptualized as lasting 5-10 years, is progressive deterioration with respect to symptoms and abnormalities of the brain. The idea that early schizophrenia is characterized by progression of symptoms as well as the progression of structural brain abnormalities, rather than stable brain abnormalities that have been present since birth, was until recently controversial; however, it has become increasingly widely accepted as evidence accumulates. Studies have also provided significant evidence regarding the beneficial effect of antipsychotic pharmacotherapy with respect to slowing or arresting the progression of structural changes in the brain. Conversely, evidence regarding the deleterious effect of repeated or extended psychotic episodes also exists.

Typically, patients who are treated relatively early in the course of their illness experience a substantial reduction in symptoms. Positive symptoms respond best, and in some cases fully, whereas cognitive and negative symptoms tend to be less prominent at the onset of psychosis, are less treatment responsive, and persist in at least a large subset of individuals. After psychotic symptom response, partial or complete, the majority of patients will not continue medication (either because they stop on their own or their doctors agree to taper and discontinue after a period of stability). However, most of these patients will subsequently experience relapse of psychotic symptoms. In the context of repeated relapses, patients often achieve remissions that are less complete than previously occurred. Through the aforementioned relapses and remissions, clinical deterioration is characteristic of the progressive stage of illness. Within the first 5 years after first-episode recovery, more than 80% of patients will have relapsed, with discontinuation of antipsychotics increasing the risk of relapse almost fivefold (Robinson et al. 1999). Furthermore, the progressive phase of illness is the period of highest suicide risk.

Importantly, evidence is accumulating that clinical deterioration is accompanied by progressive changes in brain structure. The evidence to date has been fairly consistent in suggesting that prodromal patients exhibit mild brain abnormalities that progress during and after the transition to psychosis. Gray matter volumes have been shown in multiple studies to decrease in a progressive manner when comparisons are made between prodromal patients and first-break patients. Thinning of cortex, particularly frontal, temporal, and parietal cortex, has been a frequently reported finding. Progressive reductions of white matter integrity in frontal cortex have also been reported as patients make the transition from the prodromal stage to psychosis. Finally, lateral ventricular enlargement, which may be present at the start of illness, has also been shown to be progressive.

How closely correlated clinical deterioration is to structural changes of the brain is less clear. In terms of cognitive performance, data have been inconsistent. A correlation between changes in brain morphology such as reduction in gray matter volume and progression of cognitive decline has been reported in some but not all studies (Cobia et al. 2012). Some evidence has also suggested that the magnitude of the decline in gray matter density was directly correlated with the number of hospitalizations (van Haren et al. 2007). Finally, evidence suggests that anti-psychotics can prevent, slow down, or arrest the structural changes seen in the brains of patients with schizophrenia (Lieberman et al. 2005b).

Chronic-Residual Stage

Five to 10 years after entering the progressive stage of schizophrenia, patients typically enter what may be called the chronic-residual stage, which is characterized not by inexorable progression but rather by the persistence of residual symptoms and disability. Outcomes are heterogeneous, with most of the variability related to severity and nature of symptoms, markers of chronicity such as age at onset and treatment resistance, and other predictive variables such as demographic and premorbid neurocognitive characteristics (McGlashan 1988). Although outcomes are heterogeneous, chronic illness and poor function are extremely common. Most patients exhibit significant residual positive, cognitive, and sometimes negative symptoms even after recovery from relapses, which tend to be numerous. However, a minority (<20% in some studies) experience full or near-full remission with minimal disability between relapses. Not surprisingly, the vast majority of patients tend to be rehospitalized in the first 2-5 years following the first discharge, while still in the progressive stage, and rehospitalizations continue throughout the course of the illness, including during the chronic-residual stage for many patients. Finally, although the risk of suicide is highest after the first psychotic episode and in the ensuing few years, it continues to be substantially elevated even 10 years later.

Notably, the preponderance of the evidence suggests that once the progressive stage is reached, cognitive deficits and negative symptoms remain relatively stable, with positive symptoms being the most likely to fluctuate significantly. Treatment resistance is uncommon early in the course of schizophrenia but tends to develop over the course of the illness in the context of subsequent episodes and illness progression. The level of treatment resistance may continue to worsen. In other words, individuals who may have responded to a particular medication in the past may become less responsive or unresponsive to that medication during future relapses during both the progressive and chronic-residual stages.

On average, functional outcome is poor, with most patients exhibiting significant social and occupational disability. However, many patients achieve a meaningful recovery in which illness is not the dominant part of their lives. Overall mortality is substantially increased because, in addition to an elevated risk of suicide, patients with schizophrenia have significantly increased rates of medical comorbidity, all-cause mortality, and concomitantly decreased life span. With respect to structural brain changes, the preponderance of the evidence suggests continued progressive decreases in brain tissue volume and ventricular volumes, with more pronounced brain changes associated with poorer outcomes. Thus, there may be a subset of patients with the most severe course who exhibit a very slow progression of disease even during the chronic-residual stage. Overall, however, the majority of clinical observations to date suggest that disease progression, once patients have reached the chronic-residual stage, is much less than during the progressive stage.

