Chapter 16. Schizophrenia

DSM-IV-TR Diagnostic Criteria for Schizophrenia

1. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated):

   1. delusions

   2. hallucinations

   3. disorganized speech (e.g., frequent derailment or incoherence)

   4. grossly disorganized or catatonic behavior

   5. negative symptoms, i.e., affective flattening, alogia, or avolition

Note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.

1. Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement).

2. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).

3. Schizoaffective and mood disorder exclusion: Schizoaffective disorder and mood disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.

4. Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

5. Relationship to a pervasive developmental disorder: If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).

(Adapted, with permission, from Diagnostic and Statistical Manual of Mental Disorders, 4th edn., Text Revision. Washington, DC: American Psychiatric Association, 2000.)

• Diagnostic criteria met, as specified in the box above. Note that these criteria allow the diagnosis in absence of prominent hallucinations or delusions (e.g., there is instead some combination of negative symptoms, disorganized speech, and/or disorganized or catatonic behavior).
• Duration of active psychotic symptoms for at least 1 month, or for a shorter duration if active treatment was initiated.
• Total duration of illness for at least 6 months, including prodrome, acute phase, and residual symptoms.
• Cognitive impairment, characterized by disorganized, illogical, loosely associated or bizarre speech, or by inappropriate or bizarre behaviors.
• The above symptoms are idiopathic in nature.
• Dysfunction in one or more life domains as a result of the above signs or symptoms.

Other common features:

• Lack of insight that symptoms and difficulties that stem from them are products of a mental illness that requires treatment.
• Deterioration in personal appearance and hygiene.
• Depressive and anxiety-based symptoms, including suicidal thinking.
• Abnormal motor activity, including rocking, pacing, grimacing, maintaining uncomfortable postures, stereotypies, and odd mannerisms.
• Poor compliance with treatment.
• Comorbid drug (including nicotine) and alcohol use disorders, and chronic physical health problems.

Schizophrenia is a clinical syndrome historically characterized by a heterogeneous mixture of clinical features referred to as psychosis. These clinical features include hallucinations, delusions, abnormal emotions, cognitive problems, and abnormal behaviors. The clinical diagnosis of schizophrenia is currently made on the basis of these characteristic signs and symptoms, their time course, their adverse impact on functional capacity, and their idiopathic nature (e.g., they are not the psychiatric manifestations of general medical conditions or effects of substances, and are not better accounted for by other diagnoses that feature psychotic symptoms or severe functional or cognitive incapacity).

Even after excluding the secondary causes of psychotic symptoms, the diagnosis of schizophrenia and related disorders remains challenging. For one, the etiology and the neuropathophysiology of schizophrenia is unknown. Second, no single sign or symptom is pathognomonic to schizophrenia. Finally, there is no clinically reliable biological marker, including functional or structural neuroimaging or pattern of genetic heritability.

The concept of schizophrenia as a diagnostic entity is still evolving even though the diagnostic criteria in use today have been unchanged for over two decades. Although it is likely that the schizophrenic syndrome has been described in one form or another since ancient times, the twentieth-century observations of Emil Kraepelin, Eugen Bleuler and Kurt Schneider have contributed most to our current classification of the disorder. Kraepelin was credited with distinguishing manic–depressive illness (now called bipolar disorder) from dementia praecox (the forerunner of schizophrenia) based on relative age of onset (younger in the case of manic–depressive illness), symptom course (episodic for manic–depressive illness, chronic for dementia praecox), vocational/social outcome (better for manic–depressive illness) and level of cognitive impairment (more severe in dementia praecox). Bleuler coined the term “schizophrenia” based on his observation that long-term outcome was quite variable among patients with dementia praecox and on the hypothesis that a split between thought and affect was the central feature of the illness. Bleuler specifically identified four components (also known as Bleuler's “four A’s”) as the essence of the syndrome: Autism (i.e., a disconnect from reality), Ambivalence (of affect and will), Affectivity (in Bleuler's words: an “indifference to everything”), and Association (in Bleuler's words: “the associations lose their continuity”).

Schneider contributed the concept of first-rank symptoms (e.g., thought insertion, thought withdrawal, thought broadcast, voices arguing or discussing, delusions of control, etc.), which he believed were pathognomonic of schizophrenia and became the forerunner of the notion of positive signs and symptoms. Schneider's first-rank symptoms are now known not to be specific for schizophrenia, for they may also occur in mania, drug induced states, and other disorders. Nonetheless, these and other signs and symptoms together have undergone extensive empirical testing to be criteria with sufficient diagnostic specificity, reliability, and validity for use in clinical practice

Epidemiology

Incidence & Prevalence

The incidence of schizophrenia ranges from 10 to 40 new cases per 100,000 population, while the age-corrected median point prevalence and lifetime prevalence estimates of the disorder are 4.6 and 4.0 cases per 1000 population, respectively. This figure for lifetime prevalence estimate is lower than the often reported range of 0.5% to 1.0%, which is believed to be an overestimate. Differences between site estimates of incidence and prevalence may be due to a variety of factors, including sex, urbanicity, migrant status, month of birth, recovery, suicide, and other forms of early mortality.

Life Expectancy, Drug Use, & Physical Health Problems

The life expectancy in schizophrenia is lower by about 20% relative to the general population. Increased early mortality among schizophrenics is attributed to increased rates of suicide (10–13% lifetime risk of completed suicide, 18–55% risk for attempted suicide), accidents, and poor physical health. At baseline, schizophrenics appear to be at higher risk for a host of metabolic and cardiovascular disorders, including obesity, diabetes, dyslipidemia, and coronary artery and cerebrovascular disease. Other contributors to the medical morbidity of schizophrenia include unhealthy lifestyle, alcohol and drug abuse, and high rates (70–80%) of chronic heavy smoking. High rates of substance abuse alone contribute to poor physical health, infrequent medical and psychiatric follow up, and poor compliance with medical and psychiatric treatment. In addition, several of the most efficacious treatments for schizophrenia may elevate cardiovascular risk as a result of weight gain, dyslipidemia and glucose elevation.

In spite of the health concerns that accompany schizophrenia, there is a disproportionately low rate of health service utilization among this population. Cognitive dysfunction, paranoid symptoms, apathy, comorbid disorders, poverty and illness-associated stigma may all impede utilization of necessary medical services. Concrete recommendations for health screening and monitoring are provided later (see section “Treatment”).

Demographics

Gender

Schizophrenia is slightly more common in males than in females (male:female risk ratio is 1.4); however, as noted above, the average age of onset of schizophrenia for women is at least 5 years later than for men. Others have found no statistically significant differences in prevalence estimates between males and females. Differences in sex distribution for new-onset cases are especially apparent after the age of 45, where there is a 2:1 sex ratio in favor of women. Compared with men, women with schizophrenia tend to have better premorbid functioning, fewer negative symptoms, more prominent mood symptoms, more complete recovery from episodes, better clinical response to antipsychotic medication, milder long-term course, better social functioning, less comorbid substance abuse and less potential for suicide. Symptoms in females may worsen after menopause.

Age

The age of onset for men appears to be earlier (age 18–25 years) than for women (age 25–35 years). For men, there is a second but much smaller incidence peak between age 30 and 35 years. Onset prior to the age of 10 is considered rare, though when it does occur, symptoms are typically very severe. Onset after the age of 45 (late onset) is also uncommon, and very uncommon after the age of 65 (very late onset). Patients with poor outcome, as indicated by poor response to currently available therapies, have an earlier age at onset than do those who are more responsive to treatment. The average age at onset of neuroleptic-resistant schizophrenia in female patients may be 4–5 years lower than in female patients with neuroleptic-responsive schizophrenia, but male and female patients with neuroleptic-resistant schizophrenia have similar ages at onset: 20–21 years, on average, according to one study.