Interventions and Clinical Management

Treatment Goals

Treatment goals for individuals with psychotic disorders vary according to clinical circumstances. During an acute psychotic episode, the goals are to prevent harm to the patient and others, to control disturbed behavior, to reduce the severity of psychosis and associated symptoms (agitation, aggression, negative symptoms, mood symptoms), to address any reversible factors that triggered the episode, and to promote recovery to the best level of functioning attainable (Hasan et al. 2012). In the maintenance phase, the goals are to promote recovery by sustaining symptom remission or stability, thereby preventing or reducing the frequency of relapse; to lessen the impact of the disease on the patient's life; and to maximize the patient's social function and quality of life (Tandon 2011). Optimal treatment includes both pharmacological and psychosocial interventions.

Antipsychotic Drugs

Since the first antipsychotic, chlorpromazine, was introduced in the early 1950s, more than 60 similar antipsychotic medications have been developed, all of which modulate the effects of dopamine and block postsynaptic dopamine type 2 (D₂) receptors to varying degrees (Miyamoto et al. 2012; Tandon 2011). Antagonism of dopamine in the mesolimbic and mesocortical pathways is thought to account for the drugs' antipsychotic effect. Anti-psychotics also interact with other neurotransmitter systems, a fact that contributes to their side-effect profiles and may possibly influence their therapeutic effects. Antipsychotics have a robust effect on the core positive symptoms and disorganization that are characteristic of schizophrenia (Tandon 2011). Research has shown that patients with schizophrenia who achieve remission when taking antipsychotic drugs and then consistently continue to take the drugs are about three times less likely to relapse than patients who stop taking the drugs (Hogarty et al. 1976).

The onset of antipsychotic drug action appears in patients within a few days of starting treatment, and the effect often builds over several weeks. The full effect may take several months to develop. However, there is great heterogeneity in treatment response, and not all antipsychotic medications work for all patients. Response during the first 2-4 weeks of treatment with a medication is highly predictive of long-term response (Tandon 2011). Typically, most individuals experiencing a first episode of psychosis will respond well to antipsychotic medication. First-episode patients usually respond to relatively low dosages of medicine and are often extremely sensitive to a drug's adverse effects. Other patients (e.g., those who have experienced multiple episodes or long-term illness) may take longer to respond and require higher dosages. Not all individuals diagnosed with schizophrenia have a robust response to antipsychotic medications. Those who continue to have significant psychotic symptoms and substantial disability despite multiple trials of antipsychotics are said to have treatment-resistant schizophrenia. Clozapine is the only antipsychotic that is proven to work better than other drugs for treatment-resistant schizophrenia.

Antipsychotics have limited effects on negative symptoms. Their effect is strongest when the negative symptoms are caused by positive symptoms (termed "secondary negative symptoms"). For example, a person who is socially withdrawn due to paranoia might increase social activities when less paranoid. There are no proven treatments for negative symptoms that persist after response to treatment with antipsychotics. However, because some neurological side effects of antipsychotics (e.g., akinesia, expressionless face) and sedation resemble primary negative symptoms, treating or minimizing these side effects can improve ratings of negative symptoms.

Adverse Effects of Antipsychotics

Antipsychotics cause numerous adverse effects (Tables 9-2 and 9-3), which have limited the medications' therapeutic benefits and have been important considerations in their use. Variation in side-effect profiles is the primary distinguishing feature of the various antipsychotic drugs (see Table 9-2). Perhaps the most prominent adverse effects are rigidity, bradykinesia, and tremor resembling Parkinson's disease; severe restlessness known as akathisia; and abnormal involuntary movements known as tardive dyskinesia. These neurological effects, known as extrapyramidal side effects (EPS), were extremely problematic in the early decades of antipsychotic use but are currently less of a concern. In part, this is due to the fact that newer (so-called second-generation) antipsychotics, which are now used predominantly, are less likely to cause EPS and tardive dyskinesia. In addition, because these neurological effects are dose related, more moderate dosing of antipsychotics in recent years has contributed to decreased neurological problems.

Many antipsychotics have cardiovascular effects. Some effects are relatively benign (tachycardia, orthostatic hypotension), although orthostatic hypotension can be problematic early in treatment and with elderly patients at risk of falling. Other effects are severe and potentially life threatening (QT prolongation, myocarditis). QT prolongation (>450 milliseconds for men or >470 milliseconds for women) is of concern because it can precipitate torsades de pointes arrhythmia. QT prolongation is more likely among patients who are female; who are undergoing diuretic treatment; who are taking high antipsychotic drug dosages; who have bradycardia or electrolyte abnormalities; or who have a history of prolonged QT or structural heart disease. If QT prolongation occurs, the antipsychotic should be changed to another antipsychotic that carries a lower risk of cardiac rhythm disturbance (Hasan et al. 2012). Myocarditis can occur with any antipsychotic but is most often associated with clozapine. Similarly, any antipsychotic can cause agranulocytosis, but this serious medical risk is most common with clozapine (Hasan et al. 2012).

One of the most severe antipsychotic adverse effects is neuroleptic malignant syndrome (NMS). Signs and symptoms include dystonia, rigidity, fever, autonomic instability, delirium, myoglobinuria, elevated creatine kinase, elevated leukocytes, and elevated hepatic enzymes. The prevalence is low (<1% of patients taking antipsychotics), but the condition can be fatal. Risk factors for NMS include acute agitation, young age, male gender, preexisting neurological disability, physical illness, dehydration, rapid dose escalation, use of high-potency antipsychotics, and intramuscular formulations (Hasan et al. 2012).

Note. -=minimal risk; +=low risk; ++=moderate risk; +++=high risk. EPS/TD=extrapyramidal side effects and tardive dyskinesia.

Source. Adapted from Stroup TS, Lieberman JA, Marder SA: "Pharmacotherapies," in Essentials of Schizophrenia. Edited by Lieberman JA, Stroup TS, Perkins DO. Washington, DC, American Psychiatric Publishing, 2011, pp. 173-206.

Weight gain, diabetes, hyperlipidemia, and hypercholesterolemia are common effects of antipsychotic treatment, especially among patients taking clozapine, olanzapine, quetiapine, or risperidone. A consensus has developed that all patients taking antipsychotics need regular monitoring of body weight, blood pressure, serum lipids, and glucose; however, the schedule for such monitoring has not been standardized. Weight should be monitored at least quarterly. Vital signs and laboratory chemistries, including lipids, should be taken, at a minimum, as a patient begins a new antipsychotic and by at least 3 months after beginning treatment, and then annually, unless there is a significant dosage change in the offending agent or a medication is changed. When patients develop metabolic side effects, physicians can consider changing the antipsychotic medication to another with less significant weight and metabolic side effects or managing the side effects with an agent that controls weight, glucose, and cholesterol. In addition, patients should be educated about the potential effects and should be encouraged to adopt behavioral changes to promote weight loss (Dixon et al. 2009). Some evidence suggests that metformin, topiramate, and amantadine can attenuate weight gain, and can even promote weight loss when combined with lifestyle changes. However, because these treatments have a relatively small impact on weight, this benefit must be weighed against added treatment cost and increased risk of adverse effects (Dixon et al. 2009).

Lack of Validity of First-and Second-Generation Antipsychotic Classes

Although antipsychotics are commonly divided into the so-called first-generation ("typical") and second-generation ("atypical") classes, a considerable body of recent research strongly questions the validity and utility of this distinction. The second-generation antipsychotics were introduced after clozapine was approved for treatment-resistant schizophrenia; it was hoped that these drugs would be safer and better tolerated versions of clozapine (Tandon 2011). However, recent research, including large-scale clinical trials and meta-analyses, has failed to find clear class distinctions or consistent benefits of the newer drugs. Both the newer and older antipsychotic groups are heterogeneous in many ways. There is variation within each group, as well as overlap between the groups in the propensity to cause sedation, anticholinergic effects, weight gain, hyperglycemia, and dyslipidemias. There is a tendency for the newer drugs (notably clozapine and quetiapine) to have a low propensity to cause EPS. Some of the newer drugs (clozapine, olanzapine, amisulpride, risperidone) seem to be slightly to moderately more efficacious than other antipsychotics (Leucht et al. 2009a, 2009b). Only clozapine is proven to be more efficacious than others for treatment-resistant schizophrenia. Instead of considering antipsychotics by classes that are of questionable validity, antipsychotic medications should be selected based on their individual merits and side-effect profiles according to the individual clinical circumstances (Hasan et al. 2012).

Choosing an Antipsychotic

There is no single best antipsychotic drug or dosage for all patients. Drug choice therefore entails a process that considers the patient's current symptoms, past medication response or failure, comorbid conditions, concurrent treatments, and patient preference. Medication management after a new antipsychotic drug is started requires careful monitoring of the individual patient's response and adverse effects, ongoing risk-benefit assessment, and judicious switching or managing of side effects when necessary.