Social Status

The prevalence rates of schizophrenia are higher in densely populated urban areas, as well as in industrialized nations. The prevalence of schizophrenia is lower in developing countries compared with developed nations. Patients in developing countries have a more benign illness course than those in developed countries. Especially in Western societies, individuals with schizophrenia are at higher risk for poverty, unemployment, homelessness or inadequate housing, ill health, and poor access to health care. It has been theorized that the limitations posed by the symptoms of schizophrenia result in a downward drift in socioeconomic status, or prevent upward social mobility, or both.

Individuals in lower socioeconomic classes have higher rates of schizophrenia because of the markedly impaired work function of patients with this illness. Lower income is to be expected in the families of schizophrenics because 10% of the parents of schizophrenic patients have schizophrenia themselves, and other parents may have subclinical forms of the illness, including cognitive impairments and Axis II pathology, impairing their earning capacity.

Social Support

Individuals with schizophrenia are more likely to be single (never married), divorced, or separated relative to age-matched controls. Individuals with schizophrenia who are unmarried tend to have earlier onset of psychosis, poorer premorbid functioning, and more severe illness, relative to those who have married. Conversely, adequate social support in any form and avoidance of high “expressed emotion” environments (over-critical or over-protective) both predict better long-term course.

Ethnicity

Schizophrenia affects individuals from all racial and ethnic groups. While schizophrenia was once believed to be more prevalent among nonimmigrant minority groups in the United States, especially African Americans, recent studies have shown that such groups do not appear to be at greater risk for schizophrenia compared with the general population. There is conflicting evidence as to the influence of immigration status on overall risk of developing schizophrenia. The disproportionately high prevalence of schizophrenia observed among first-generation immigrants in Western countries appears to normalize in subsequent generations.

Other Factors

Epidemiologic data consistently show that schizophrenic patients have an increased likelihood of having been born in the late winter and spring months. The seasonal effect has been linked to epidemics of influenza or viral infections that occur more frequently during winter months. A number of epidemiologic studies have attributed the increased rate of schizophrenic births to maternal influenza or other viral infections during the second trimester. Maternal influenza during the second trimester may impair fetal growth and predispose to obstetric complications and lower birth weight in about 2% of individuals destined to develop schizophrenia. Recent epidemiologic evidence based on 2669 cases of schizophrenia in a population cohort of 1.75 million showed significant relative risks of developing schizophrenia with increased urbanization and season of birth. The highest association was for births in the months of February and March, presumably due to the increased risk of viral infection during pregnancy. Other complicating factors such as maternal malnutrition and Rh incompatibility during gestation have been associated with increased vulnerability to schizophrenia.

Etiology

Kraepelin conjectured that schizophrenia was caused by a biological abnormality, even though the attempts to identify an abnormality (including neuropathological studies by Alois Alzheimer) were unsuccessful. In the middle of the twentieth century, the view that schizophrenia was the result of specific disturbances in child-rearing received considerable attention. In particular, communication deviance between parents and the child who was diagnosed with schizophrenia was considered by some clinicians to be a sufficient cause of schizophrenia. Although communication deviance in families with a schizophrenic child has been demonstrated in a number of studies, evidence that this feature was specific for schizophrenia or causative was unconvincing. Nevertheless, this line of research led to a continual interest in how family (and other caregiver) interactions can contribute to or diminish the stress and coping skills of patients with schizophrenia and, thus, modulate the course of the illness.

The view that schizophrenia is a brain disease now prevails, based on evidence from studies of neurotransmitter systems, histological, and neuroimaging studies of brain structure, and studies of brain function.

Dopamine Hypothesis

The most widely accepted original hypothesis of the etiology of schizophrenia and of the action of antipsychotic drugs implicates the neurotransmitter dopamine (DA). Dopaminergic neurons arise from two midbrain nuclei: (1) the nigrostriatal tract originates in the substantia nigra, terminates in the striatum, and is involved in modulation of motoric behavior, cognition, and sensory gating; and (2) the mesolimbic and mesocortical tracts originate in the ventral tegmental area and terminate in limbic and cortical structures, respectively, affecting cognitive, motivational, and reward systems. The dopamine 1 (D1) receptor family, which includes D1 and D5 receptors, is present in high concentration in the cortex and striatum. The dopamine 2 (D2) receptor family consists of D2, D3, and D4 receptors and is concentrated in the limbic and striatal regions. Presynaptic DA receptors (i.e., D2 and D3) can consist of either somatodendritic autoreceptors localized to cell bodies in the substantia nigra and ventral tegmental area or terminal autoreceptors limited to axons of these DA cells. The somatodendritic and terminal autoreceptors affect the firing of DA cells and the synthesis and release of DA, respectively.

Positive Symptoms

The DA hypothesis of schizophrenia, as originally postulated, proposed that schizophrenia is due to an excess of DA activity in limbic brain areas, especially the nucleus accumbens, as well as the stria terminalis, lateral septum, and olfactory tubercle (e.g., mesolimbic dopamine hyperactivity). This hypothesis was based on evidence that chronic administration of the stimulant d-amphetamine produced a psychosis that resembles paranoid schizophrenia. d-Amphetamine increases the release of DA and norepinephrine (NE) and inhibits their reuptake. Isomers of d-amphetamine with different effects on the availability of NE and DA in rodents were used to show that increased locomotor activity, which correlates best with psychosis in humans, is due to an increased release of DA rather than NE.

The second line of evidence relating DA to schizophrenia is that antipsychotic drugs decrease DA activity by receptor depletion (reserpine) and blockade (neuroleptics). The most compelling evidence that linked DA to the positive symptoms of schizophrenia was the finding that chlorpromazine was an effective antipsychotic drug and that it blocked DA receptors in vivo, inhibiting the effect of d-amphetamine on locomotor activity. The discovery that a number of different chemical classes of DA-receptor antagonists are effective as antipsychotic drugs and that there is a high correlation between the drug's average daily dosage and its affinity for the D2-receptor family led to the view that increased stimulation of these receptors caused schizophrenia.

Negative Symptoms and Cognitive Dysfunction

Decreased dopamine activity in the prefrontal cortex (mesocortical dopamine deficit) may mediate the negative symptoms and cognitive dysfunction associated with schizophrenia.

The concept of increased DA activity as the core deficit in schizophrenia was developed at the time when delusions and hallucinations were central to the diagnosis of schizophrenia, whereas negative symptoms, affective symptoms, and cognitive dysfunction were relegated to a secondary role. The latter aspects of schizophrenia have never been associated with excessive DA activity. As mentioned earlier in this chapter, researchers have proposed that decreased DA activity may lead to cognitive impairment and depression. There is little evidence that blockade of D2 or D4 receptors induces depression or cognitive impairment. Recent studies in primates have implicated the D1-receptor family in the control of working memory, a cognitive function impaired in schizophrenia.

Limitations of the Dopamine Hypotheses

Clinically, factors that challenge the primacy of dopamine imbalance at the expense of other transmitter systems stem from at least two observations. First, drugs that act on other transmitter systems, such as hallucinogens (e.g., lysergic acid, psilocybin) and dissociative anesthetics (e.g., phencyclidine, ketamine), also cause psychotic symptoms. Phencyclidine exposure results in a psychotic syndrome that models schizophrenic psychosis more accurately than amphetamine does (see below). Second, while D2-receptor blockade occurs very quickly after antipsychotic dosing, clinical antipsychotic effects typically require several weeks to ensue.

Furthermore, postmortem studies of patients with schizophrenia have not found consistent abnormalities in the density of any of the five DA receptors or changes in their affinities for DA, with the possible exception of the D3 receptor, which may have an abnormal form. Several research groups have also reported a link between D3 polymorphisms and schizophrenia. There is no reliable evidence, from either postmortem studies or positron emission tomography (PET) studies, for an increase in the density of D2 receptors in schizophrenia. Recent PET studies of the release of DA in the striatum of patients with schizophrenia suggest that the extracellular concentration of DA in this region is increased compared to that in normal subjects. Plasma and cerebrospinal fluid (CSF) levels of homovanillic acid, the major metabolite of DA, are not elevated in patients who have schizophrenia. Some researchers have suggested that DA-receptor sensitization occurs in schizophrenia, but only indirect evidence supports this hypothesis.

Serotonin Hypothesis

Serotonin (5-HT) neurons originate in the midbrain dorsal and median raphe nuclei, which project to the cortex, striatum, hippocampus, and other limbic regions. There are at least 15 types of 5-HT receptors; of these, the most relevant to schizophrenia are the 5-HT1, 5-HT1D, 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptors. Somatodendritic autoreceptors (of the 5-HT1A type) are present on the cell bodies of 5-HT raphe neurons and inhibit firing of serotonergic neurons. Terminal autoreceptors (5-HT1D in humans) regulate the synthesis and release of 5-HT. 5-HT3 receptors stimulate DA release. Postsynaptic 5-HT2A receptors are localized on pyramidal neurons in mesocortical areas. The complex interaction between 5-HT and DA varies by brain region and by types of 5-HT and DA receptor.

An early theory of the etiology of schizophrenia was that it is due to an excess of brain serotonergic activity. This theory was based on the belief that the psychotomimetic properties of lysergic acid diethyl amide (LSD), an indole compound, are due to its 5-HT agonist properties. This led to a search for endogenous indole hallucinogens in the brain, blood, and urine of schizophrenic patients. The enzymes that synthesize and catabolize indoles, of which 5-HT is the most important, were also studied in detail; however, none of the putative abnormalities was confirmed by subsequent careful study.

The notion that the effects of LSD and other indole hallucinogens, such as psilocybin and N,N′-dimethyltryptamine, provide an adequate model of schizophrenia was also rejected because the primary effect of these drugs is to cause visual hallucinations. The potency of these agents as hallucinogens is highly correlated with their 5-HT2A-receptor affinity. The thought disorder, auditory hallucinations, and bizarre behavior usually present in schizophrenia are generally absent in normal individuals given these agents. However, ingestion of these agents can cause an exacerbation of positive symptoms in schizophrenic patients.

Neuroleptic drugs are not particularly useful in decreasing the effects of the indole hallucinogens. Newer antipsychotic drugs such as clozapine, olanzapine, risperidone, quetiapine, and sertindole are potent antagonists of the 5-HT2A receptor. Some of the advantages of these drugs may result from their greater potency as 5-HT2A-receptor antagonists, relative to D2-receptor blockade. The most likely advantages of these drugs, related to their higher affinity to 5-HT2A versus DA receptors, are their low D2-induced extrapyramidal symptoms (EPS) profile and their ability to improve negative symptoms. Increased stimulation of 5-HT2A receptors may be important in the etiology of negative symptoms and EPS. Although this concept of the role of 5-HT in schizophrenia is no longer considered viable, alternative theories of the role of 5-HT are of interest and are discussed in subsequent sections.

Glutamate Hypothesis

Clinical and experimental evidence has supported a complex role for glutamate in the etiology of schizophrenia. The original evidence for an abnormality of the glutamatergic system was a decreased level of glutamate in the CSF of patients with schizophrenia. Subsequent studies have revealed decreased expression of glutamatergic receptors, such as the N-methyl-d-aspartate (NMDA) and AMPA/Kainate receptors. Evidence indicates that decreased glutamatergic activity is the result of decreased levels of glutamate receptors of the NMDA subtype. Consistent with the role of glutamate in schizophrenia, three noncompetitive antagonists of NMDA receptors (phencyclidine [PCP], ketamine, and MK-801), and three competitive antagonists (CPP, CPP-ene, and CGS 19,755), can produce a range of positive and negative symptoms and cognitive dysfunction in normal control subjects closely mimicking the clinical signs and symptoms of schizophrenia. Exposing schizophrenic patients to these agents results in marked intensification of core schizophrenic symptoms.

Neuroleptics can block some of the clinical effects of PCP. The ability of the 5-HT2A- and D2-receptor antagonists, such as clozapine and olanzapine, to block the clinical effects of these NMDA-receptor antagonists is unknown. However, the preclinical effects of PCP, such as disruption of sensory gating, can be blocked by selective 5-HT2A-receptor antagonists, such as MDL100,907, and by clozapine. Several compounds that enhance NMDA receptor function (e.g., glycine, d-serine, d-cycloserine) have been reported to alleviate negative and positive symptoms in patients with schizophrenia when administered in conjunction with typical neuroleptic drugs. It has also been suggested that increased levels of glutamate can have neurotoxic effects on various neurons; however, there is no conclusive evidence for neurodegenerative change in schizophrenia.

Gamma-Aminobutyric Acid

The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia. After initial reports of decreased GABA levels in CSF, recent postmortem studies have implicated a decreased function of GABAergic neurons in schizophrenia. The most replicated finding is a decreased expression of the messenger RNA for glutamic acid decarboxylase (GAD), the enzyme necessary for the synthesis of GABA. The 67 kDa isoform of GAD has been reported as decreased in the cerebral cortex and hippocampus of schizophrenic subjects. Subsequent studies have identified gene and protein expression changes in specific subsets of GABAergic neurons in the cerebral cortex, such as parvalbumin-positive GABAergic neurons in the prefrontal cortex, which play a crucial role in the modulation of pyramidal cell firing and the synchronization of cortical activity.

The neuropathological exploration of schizophrenia is experiencing a renaissance and has been complemented recently by neuroimaging studies of the cortical gray and white matter, and subcortical regions.

Cortex and Hippocampus

The study of the cerebral cortex remains at the center of schizophrenia research. Ever since Kraepelin's original conceptualizations of dementia praecox as a disorder of uniquely human qualities (such as volition and insight), most studies of brain structure have focused on the prefrontal cortex, primarily its dorsolateral aspects (i.e., dorsolateral prefrontal cortex [DLPFC]). Recently, the medial temporal lobe, especially the hippocampus, has attracted significant interest, originally because of the reports of psychotic symptoms in patients with medial temporal lobe lesions. Other regions of interest include the anterior cingulate cortex and the superior temporal gyrus. Improved neuroimaging methods allow for the in vivo measurement of regional brain volumes, the estimation of cortical thickness, and the shape analysis of cortical and subcortical structures. Two important morphometric findings have been replicated, with achieve significant effect sizes in meta-analyses. First, the lateral and third ventricles are enlarged. Second, the volumes of several cortical regions are decreased in the medial temporal lobe.

At the cellular level of cortical organization, abnormalities of cell number, protein expression, and gene expression have been reported. The well-established finding of decreased cortical volume in schizophrenia is not mirrored, as in most neurological disorders, by reports of marked neuronal loss. Some investigators have interpreted the lack of marked cell loss and the lack of an associated increase in the number of glial cells as evidence against a neurodegenerative and in favor of a neurodevelopmental abnormality.

Some studies provide evidence of a decreased prominence of dendrites and axons (referred to, in aggregate, as neuropil), resulting in an increased density of cortical neurons. This is complemented by emerging evidence for decreased oligodendrocyte functioning, i.e., of the glial cells crucial for the myelination of fiber pathways.

The application of sophisticated methods of protein and gene expression in postmortem brain tissue has provided researchers with the opportunity to study subtle abnormalities of cellular architecture, not detected by the standard neuropathological examination of brain tissue. Such studies have demonstrated deficits in cortical and hippocampal neurons, such as subtypes of GABAergic neurons in the prefrontal cortex.

Longitudinal neuroimaging studies have shown convincingly that the changes in cortical structure are visible at the time of the first episode of schizophrenia, and not simply the effect of longstanding illness or treatment. Furthermore, some studies provide evidence that abnormalities of brain structure can be found in individuals who are at high risk of developing schizophrenia, but have not yet become symptomatic. Finally, neuroimaging studies reveal that some of the abnormalities found in schizophrenia are present also in unaffected first-degree relatives. Taken together, there is a compelling evidence for structural abnormalities of the cortex and hippocampus in schizophrenia.

Subcortical Regions

Initial reports indicated a significant decrease of mediodorsal thalamic nucleus volume and neuronal population. Some reports specifically implicated those neurons of the mediodorsal thalamic nucleus that establish strong reciprocal connections with the DLPFC. Recent rigorous, larger studies, however, have not been able to replicate the finding of thalamic neuronal loss.