The optimal antipsychotic medication choice is influenced by the stage of the patient's illness. For first-episode patients, avoiding unnecessary side effects that may have adverse health consequences or taint an individual's opinion about medications is a key consideration. Prudent first-line choices are those with low or only moderate risk of EPS, weight, and metabolic problems. Whichever drug is chosen, patients experiencing a first episode of psychosis are usually sensitive to adverse effects and are expected to respond to lower dosages than patients who have experienced multiple episodes of psychosis (Hasan et al. 2012).

Relapses are often triggered by medication nonadherence, substance use, and stressful life events. When a patient has a relapse, the antipsychotic should be chosen based on the patient's response history, the patient's comorbid conditions, the adverse effect profile, and the patient's preference. Rapid dose escalation, high loading doses, and doses above the recommended range are not advised; these tactics typically increase the rate of side effects without improving efficacy (Hasan et al. 2012).

Although many patients diagnosed with schizophrenia benefit greatly from antipsychotic medications, 10%-30% of patients have little or no response, and another 30% have only partial response. The first step for patients with poor response is to ensure adequate antipsychotic drug trials in terms of dosage, duration, and adherence (Hasan et al. 2012). Additionally, clinicians should consider comorbid substance use, concurrent use of other prescribed medicines, pharmacokinetic and pharmacodynamic interactions, physical illness, and poor social environment and support (Hasan et al. 2012). Expert consensus recommends that if the patient shows any response to the initial antipsychotic, that medication should be continued for another 4—10 weeks. If the patient shows any response to a second antipsychotic, it should be continued for 5-11 weeks. If the patient has little or no response to the initial or to the second antipsychotic prescribed, the recommendation is to wait 2-4 weeks before making a major change in treatment regimen (Hasan et al. 2012). When a patient does not respond to a medication, neither dose escalation nor combining antipsychotics is recommended (although polypharmacy is common in clinical practice) (Hasan et al. 2012). Rather, the medication should be changed, preferably to a drug that is pharmacologically dissimilar (Hasan et al. 2012). Clozapine is indicated when a patient has not gotten sufficient benefit from two adequate trials of different antipsychotics.

Changing an Antipsychotic

Antipsychotics sometimes need to be changed when a patient does not respond or experiences adverse effects. Unless the patient shows no initial improvement of symptoms, cannot tolerate the medicine, or develops a contraindication, the patient should receive a trial with the optimal dose for 2-8 weeks before changing to a different antipsychotic. Evidence about how best to change from one antipsychotic to another is lacking, but the preferred methods are to cross-taper (gradually decreasing the dosage of the first medicine while gradually increasing the dosage of the second) or to overlap and taper (continue the first medicine at the full dosage while gradually increasing the dosage of the second medicine, then tapering off the first medicine) (Hasan et al. 2012).

Other Biological Interventions

Benzodiazepines

Benzodiazepines are often prescribed for patients diagnosed with schizophrenia, but there is little evidence to support their use (Buchanan et al. 2010; Volz et al. 2007). Although they are not effective for the psychotic symptoms, they are used symptomatically for anxiety, insomnia, or agitation (Hasan et al. 2012). Some caution is indicated because of evidence that benzodiazepines combined with antipsychotics increase mortality in patients with schizophrenia (Tiihonen et al. 2012). In the absence of evidence for their effectiveness and with some indication of an increased risk of mortality, benzodiazepines may be used for short-term treatment of insomnia or anxiety and should only be used long term if there is clear justification.

Lithium and Anticonvulsants

No evidence is available to support the use of lithium or carbamazepine or valproate as sole treatments for schizophrenia. Similarly, there is inadequate evidence to recommend any of these drugs to augment the effects of antipsychotics. Although a meta-analysis found that lithium augmentation was associated with a higher treatment response rate than placebo augmentation, it is unclear whether this benefit is restricted mainly to affective symptoms rather than core symptoms of schizophrenia (Leucht et al. 2007). Valproate is widely used as an adjunctive treatment for refractory psychotic symptoms and aggressive behavior, but this use is not supported by evidence from randomized controlled trials (Buchanan et al. 2010; Schwarz et al. 2008).

Antidepressants

Antidepressants are widely prescribed as an add-on to antipsychotics to treat the depressive symptoms that are common in persons diagnosed with schizophrenia, but no strong evidence is available to support this use (Buchanan et al. 2010; Whitehead et al. 2002). Some evidence suggests that adjunctive antidepressants reduce negative symptoms (Rummel-Klugge et al. 2006), but a systematic review by the Schizophrenia Patient Outcomes Research Team concluded that the evidence did not merit a clear recommendation (Buchanan et al. 2010). The most appropriate role for antidepressants may be for patients whose depressive symptoms persist in spite of antipsychotic treatment or for patients who develop depression when psychotic symptoms have remitted (i.e., postpsychotic depression).

Other Somatic Treatments

Guidelines suggest that electroconvulsive therapy (ECT) may be useful as an add-on to antipsychotic treatment, especially for treatment-resistant patients not responding to clozapine or for patients who do not tolerate clozapine. Catatonic patients seem most responsive to ECT (Hasan et al. 2012).