The basal ganglia have been studied extensively in schizophrenia, as they are a projection site of dopaminergic fibers from the substantia nigra. While several studies have demonstrated an increased release of dopamine into the striatum (especially during periods of acute psychosis), there is little evidence for an abnormality in basal ganglia volume, cell number, or protein and gene expression.

White Matter

Recent studies reveal abnormalities of glial cells and myelinated fiber pathways in schizophrenia. The cellular abnormalities include a decreased number of oligodendroglia and a decreased expression of myelin-related genes. Either abnormality could lead to a disturbance of myelinated fiber pathways in the brain. Neuroimaging studies of fractional aniostropy, a measure of the alignment and organization of fiber bundles in the brain, have indeed revealed such patterns of cortical disconnection. They appear to affect regions in the prefrontal cortex as well as several large-scale networks of brain regions, such as the frontal and temporo-parietal brain regions subserving language function.

There is little doubt that the core features of schizophrenia (i.e., the positive and negative symptoms and the significant decline in social functioning) are caused by abnormalities of brain function. The extensive literature on neuropsychological deficits in schizophrenia is supported by more recent reports of the neural basis of such deficits.

Neuropsychological Studies

Most patients with schizophrenia show significant deficits on standard neuropsychological tests. While some investigators have proposed that such deficits are selective (e.g., for verbal memory or attention), meta-analyses reveal abnormalities in most aspects of cognition in schizophrenia. The deficits of cognition are present in the early stages of the illness. Cohort studies of subjects, who later develop schizophrenia reveal significant cognitive deficits before the onset of the illness. While schizophrenia as a whole is characterized by cognitive deficits, their severity varies and predicts the level of functioning in the community.

Prefrontal Cortex Function

Behavioral, neuroimaging, and electrophysiological studies have shown convincingly that several functions of the prefrontal cortex are impaired in schizophrenia. These include abnormal DLPFC function during the storage of information as well as the retrieval of information from working memory. Abnormal anterior cingulate cortex function is found when inhibiting responses to sensory stimuli. Functional neuroimaging studies using PET and functional magnetic resonance imaging (fMRI) reveal a complex pattern of abnormal DLPFC activation in schizophrenia. While patients show a decreased activation of the DLPFC compared to healthy control subjects (referred to as hypofrontality) during some cognitive tasks, they show normal or increased DLPFC activation on other tasks. Task performance, which is typically lower in schizophrenia, explains some of the variable patterns. When the performance on tasks of DLPFC function is equilibrated between subjects, subjects with schizophrenia typically show an increased pattern activation. This has been interpreted as a sign of decreased cortical efficiency, since greater DLPFC activation (i.e., more activity in the same number of cortical neurons or the same degree of activity in a larger number of neurons) is required for the same level of task performance. Some have speculated that such patterns could be the result of abnormal dopaminergic modulation of cortical neurons, while others have proposed decreased cortical inhibition and impaired cortical synchronization as the cause.

Hippocampal Function

Some aspects of hippocampal function during the encoding and retrieval of memory are abnormal in schizophrenia. There are patterns of increased hippocampal activity at baseline and during passive viewing of stimuli, and a decreased ability to modulate hippocampal responses during the retrieval of previously stored information. The impairment of hippocampal function appears to be particularly pronounced when the relationship between previously learned items has to be recalled.

Sensory Functions

The reception and integration of sensory information is abnormal in schizophrenia. An extensive electrophysiological literature has documented abnormalities in early sensory processing. These abnormalities involve the thalamic nuclei, the primary sensory cortices, and the multimodal cortices.

Other Functions

Several other brain regions, including thalamus, basal ganglia, and cerebellum have been shown to be impaired during the performance of cognitive tasks in schizophrenia.

It has been known for many years that the risk of schizophrenia is increased if another family member is affected (Table 16–1). Family, twin, and adoption studies of schizophrenia have revealed a high degree of heritability, approximately 80%. Heritability is the proportion of phenotypic variance accounted for by genetic effects. It refers to variance in the population and does not translate into a straightforward risk assessment for an individual. Furthermore, high heritability does not exclude a role for nongenetic factors. This is evidenced by the fact that, despite the high heritability of schizophrenia, the concordance rate in monozygotic twins is only 50%, pointing to the importance of environmental factors. Taken together, there is convincing evidence that a combination of risk genes contributes to the development of schizophrenia. However, it is also apparent that schizophrenia is not completely determined by genes (as in an autosomal dominant condition with full penetrance, such as Huntington disease).

The exact genetic mechanism of schizophrenia remains elusive. The introduction of molecular biological techniques has resulted in many reports of linkages between the diagnosis of schizophrenia and polymorphisms in the human genome. However, linkage to particular chromosomal regions has been hard to confirm in independent replication studies, most likely due to a combination of small genetic effects, inadequate sample sizes, and the use of marker maps of insufficient density. Two recent meta-analyses have attempted to overcome the issue of limited power in individual studies. Both analyses provided support for the existence of susceptibility genes on chromosomes 8p and 22q, but they differed with regard to specific regions on chromosomes 1q, 3p, 5q, 6p, 11q, 13q, 14p, and 20q.

Recently, the detailed mapping of chromosomal regions has led to the identification of several genes that are being examined (Table 16–2). Several genes code for proteins known to affect pathways relevant to schizophrenia. For example, the newly found protein neuregulin 1 (NRG1), which is coded for by gene G72 on chromosome 13q34, and the enzyme d-amino acid oxidase (DAAO) are all in a position to affect glutamatergic neurotransmission. On the other hand, a mutation in the gene coding for catechol-O-methyl transferase (COMT), the catabolic enzyme of dopamine, is associated with impaired brain function in schizophrenia. Thus, there is now compelling evidence for specific risk genes for schizophrenia. This could lead to a better understanding of disease mechanisms and the identification of targets for drug development.

Genetics

There is clear evidence that genetic factors influence the risk of developing schizophrenia.

The concordance rate in monozygotic twins, about 48%, is nearly three times that in dizygotic twins. Higher estimates of disease heritability range from 60% to 85%. The concordance rate for children of two schizophrenic parents is nearly that for monozygotic twins (Table 16–1), and the odds of being diagnosed with schizophrenia decline precipitously the greater the distance from a proband case. A more detailed discussion of genetic factors is provided later (see section “Etiology”).

Genetic profile is responsible, on the other hand, for only about 50–70% of the risk for developing schizophrenia; thus, environmental (nongenetic) factors are involved in the development of the disorder. The stress–diathesis model posits that a biological predisposition toward developing schizophrenia is inherited genetically, and that this vulnerability interacts with environmental challenges, which, together, lead to development of the full syndrome. Several nongenetic factors have been explored, including obstetric, birth and early childhood complications, season of birth (e.g., during spring and early winter months), exposure to infection, drug use, stressful life events and societal modernization. The precise contribution of these and other factors to the overall risk of developing schizophrenia is difficult to assess, given the heterogeneity of the disorder, its course, and the wide variety of exposures that individuals with the disorder encounter.

The Diagnostic and Statistical Manual of Mental Disorders, fourth edn, Text Revision (DSM-IV-TR) (see “DSM-IV-TR Diagnostic Criteria for Schizophrenia” box) requires at least two of five types of positive and negative symptoms (Criterion A). The four positive symptoms (Criteria A1–A4)—delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior—are considered psychotic symptoms, in that these behaviors, beliefs, and precepts are not considered consistent with normal human experience.

Signs & Symptoms

Delusions

Delusions are defined by the DSM-IV-TR as “fixed, false beliefs that are not widely held within the context of the individual's cultural or religious group,” that persist despite contradictory evidence or dysfunction clearly linked to the belief. Most often, delusions have the form of distorted and highly illogical misinterpretations of actual events or experiences (errors of inference). In the clinical setting, it can sometimes be difficult to determine if a patient's conviction is so distorted, illogical and impermeable as to be considered delusional. It is helpful to garner as much detail as possible from the patient about their belief(s) in order to uncover errors of inference. Suggesting rational explanations for a patient's belief may elicit a willingness to consider alternatives (less consistent with delusional thought). On the other hand, it may demonstrate that the patient is unwilling or incapable of doing so (more consistent with delusional thought, especially if the belief clearly leads to dysfunctional behavior). Common delusional themes are exemplified in Table 16–3.

Hallucinations

Hallucinations are typically prominent, occurring several times a day. They usually appear in the form of one or more voices that keep a running commentary on the patient's everyday activities. They occasionally are unfriendly, insulting, or accusatory. Hallucinations are usually associated with delusions and are consistent with delusional themes. On occasion, voices command patients to perform acts that could result in harm to themselves or others (command auditory hallucinations). Only rarely do patients carry out the commands; however, command auditory hallucinations increase risk of suicidal and violent behaviors. Although patients with schizophrenia can experience visual, olfactory, gustatory, somatosensory, viscerosensory, or tactile hallucinations, these types of hallucinatory activity should raise the suspicion of a general medical cause (Table 16–4). The same may generally be said for single auditory hallucinations that occur in the context of cognitive dysfunction and altered sensorium, or in the absence of delusion.

Disorganized Speech & Behavior

Examples of disorganized speech (Criterion A3) and behavior (Criterion A4) are many, as summarized in Table 16–5. In general, disorganized speech is believed to reflect an underlying impairment in thought processes—that is, the inability to process stimuli accurately and link thoughts or ideas in a coherent and logical manner. Alternatively referred to as thought disorder, these clinical signs are believed by many to be the cardinal feature of schizophrenia, and to be more closely associated with functional disability than positive symptoms are. As is the case with speech, for a behavior to be considered disorganized, it must result in significant impairment and be obvious to casual observers. Organized behaviors that occur in response to delusions are not considered to be “disorganized.” Catatonic behaviors (Table 16–6) are found in other mental disorders, medical conditions, and drug toxicity. They warrant immediate medical evaluation if new in onset.

Negative Symptoms

The fifth group of symptoms (Criterion A5) are referred to as negative symptoms because they represent deficits of normal function and are not psychotic, per se (Table 16–7). It is generally accepted that there are primary and secondary negative symptoms, the former of which represent longstanding illness features that persist between psychotic episodes and may even predate the onset of psychotic symptoms. Primary negative symptoms tend to respond less well to drug treatment and cause more dysfunction than positive symptoms. Secondary negative symptoms are believed to stem from side effects of medication, depression or demoralization associated with the illness, or as a reaction to psychotic symptoms. Secondary negative symptoms may not persist and can respond to treatment of the underlying cause.

Diagnostic Threshold

While the diagnostic threshold put forth by the DSM-IV-TR generally calls for two or more symptoms from Criteria A1–A5, there are three exceptions. The diagnosis of schizophrenia can be made on the basis of presence of only bizarre delusions (i.e., completely implausible beliefs), or the auditory hallucination of a voice keeping a running commentary on the subject's daily activities, or two or more voices conversing with each other.

Even though the above symptoms are not necessarily present in all schizophrenic patients, many patients express all of these symptoms at one time or another. The clinical manifestations of the illness as described above can vary greatly in intensity over time in a particular patient. The DSM-IV-TR requires that the symptoms result in significant functional impairment in work, relationships, self-care, or other life domains. The symptoms must be present in one form or another (e.g., prodromal or residual symptoms) for a period of 6 months or greater, but with at least 1 month of fully expressed, active symptoms as described in Criterion A. The signs and symptoms should not be better accounted for by another psychiatric disorder, general medical illnesses or the effects of substances (see section “Differential diagnosis” below).

Subtyping in Schizophrenia

Considerable effort has been made to sort through the heterogeneous clinical presentations of schizophrenia and identify homogenous groups that share characteristic symptoms, course, prognosis, and patterns of response to treatment. The DSM-IV-TR describes five such subtypes (Table 16–8). These subtypes were intended for use as a hierarchical system based on the most recent examination of the patient. Under this scheme, the catatonic type is considered first and is diagnosed as long as the criteria in Table 16–6 are met, even in the presence of prominent positive symptoms. If these criteria are unmet, the disorganized type is considered next, and is diagnosed if all three criteria in Table 16–6 are met, again regardless of positive-symptom load. Therefore, the paranoid type can be diagnosed only if the criteria for the first two are not met. The undifferentiated type is left for cases that manifest disorganization in combination with delusions and/or hallucinations but do not fit neatly into one of the above categories, while the residual type is reserved for cases in which delusions, hallucinations, disorganization and/or catatonic behaviors are no longer prominent, but persist in an attenuated or less severe form.

Other Clinical Features

Mild neurologic deficits are often present in schizophrenia: Abnormal body movements, gait, mannerisms, or reflexes; increased or decreased muscle tone; abnormal rapid eye movements (saccades); frequent blinking; dysdiadochokinesia; astereognosis; and poor right–left discrimination.

Cognitive dysfunction is a cardinal feature of schizophrenia. On average, the intelligence quotient (IQ) of schizophrenic patients, when first diagnosed with the disorder, is 10 points lower than comparison groups, including unaffected siblings or co-twins. Children at risk of schizophrenia have lower IQs than do control subjects with abnormalities in attention and concentration. Patients in their first episode of schizophrenia exhibit impairments in attention, working memory, visual–spatial memory, semantic memory, recall memory, and executive function.

The diverse nature of the cognitive disturbance in schizophrenia suggests that the disturbance is based on diffuse rather than localized brain disease. With treatment, that impairment might improve slightly, but there is little evidence that antipsychotic drugs, with the exception of clozapine, have a significant effect on the cognitive disturbance in schizophrenia. Cognitive impairment is often independent of positive and negative symptoms and even of disorganization. Over the course of the illness, a small percentage of schizophrenic patients experience a great deterioration in cognition and reach the levels of impairment of patients with senile psychosis, such as Alzheimer's disease. The majority of schizophrenic patients do not exhibit such marked dilapidation of cognitive function. Cognitive disturbance plays a major role in limiting the social life and occupational performance of schizophrenic patients. For this reason, therapies that reverse cognitive disturbance in schizophrenia will be of immense value.

Psychological Testing

The presence of significant cognitive abnormalities in schizophrenic patients warrants the use of neuropsychological testing to establish evidence of brain disorder early during the diagnosis of the disease, or to establish a cognitive pretreatment baseline. Formal neuropsychological assessment using objective tests, such as the Halstead-Reitan Battery, the Luria-Nebraska Battery, the Wechsler Adult Intelligence Scale, the Wechsler Intelligence Scale for Children, and the Wisconsin Card Sorting Test (WCST), can identify various abnormalities involving the frontotemporal areas of the brain. The usefulness of projective and personality tests in the diagnosis of schizophrenia may be limited because, although these tests identify bizarre ideations and abnormal personality traits, respectively, they are prone to unreliable, subjective interpretation.

Laboratory & Neuroimaging Findings

No laboratory or neuroimaging findings are considered pathognomonic for schizophrenia. The utility of these investigations is therefore limited to the ruling out of nonpsychiatric etiologies for psychotic presentations (discussed later). Some findings have been replicated and have shed light on neuropathological processes that may eventually be found to characterize schizophrenia.

Cerebral Ventricular Enlargement

Despite the large body of supportive imaging studies, ventricular enlargement is not present in all patients with schizophrenia and is not specific for schizophrenia. For example, ventricular enlargement and increased sulcal prominence can also be observed in patients with mood disorders.

Structural and Functional Brain Abnormalities

A number of brain abnormalities have been identified with neuroimaging (reviewed above). However, none of the findings reported so far have achieved the status of a diagnostic test. There is an emerging literature on the longitudinal aspects of brain changes in schizophrenia. Such studies will be helpful to better understand the differences in disease outcome and treatment response.