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment of uncertain efficacy. Limited evidence supports using low-frequency rTMS to treat persistent auditory hallucinations and using high-frequency rTMS to the dorsolateral prefrontal cortex for the treatment of negative symptoms. The treatment is thought to have minimal side effects or health risk (Hasan et al. 2012). Direct current stimulation has also been investigated as an adjunct treatment for residual psychotic symptoms, with encouraging preliminary findings (Brunelin et al. 2012).

Psychological Interventions

Cognitive-behavioral therapy (CBT) is recommended by the American Psychiatric Association's schizophrenia treatment guidelines for people with psychotic symptoms that persist in spite of treatment with antipsychotics (Dixon et al. 2009). In this treatment, the patient chooses symptoms and problem areas, and the therapist supportively guides the patient to implement coping methods and to develop more rational cognitive perspectives about the symptoms. The therapist does not challenge the patient's beliefs as irrational, but rather elucidates the patient's beliefs about the symptoms and draws on the natural coping mechanisms the patient has developed to deal with the symptoms. Specific techniques include belief modification (gently challenging delusional beliefs, starting with loosely held delusions first), behavioral experiments (examining evidence for and against distressing beliefs), focusing/reattribution (helping patients to reattribute auditory hallucinations to an internal source), normalizing psychotic experiences (helping patients to view symptoms as responses to life stresses, making the symptoms seem more normal and less "crazy"), and thought challenging (identifying "mistakes" in thinking). Patients most likely to benefit from CBT are those with distressing positive symptoms (delusions or hallucinations) that are resistant to medication, outpatients with long-standing psychotic illness, and patients with low conviction about their delusions. Acutely psychotic patients and patients with prominent negative symptoms are less likely to benefit (Dickerson and Lehman 2011).

The American Psychiatric Association also recommends family psychoeducation for individuals with schizophrenia who are in regular contact with family members or significant others (Dixon et al. 2009). Family psychoeducation includes family support, education, crisis intervention, problem-solving skills training, and coping skills training. When delivered for 6-9 months, it can improve patients' and family members' knowledge of the illness, improve treatment adherence, improve social and vocational outcomes, increase perceptions of professional and social support, reduce relapse rates, and reduce family burden (Dixon et al. 2009).

Personal therapy is a long-term therapy (sometimes lasting for years) that focuses on affect regulation and promotes adaptive responses to emotional stress. It incorporates illness education workshops, social skills training, and behavioral exercises that build awareness of oneself and others. This therapy has not been shown to reduce relapse rates, but it can improve psychosocial functioning (Dickerson and Lehman 2011).

Compliance therapy is a short intervention (four to six sessions) that is applied during the acute illness phase, followed by several "booster" sessions. The therapy borrows from motivational interviewing and focuses on medication adherence. It has been shown to improve insight, attitudes toward medication, treatment compliance, and global functioning. However, long-term studies have not found improvements in medication compliance or psychiatric symptoms 1 year after hospital discharge (Dickerson and Lehman 2011).

Social Interventions

The American Psychiatric Association recommends several social interventions: assertive community treatment, supported employment, and social skills training. Assertive community treatment is recommended particularly for individuals who are frequently hospitalized. The model uses a multidisciplinary team that includes a medication prescriber. Team members share a caseload, and there is a low patient-to-staff ratio. The team provides direct patient services, frequently contacts patients, and performs outreach to patients in the community (Dixon et al. 2010). Assertive community treatment has been shown to reduce hospitalization rates and homelessness among patients with schizophrenia (Dixon et al. 2009).

The core principle of supported employment is that any person with schizophrenia who wants to work should be offered assistance in obtaining and maintaining employment. The supported employment model uses individually tailored job development (emphasizing patient preference and choice), a rapid job search (rather than prolonged preemployment preparation), ongoing job supports, and integration of vocational and mental health services (Dixon et al. 2010). It is effective for helping persons with schizophrenia obtain competitive employment, earn more wages, and work more hours (Dixon et al. 2009).

Some evidence suggests that social skills training improves functional outcomes, illicit drug refusal skills, and communication in the workplace and with health care professionals (Dixon et al. 2009). However, a Cochrane review of "life skills programs," which target communication skills, money management, household tasks, and self-care, found no significant improvement in Positive and Negative Syndrome Scale scores, quality-of-life scores, or social performance (Tungpunkom et al. 2012).

Etiology and Pathophysiology

Etiology

Genetic Architecture

Schizophrenia has long been known to run in families, and risk increases according to an individual's genetic relatedness to a person with schizophrenia. Twin, adoption, and extended family studies consistently show that genetic factors account for 60%-80% of the risk for developing the disease (MacDonald and Schulz 2009). Despite this substantial genetic influence, the genetic lesions that predispose to schizophrenia remain obscure.