Onset & Natural Course

Onset

The onset of the disorder is quite variable. Classically, the onset is gradual, with a prodromal phase of varying duration that predates the first psychotic break. The prodromal phase is generally considered the first of three phases of schizophrenia (prodromal, active, and residual phases). During this time, patients may evidence gradually increasing social withdrawal, poor motivation, restricted affective range, cognitive difficulties, and increasingly odd behavior. These changes are subthreshold for a diagnosis of schizophrenia. For others, the onset can be quite rapid, evolving over a period of weeks.

Course

Active phase symptoms emerge following the prodrome (referred to as a “first psychotic break”) often in the context of significant life stress or substance use. Treatment may begin after a variable period of time, referred to as the duration of untreated psychosis. There is considerable evidence that the longer the duration of untreated psychosis, the poorer the response to treatment, though not all studies are in agreement. After initiation of treatment, pooled data analysis suggests that about one third of patients with first-break schizophrenia have a benign illness course (i.e., they fully or nearly fully recover, with minimal or no impairment), while the remainder have either an intermediate or poor outcome.

The residual phase is characterized by persisting schizophrenic symptoms. Of the two thirds of patients who do not achieve full or nearly full recovery during active phase treatment, approximately half experience a stable course without further deterioration, but significant residual deficits remain. The remaining group of patients with poor treatment outcome often exhibit progressive deterioration. Thus, the level of psychopathology and impairment during the residual phase can vary considerably. In general, the more incomplete the symptom recovery, the more likely the patient is to function poorly and relapse in the future. Relative to positive symptoms, negative symptoms are less responsive to medication.

Late- and Very-Late-Onset Disease

Most older patients with schizophrenia have had an onset of illness during early adulthood (early-onset schizophrenia); however, about 20% of patients manifest psychotic symptoms for the first time during middle (late-onset, after age 45 years) or old age (very-late-onset, after age 65 years). In general, the clinical symptoms of early- and late-onset schizophrenia are similar, though some important differences characterize late-onset illness. These include higher prevalence among women, less severe negative symptoms and cognitive impairment, the predominance of paranoid delusions, and lower dose requirement for antipsychotic medication.

A detailed workup, often in the context of the safety and structure afforded by psychiatric hospitalization, is necessary, especially at the first onset of psychotic symptoms. Serial patient interviews and additional history from collateral sources (e.g., prior medical records, collateral informants) are required.

Organic Etiologies of Psychotic Symptoms

Most reversible secondary causes of psychosis (Table 16–9) can be ruled out on the basis of a meticulous history, mental status examination, physical and neurological examination and appropriate laboratory and neurodiagnostic testing (Table 16–10). Some general clinical guidelines can be applied to the raising of suspicion of an organic etiology for psychotic symptoms (Table 16–11). They must always be followed by adequate clinical assessment.

Psychiatric Disorders that Present with Psychotic (or Psychotic-Like) Symptoms

Other Psychotic Disorders

In differentiating between schizophrenia and other psychotic disorders, the duration of symptoms must be accurately assessed. Schizophreniform disorder involves prodromal, active-phase and residual symptoms identical to schizophrenia, but the total duration of illness is less than 6 months before full recovery. It should be noted, however, that while about one third of patients fully recover within 6 months and retain a diagnosis of schizophreniform disorder, two thirds eventually progress to schizophrenia or schizoaffective disorder. With brief psychotic disorder, psychotic symptoms endure for less than 1 month before full recovery. Delusional disorder is distinguished by its later age of onset (35–50 years) and the persistence of nonbizarre delusions in absence of hallucinations, disorganized thoughts or behaviors, and negative symptoms. Patients with delusional disorder do not typically manifest the degree of functional incapacity observed among patients with schizophrenia, and do not experience significant changes in cognition. Therefore, delusional disorder is a very difficult diagnosis to recognize in the clinical setting.

Mood Disorders with Psychotic Features

In distinguishing between mood disorders (bipolar I disorder and major depression) with psychotic features, schizoaffective disorders (bipolar or depressed subtype) and schizophrenia, it is helpful to determine whether the mood and psychotic symptoms occurred simultaneously, whether the psychotic symptoms persisted at any point independent of mood symptoms, and whether the mood symptoms were brief relative to the total period of the disturbance. In mood disorder with psychotic features and schizoaffective disorder, psychotic symptoms occur at the same time as mood symptoms; however, in schizoaffective disorder, psychotic symptoms exist independently of mood changes for at least 2 weeks (and often longer). For mood disorders with psychotic features, psychotic symptoms do not persist apart from mood dysfunction. Another important distinction between mood disorder and schizophrenia is that, after resolution of acute mood and psychotic symptoms, there is a return to normal functioning. Schizophrenic patients rarely return to baseline functioning, and each subsequent psychotic relapse may result in progressive dilapidation.

Personality Disorders

Individuals with personality disorders may be suspicious and hypervigilant (paranoid personality disorder), with marked eccentricities of appearance and behavior, perceptual distortions and diminished capacity for close relationships (schizotypal personality disorder). They may evidence an incapacity for relationships of any kind and extreme isolativeness (schizoid personality disorder). Individuals with cluster-disorders and those with borderline personality disorder are prone to severe stress-induced paranoia, which may be difficult to distinguish from a primary psychotic disturbance on the basis of only one clinical encounter. However, personality disorders have mild relative symptoms compared to those observed among schizophrenics, and the symptoms have been present throughout the patient's lifetime. None with personality disorder present with prominent hallucinations or frank delusions. They also lack chronic negative symptoms or disorganization.

Anxiety Disorders

Patients with posttraumatic stress disorder (PTSD) are prone to severe hallucinatory-like symptoms and fearful (paranoid) behavior; however, patients with PTSD usually retain insight in to the nature of their disturbances, which are inextricably linked to exposure to past traumatic event(s). Insight is typically preserved in obsessive–compulsive disorder (OCD), even though uncontrollable intrusive thoughts and compulsive mental or physical rituals can mimic psychosis. A rare subtype of OCD is characterized by poor insight; however, these disorders do not feature negative or disorganization symptoms and are not associated with the same degree of functional incapacity as the typical patient with schizophrenia.

Other Disorders

Patients with hypochondriasis or body dysmorphic disorder are convinced of the presence of an occult disease or bodily defect in absence of objective evidence to support their belief(s). The absence of hallucinations and disorganization symptoms, and exclusively somatically circumscribed preoccupations, quickly distinguish these disorders from schizophrenia.

Differential Diagnosis of Negative Symptoms

The workup of a patient who presents with prominent negative symptoms must be especially thorough. Many conditions, some very serious, can mimic the negative symptoms of schizophrenia. These include malignant catatonia, delirium, frontal lobe injury, intracranial space occupying lesions (e.g., tumors, etc.), substance abuse, hypothyroidism, severe depression, bipolar mania (catatonic presentation), parkinsonism (idiopathic or neuroleptic-induced), and neuroleptic-induced akinesia.

The modern treatment of schizophrenia has as its goals the reduction of symptomatology and the maximization of functioning. To achieve this, a number of treatment targets have been identified, including (1) positive symptoms, (2) negative symptoms, (3) conceptual disorganization, (4) neurocognitive deficits, and (5) anxious/depressive symptoms and suicidality. The situation is more complicated in cases of comorbid substance abuse or severe physical morbidity, both of which are common in community mental health settings. A number of treatment modalities—both pharmacological and nonpharmacological—must therefore be utilized.

As a general rule, positive symptoms such as hallucinations and delusions, as well as disorganized speech and behavior and psychotic agitation, all respond very well to antipsychotic drug treatment. Though dramatic in appearance and distressing and potentially dangerous to the patient and others, the severity of positive symptoms does not appear to correlate significantly with long-term functioning.

By contrast, negative symptoms such as anhedonia, affective flattening, alogia, avolition, and social withdrawal are far more difficult to treat pharmacologically, and are robust predictors of long-term functional incapacity. Older generation (“typical”) neuroleptic medications, such as haloperidol and perphenazine, have little impact on these devastating symptoms. On the other hand, the efficacy profile of atypical antipsychotic drugs in treating negative symptoms is more encouraging.

Cognitive function is severely impaired in schizophrenia. Patients demonstrate neuropsychological deficits in a broad array of domains; however, impairments in executive skills, working memory, verbal skills, and learning and memory are especially severe. Cognitive impairment has important consequences for the everyday functioning, and is a critical determinant of capacity for work, social functioning, and independent living. Not surprisingly, cognitive impairment has become an important therapeutic target, based on the rationale that improvements in cognitive function will lead to subsequent improvement in functional status.

An underappreciated phenomenon is the severity and pervasiveness of depression and anxiety symptoms associated with schizophrenia. Depression in schizophrenia is very common; however, mood symptoms have only been recently recognized as a core feature of the illness. Depressive symptoms frequently emerge during acute psychotic episodes or shortly after their resolution (i.e.,postpsychotic depression). Over time, they tend to occur and persist independently of positive symptoms, and may occur at any stage of the illness. By the same token, suicidal behavior, though common among schizophrenic patients, has only recently become an independent treatment target.

Psychopharmacologic Interventions

Antipsychotic drugs are the treatment of choice for virtually all patients with schizophrenia. There are two broad classes of antipsychotic drugs: The typical (a.k.a., “first-generation” or “conventional”) antipsychotic drugs and the atypical (a.k.a., “second-generation” or “novel”) antipsychotics (Table 16–11). What follows is a description of each of these broad classes, followed by guidelines for choosing antipsychotic medications and for their clinical use in treating schizophrenia during the acute phase and long-term treatment.

Typical Antipsychotic Drugs

The discovery of chlorpromazine in 1950 revolutionized the treatment of schizophrenia. It and the other typical drugs have a simple mechanism of action: They are direct-acting dopamine D2-receptor antagonists. Thus, they occupy D2 receptors in each of the relevant dopamine pathways, including the mesolimbic tract (where excessive dopamine transmission is believed to underlie positive symptoms), mesocortical tract (where deficits in dopamine transmission are thought to cause cognitive dysfunction and negative symptoms), nigrostriatal tract (where D2 blockade results in extrapyramidal adverse effects, as will be discussed shortly), and the tuberoinfundibular tract (where activation of D2 receptors controls pituitary prolactin release). By this one mechanism, typical neuroleptics remedy positive symptoms but coincidentally result in troublesome antidopaminergic adverse effects (EPS, hyperprolactinemia) and either fail to address adequately or even worsen negative symptoms and cognitive dysfunction. This class of agents does not have a useful impact on work capacity and social functioning.

Clinical Use

In terms of treatment response, about 70% of patients with schizophrenia who manifest delusions or hallucinations during some phase of their illness will have a good response of those symptoms to these agents. The therapeutic lag time is about 4–6 weeks. For many, an antipsychotic response will be observed sooner, sometimes within the first week of treatment. The other 30% will have moderate to severe positive symptoms despite adequate doses of these agents for at least 6 weeks, which is considered the minimum, adequate therapeutic trial length. Evidence suggests that lower dosages of typical antipsychotics can bring relief to patients as rapidly and effectively as higher doses and with fewer side effects. For instance, daily dosages of 5–10 mg of haloperidol, or its equivalent (Table 16–11), may be adequate for many, if not most, patients with acute psychosis. First-episode and recent-onset patients almost always respond to lower dosages. Ordinarily, higher dosages should not be tried until at least 4–6 weeks of treatment at the starting dose have been tried. Then, if positive symptoms persist, the dosage may be increased. Plasma levels of antipsychotics and their metabolites vary greatly between patients. The only typical agent with a possible therapeutic window is haloperidol. For haloperidol, a steady-state plasma range of 12–17 ng/L has been associated with optimal antipsychotic action.

Adverse Effects

The term neuroleptic refers to the neurologic side effects of the typical antipsychotics, such as catalepsy in rodents and EPS in humans. These effects occur in the same dosage range as is associated with an antipsychotic effect; therefore, for typical antipsychotics, treatment emergent EPS is a common and significant treatment-limiting factor. The EPS may be divided into acute and delayed effects. The predominant acute effects are parkinsonism (coarse resting tremor, bradykinesia, hypertonia, unstable gait), akathisia (subjective restlessness and psychomotor agitation), and dystonic reactions (sudden-onset, sustained, intense and often painful muscular contraction). The late occurring side effects are tardive dyskinesia and tardive dystonia. The late occurring effects are sometimes irreversible and, rarely, life threatening. No one with tardive dyskinesia should be treated with a typical neuroleptic now that the atypical antipsychotics are readily available.

As mentioned beforehand, the antipsychotic action and motor side effects of neuroleptics are secondary to their ability to decrease dopaminergic activity due to blockade of D2 receptors in the mesolimbic and nigrostriatal pathways of the brain, respectively. The affinities that antipsychotic agents have for D2, 5-HT2A, and muscarinic receptors are key determinants of their liability to cause EPS. These drugs also have variable affinities for other neurotransmitter receptors which have predictable effects on antipsychotic profile (Table 16–12). These receptors include histamine 1 (H1, antagonism of which may result in sedation and weight gain), alpha-1 (α-1) adrenergic (antagonism of which may result in sedation, orthostatic hypotension, and reflex tachycardia), muscarinic-1 (M1) cholinergic (antagonism of which may result in blurring of vision, dry mouth, urinary retention, constipation, and cognitive dulling) receptors. Hematologic effects, jaundice, cardiac effects (e.g., electrocardiographic changes such as QTc interval prolongation, especially for thioridazine, pimozide, and droperidol), photosensitivity, and retinitis pigmentosa (associated especially with the use of higher doses of thioridazine, which may result in blindness) result from toxic effects on specific target tissues.

Choice of Agent:

The choice of typical neuroleptic drug is based on a variety of initial considerations, which include the following:

• side-effect profile,
• past response(s) to antipsychotic drugs,
• the availability of long-acting preparations (e.g., fluphenazine and haloperidol decanoate) required for patients who frequently relapse due to poor medication compliance. In chronically noncompliant patients who are unwilling to take oral medication, biweekly or monthly injections of fluphenazine decanoate or haloperidol decanoate (given at clinics or by visiting nurses) often decrease relapse rates significantly.
• the availability of short-acting injectable or intravenous formulations for use in acute situations (to control agitation and combative behavior) where oral dosing is not feasible, or when the oral route is not available.

Other considerations are based on the side-effect profile. Differences in side-effect profile between low- and high-potency typical neuroleptics are predicted to a great degree by their receptor-binding profiles. For instance, low-potency drugs (e.g., chlorpromazine, thioridazine, mesoridzaine), so named because of their relatively lower affinity for D2 receptors and therefore higher dose requirement for antipsychotic potency (300 mg/d or greater), may result in lower EPS or hyperprolactinemic liability compared to high-potency agents (e.g., haloperidol, fluphenazine). However, low-potency drugs result in more sedation, weight gain, orthostasis, and antimuscarinic effects than high-potency agents do because of their higher affinities for H1, α-1 and M1 receptors. The latter agents produce more EPS than do the low-potency agents (see Table 16–11).

If the patient's history of drug response does not indicate an unusual sensitivity to EPS, high-potency agents such as haloperidol and fluphenazine are preferred to low-potency agents. Thioridazine is believed to have more risk of causing a ventricular arrhythmia than other typical antipsychotic drugs. If EPS develop, anticholinergic agents such as benztropine, diphenhydramine, biperiden, or trihexyphenidyl can be used as a pharmacological adjunct, or the patient can be switched from a high-potency agent to a medium-potency drug (e.g., trifluoperazine) or to a low-potency drug (e.g., thioridazine). A more important strategy for the minimization of EPS is to keep the dose as low as possible (e.g., no more than 5–10 mg/d of haloperidol equivalents), assuming there is a reason why an atypical antipsychotic drug could not be substituted. Persistent EPS, especially akathisia, can contribute to noncompliance or lead to increased agitation or even suicide risk. Thus, in cases of apparently increased agitation and disorganized behavior in the face of ongoing treatment especially with typical antipsychotics, screening for akathisia should always be considered.