Schizophrenia is not transmitted through families in patterns that implicate dominant or recessive alleles conferring substantial disease risk. Susceptible individuals may harbor multiple risk alleles that each confer modest effects on disease susceptibility and that, when combined, may substantially increase the risk for disease. These modest risk genes must also be common in order to combine frequently enough to account for the disease incidence. This common disease-common variant model is a leading hypothesis in the field.

Linkage studies and candidate gene association studies revealed the first proposed schizophrenia risk alleles. These studies yielded dozens of candidate genes with polymorphisms associated with modest risk for the disease (Owen et al. 2005). Many of these results, however, failed to replicate in subsequent studies, and the validity of these initially identified risk alleles is uncertain. Among the most consistently identified candidate genes are neuregulin 1 (NRG1 ), dystrobrevin binding protein 1 (DTNBP1 ), regulator of G-protein signaling 4 (RGS4 ), and disrupted in schizophrenia 1 (DISCI). They are all attractive candidates because they have known roles in neurodevelopment or synaptic transmission, but more work is needed to confirm their role in schizophrenia.

Genome-wide association studies extended the search for common genetic variants that modestly increase the risk for schizophrenia. In this case-control approach, DNA from patients and controls is run across a chip to detect common single-nucleotide polymorphisms (SNPs) densely distributed throughout the entire genome. Numerous genomewide association studies have been reported, encompassing many thousands of patients and controls. Meta-analyses identified four loci associated with increased risk of schizophrenia: the major histocompatibility complex (MHC) region on chromosome 6, transcription factor 4 (TCF4 ), neurogranin (NRGN ), and zinc finger protein 804A (ZNF804A) (Rodriguez-Murillo et al. 2012). Although these associations are robust, they can only account for a small fraction of the heritability of schizophrenia (Duan et al. 2010; Keshavan et al. 2011).

An alternative hypothesis now gaining influence is the common disease/rare variant model. This model posits that there are numerous very rare genetic lesions that substantially increase the risk for schizophrenia in individuals. This model may account for the puzzling fact that the majority of schizophrenia cases are sporadic despite the high degree of heritability found in twin and adoption studies. The 22q11.2 chromosomal microdeletion associated with velocardiofacial syndrome is the one lesion convincingly shown to fit this alternative model. More than 90% of individuals with 22q11.2 microdeletion have de novo mutations, and these lesions greatly increase the risk for schizophrenia: 25%-30% of affected young adults have schizophrenia or schizoaffective disorder. However, this lesion only accounts for around 1% of schizophrenia cases (Drew et al. 2011).

Rare variants with high penetrance cannot be detected by genome-wide association studies that search for common SNPs associated with disease, but sequencing technology now makes it possible to conduct genome-wide searches for rare and possibly idiosyncratic lesions. Initial genome-wide studies have searched for rare copy number variations (CNVs)—that is, small-scale chromosomal deletions and insertions that affect gene dosage. Multiple independent groups have found a higher incidence of rare CNVs in individuals diagnosed with schizophrenia than in control subjects (International Schizophrenia Consortium 2008; Walsh et al. 2008; Xu et al. 2008). These CNVs frequently affect genes involved in neurodevelopment (Walsh et al. 2008), and many are de novo lesions (Xu et al. 2008).

Genome-wide scans for rare variants have focused on CNVs, but there are also likely important rare point mutations. It is too soon to know if rare CNVs and point mutations directly increase the risk of schizophrenia, but their increased incidence in schizophrenia is highly suggestive.

Environmental Factors

Nongenetic factors also contribute to the risk of schizophrenia. Meta-analyses of epidemiological studies have identified numerous environmental factors associated with an increased odds ratio (OR) for developing schizophrenia. These include chronic psychostimulant use (OR=10), migrant status (OR=4.6), advanced paternal age (OR=3.8), Toxoplasma gondii antibodies (OR=2.73), prenatal nutritional deprivation (OR=2.3), cannabis use (OR= 2.1), complications during childbirth (OR=1.79), urban residence (OR=1.72), and winter or spring birth (OR=1.07) (MacDonald and Schulz 2009). There are plausible mechanisms by which many of these exposures could increase risk for schizophrenia. For instance, dopamine dysregulation can result from substance abuse, prenatal malnutrition, and birth complications (Howes and Kapur 2009). Increased paternal age may increase the incidence of de novo mutations.

Neurodevelopment and Degeneration

How do genetic and environmental risk factors translate into the widespread deficits found in schizophrenia? A popular working model is that schizophrenia is a neurodevelopmental disease that emerges when environmental stress is imposed on a genetically susceptible background.

Converging lines of evidence support this neurodevelopmental model. For instance, many of the putative schizophrenia risk genes affect neurodevelopment. Although a direct link between these genes and abnormal brain development in schizophrenia has not been established, postmortem histological studies do reveal evidence of neurodevelopmental defects. Pyramidal neurons of the prefrontal cortex have decreased density of dendrite spines, their primary site of excitatory synaptic inputs (Lewis et al. 2003). Within the hippocampus there is evidence of abnormal connectivity (Harrison 2004). Although these findings are consistent with a developmental defect, they may be confounded by a lifetime of disease burden and treatment.

Schizophrenia is also associated with signs of abnormal development at the macroscopic level, and studies using computed tomography (CT) and magnetic resonance imaging (MRI) consistently show structural brain abnormalities. The most reproducible findings are a slight overall decrease in brain volume and an increase in size of ventricles. Localized findings are less reproducible, but among the most robust are decreased size of the hippocampus, superior temporal lobe, prefrontal cortex, and thalamus. Many of these deficits are present at first psychotic break and in nonaffected relatives with high genetic risk for schizophrenia, suggesting that they contribute to susceptibility to disease rather than result from disease and treatment (Fornito et al. 2009; Vita et al. 2006). There is also evidence of abnormal connectivity between brain regions. Areas are disconnected at both structural and functional levels, implicating both impaired axon tract formation and synapse development.

Despite the evidence for impaired neurodevelopment, many features of schizophrenia are not well explained by a static developmental defect. For instance, it is not clear how an early developmental defect triggers a switch from relatively normal functioning to full-blown psychosis later in life. As neurodevelopment continues into adolescence with synaptic priming, myelination, and maturation of cortical dopaminergic projections in particular, disruptions of late stages of development could result in conversion to disease. Alternatively, however, a degenerative process could also lead to this decline. Neurodegeneration may also contribute to the functional deterioration and medication resistance that often develop over the subsequent course of illness after its formal onset. Psychosis itself may promote a degenerative process, and this may account for the finding that longer initial periods of untreated psychosis are predictive of a poorer recovery after treatment (Perkins et al. 2005). Although postmortem studies do not show signs of widespread neuronal loss or neuropathological stigmata of degeneration (e.g., gliosis, protein aggregates, ubiquitination), more subtle findings such as decreased neuropil and synapse density may result from a degenerative process.

Pathophysiology

Genetic and environmental factors affect development and possibly promote degeneration to set the stage for schizophrenia. Once the disease develops, what are the neural underpinnings of the positive, negative, and cognitive signs and symptoms? Our understanding of this pathophysiology is limited, but evidence points to dysfunction of the major neurotransmitter systems of the brain and to disruption of neural circuits.

Neurotransmitter Systems

The serendipitous discovery that chlorpromazine ameliorates the positive symptoms of schizophrenia revolutionized psychiatry and implicated dopamine in psychosis. Several findings led to the hypothesis that positive symptoms result from hyperactive dopaminergic transmission (Snyder 1976). Early studies showed that antipsychotics block the effects of dopaminergic agents in animal models, suggesting that they can inhibit dopaminergic transmission (Carlsson and Lindqvist 1963). The potency of antipsychotics is proportional to their affinity for D₂ receptors. In addition, increasing dopamine by the administration of amphetamine has been found to induce positive symptoms (Lieberman et al. 1990).

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide direct evidence for overactive dopaminergic transmission in schizophrenia. Striatal dopamine synthesis capacity, dopamine release, and D₂ receptor occupancy by dopamine are all increased in schizophrenia (Howes and Kapur 2009). Furthermore, the degree of D₂ receptor occupancy correlates with the degree of response to antipsychotics (Abi-Dargham et al. 2000).

The dopamine hyperactivity hypothesis is highly clinically relevant because all antipsychotics approved by the U.S. Food and Drug Administration block D₂ receptors to some degree. However, the hypothesis has many shortcomings. Patients often have persistent symptoms despite effective D₂ receptor blockade. Also, hyperdopaminergia is likely not specific to schizophrenia because anti-dopaminergic agents can improve psychotic symptoms resulting from dementia and affective disorders. Therefore, hyperdopaminergia likely promotes psychosis generally.

Glutamate is the major excitatory neurotransmitter in the brain. There are three general families of glutamate receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), kainate, and N-methyl-D-aspartate (NMDA). Inhibition of NMDA receptors with phencyclidine (PCP) and ketamine can cause a cluster of symptoms resembling the core elements of schizophrenia: hallucinations, delusions, social withdrawal, and cognitive deficits. In contrast, dopaminergic agents only promote positive symptoms. NMDA receptor hypoactivity is therefore an attractive unifying theory of schizophrenia. Many candidate schizophrenia susceptibility genes regulate glutamatergic transmission, and postmortem studies show abnormalities in glutamatergic synapses.

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and a tight balance of glutamatergic excitation and GABAergic inhibition is essential for normal brain function. Glutamic acid decarboxylase 67 (GAD67), an enzyme that completes the final step in GABA synthesis, is decreased in postmortem schizophrenic brains (Lewis et al. 2012). This decrease is most reliably found in parvalbumin-positive interneurons within the prefrontal and temporal cortices, and many of the core features of schizophrenia may be due to a cortical excitation-inhibition imbalance.

Neural Circuits

Functional neuroimaging holds the promise of mapping core elements of schizophrenia to dysfunctional neural circuits. Initial PET studies of baseline brain metabolism revealed decreased blood flow in the frontal lobes with a relative increase in temporal-occipital regions (Ingvar and Franzen 1974). A hypofrontality model is attractive because many deficits in schizophrenia, including working memory and executive control, rely heavily on frontal structures.

When brain activity is imaged during cognitive tasks, a more complex picture emerges. The dorsolateral prefrontal cortex, which is critical for working memory tasks, is hyperactive in individuals with schizophrenia when doing tasks of intermediate difficulty. Dorsolateral prefrontal cortex activity then falls off as task difficulty increases, and performance suffers. Individuals with schizophrenia may therefore have an inefficient engagement of frontal areas rather than general frontal hypoactivity (Brown and Thompson 2010; Potkin et al. 2009).

Recently, many studies have sought to define the network-level dysfunction in schizophrenia by quantifying the correlated activity between multiple brain regions. Research demonstrates that individuals with schizophrenia have difficulty engaging the correct networks, as well as signs of abnormal connectivity within individual networks. Among the most consistent findings, during both resting states and cognitive tasks, is decreased coactivation of frontal and temporal regions (Libby and Ragland 2012; Pettersson-Yeo et al. 2011).

Anatomical studies of major white matter tracts using diffusion tensor imaging reveal a general trend toward uniformly decreased white matter integrity along with a consistent deficit in tracts connecting frontal and temporal regions in schizophrenia (Ellison-Wright and Bullmore 2009; Fornito et al. 2012; Williamson and Allman 2012). However, functionally defined networks do not map directly onto anatomical networks. Network abnormalities in schizophrenia likely result from a combination of disordered white matter tracts, dysfunctional neurotransmitter systems, abnormal synapse development, and aberrant experience-dependent plasticity during development and beyond. These could all contribute to a functional disconnection syndrome reminiscent of Eugen Bleuler's original conception of schizophrenia as a splitting of psychic functioning.

Conclusion

Schizophrenia is a complex mental disorder that imposes a costly burden on those who live with it and society. Progress through scientific research over the past half century has led to an extensive understanding of its etiologies and pathophysiology, in addition to its phenomenology and natural history. In addition, by dint of serendipity, as well as subsequent research, an impressive array of treatments, both pharmacological and psychosocial, have demonstrated efficacy and can be usefully applied to suppress symptoms, enhance functioning, and improve quality of life in individuals with schizophrenia. With the application of existing information and the prospect of new knowledge through scientific research, clinicians have reason for optimism about the future of schizophrenia prevention and treatment.

Key Clinical Points

• Schizophrenia has a variable course; some people recover and function at a high level, whereas others are severely disabled.
• Longer periods of untreated psychosis are associated with poorer outcomes; early intervention has the potential to reduce disability.
• Antipsychotic medications are the cornerstone of treatment, but optimal treatment includes psychosocial interventions such as assertive community treatment, family psychoeducation, and supported employment.
• Continuous long-term treatment with antipsychotics is recommended; relapse is far more likely when medications are stopped.
• Clozapine is the only antipsychotic proven to be more effective than other antipsychotics in treatment-resistant schizophrenia; its underuse is a barrier to improved outcomes.

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Suggested Readings

Lieberman JA, Stroup TS, Perkins D (eds): Essentials of Schizophrenia. Washington, DC, American Psychiatric Publishing, 2012

Saks ER: The Center Cannot Hold: My Journey Through Madness. New York, Hyperion, 2007

Stroup TS, Lieberman JA: Clinical Antipsychotic Trials of Intervention Effectiveness: The CATIE Project. Cambridge, UK, Cambridge University Press, 2010

Torrey EF: Surviving Schizophrenia: A Manual for Families, Patients, and Providers, 5th Edition. New York, Harper Perennial, 2006

Yung A, Phillips L, McGorry PD (eds): Treating Schizophrenia in the Prodromal Phase: Back to the Future. London, Taylor & Francis, 2004

Online Resources

National Alliance on Mental Illness: Schizophrenia. www.nami.org/Template.cfm?Section=schizophrenia9

National Institute of Mental Health: Schizophrenia. www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

Schizophrenia Research Forum: www.schizo-phreniaforum.org