Atypical Antipsychotic Drugs

The “atypical” antipsychotic drugs were given this name because they were able to produce an antipsychotic effect at doses which produced little or no EPS (and very few cases of tardive dyskinesia). The prototypical atypical is clozapine, a dibenzodiazepine, which was first identified in 1959. After the hypothesis was advanced that its atypicality was due to a weak D2-receptor blockade coupled to potent serotonin (5-HT2A) antagonism (mechanism of action), a number of other atypical antipsychotic drugs were discovered which shared this mechanism: Risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. The latter differs from the others in substituting partial D2-receptor blockade for D2-receptor antagonism. Other atypical antipsychotics including asenapine, Iloperidone, laurisdione, paliperidone, and perospirone are in development, and have mechanisms of action similar to clozapine. Bifeprunox has a mechanism similar to that of aripiprazole (partial dopamine D2-receptor agonism). Besides being a partial D2 agonist, aripiprazole is also a 5-HT2A antagonist (like most other atypicals) and a 5-HT1A-partial agonist (similar to clozapine, quetiapine and ziprasidone). Bifeprunox is a 5-HT1A-partial agonist and has weak 5-HT2A-antagonist properties.

Clozapine

Clozapine was the first antipsychotic drug shown in controlled clinical trials to alleviate both positive and negative symptoms in patients who had failed to respond to adequate trials of typical neuroleptic drugs. In this treatment-resistant group, clozapine treatment results in a clinical response in 30–60% of cases. It produces almost no EPS, akathisia, tardive dyskinesia, or hyperprolactinemia. The onset of a significant response to clozapine in treatment-resistant patients may be delayed for up to 6 months. Primary negative symptoms tend to improve more slowly than do other types of symptoms. The response to clozapine is usually only partial, but for patients whose symptoms have been virtually nonresponsive to all other therapies, the change can be highly significant.

The remarkable advantages of clozapine (described later in this section) must be balanced against its ability to cause agranulocytosis, in 1% of patients. As a result, clozapine has been approved in the United States only for patients with schizophrenia who have failed to respond adequately to typical neuroleptic drugs (treatment-resistant schizophrenia) or who are intolerant of typical neuroleptic drugs because of EPS or tardive dyskinesia, or who are at high risk for suicide. Poor work function or moderate-to-severe residual negative symptoms are considered a poor response, even if only mild positive symptoms are present.

Clozapine has been shown to reduce depression and suicidality. The latter effect leads to a major decrease in the overall mortality rate associated with schizophrenia, despite the slight increase due to agranulocytosis. Numerous studies have reported that clozapine can improve some aspects of cognitive function, especially verbal fluency, attention, and recall memory. This effect appears to be unrelated to the drug's lack of adverse effect on motor function.

About 40% of patients have positive symptoms that fail to respond adequately to clozapine monotherapy. As previously mentioned, it often takes 6 months and sometimes longer for positive symptoms to be controlled in very treatment-resistant patients. Patience is required. Polypharmacy with other antipsychotic drugs should be avoided, if possible. Only ECT has sometimes been found to be effective as an adjunctive treatment. The effectiveness of adding of mood stabilizers and antidepressants when mood instability or depression is inadequately treated with clozapine has not been studied in a controlled manner. On clinical grounds, trials with various mood stabilizers may be attempted. There is some evidence that lamotrigine and valproate are useful.

Agranulocytosis during clozapine treatment generally occurs within 4–18 weeks after treatment begins, but it can occur rarely at later times. In the United States, white blood cell and absolute neutrophil count (ANC) must be monitored weekly for 6 months, then every 2 weeks for months 7–12, followed by monthly monitoring on an indefinite basis. When the white blood cell count falls below 3000 cells per mm3, or the ANC below 1500 cells per mm3, clozapine should be stopped and not restarted. If agranulocytosis has developed, granulocyte colony stimulating factor (G-CSF) or other growth factors can be used to hasten the recovery process. Recovery generally takes 7–14 days. Hospitalization to prevent or treat sepsis is essential. To date, the death rate from clozapine due to agranulocytosis is about 1 per 10,000.

Clozapine can also cause leukocytosis and eosinophilia in the early stages of treatment. The development of these disorders does not predict later development of agranulocytosis. Other side effects of clozapine include sedation, weight gain, type II diabetes, hyperlipidemia and atherosclerotic heart disease, major motor seizures, obsessive–compulsive symptoms or treatment-emergent obsessive–compulsive disorder, hypersalivation, tachycardia, hypotension, hypertension, stuttering, neuroleptic malignant syndrome, urinary incontinence, myocarditis, and constipation. Many of these side effects diminish over time or are responsive to pharmacologic agents and decreased dosage.

The dosage of clozapine ranges from 100 to 900 mg/d for most patients. It must be titrated slowly because of tachycardia and hypotensive side effects, with a starting dosage of 25 mg/d. The average dosage is 400–500 mg/d, usually given twice daily. Plasma levels of 350–400 ng/L are more likely to be associated with clinical response than are lower levels.

Clozapine has a very complex pharmacologic profile. It has a high affinity for serotonergic (5-HT2A,2C,6,7), adrenergic (a1,2), muscarinic, and histaminergic receptors. Clozapine and related drugs are inverse agonists at 5-HT2A and 5-HT2C receptors, meaning they can block the constitutive activity of these receptors, (i.e., activation of the receptor that is independent of 5-HT stimulation). The major metabolite of clozapine, N-desmethylclozapine is a M1 muscarinic agonist. This mechanism may improve cognitive function and reduce psychosis. No other atypical or a metabolite thereof has M1 muscarinic properties.

Other D2 and 5-HT2a Antagonists

This group of drugs includes quetiapine, olanzapine, risperidone, and ziprasidone. As a class, these agents are as effective as the typical antipsychotic drugs with regard to the control of positive symptoms. The recent CATIE study suggested that olanzapine is superior with regard to some outcome measures; however, CATIE permitted olanzapine to be dosed at a higher than the approved dose range which probably enabled it to be more effective in the subset of patients who were treatment resistant. At clinically equivalent doses, there is no reliable evidence that any of these drugs is significantly more efficacious than the others. Anecdotal evidence suggests that ziprasidone causes an activation syndrome earlier and at lower doses than other treatments do. However, controlled clinical trials do not support this. It may be that patients vulnerable to this type of activation are underrepresented in clinical trials.

These drugs differ in side-effect profiles (Table 16–11). Olanzapine, like clozapine, has the greatest likelihood of causing metabolic side effects. Both drugs show relatively high-affinity binding to H1, α-1 and M1 receptors and thus are associated with corresponding adverse effects. Metabolic effects include weight gain and abnormalities in indices of insulin resistance, including increased fasting blood sugar and an atherogenic lipid profile. Some patients develop type II diabetes or diabetic ketoacidosis. In rank order, the other drugs likely to produce these effects are quetiapine and risperidone (moderate risk), and ziprasidone and aripiprazole (lower risk). Both risperidone and ziprasidone are mild, overall, in this regard. Nevertheless, some patients treated with any of these drugs will gain weight or have glucose and lipid changes. Despite the fact that many patients who develop insulin resistance also experience significant weight gain, these two factors are not highly correlated in many patients. Patients who do not gain weight may therefore show other facets of the insulin resistance syndrome and vice versa. Patients should be monitored for increased lipids and fasting blood sugar after the first 3 and 6 months of treatment, and every 6 months thereafter.

Relative to typical neuroleptics, atypical antipsychotic drugs have less treatment-emergent antidopaminergic side effects than typical neuroleptics do. At higher doses (e.g., above 6 mg/d), dose-dependent EPS and hyperprolactinemic effects can be observed with risperidone, however.

The dose of these drugs should be kept as low as possible in non–treatment-resistant patients. First-episode patients and those within the first 5 years of illness usually require the low end of the dose range. All atypical drugs, with the exception of quetiapine, which has a very short half-life, can be given once a day, generally prior to sleep, to minimize daytime sedation, for example, olanzapine, 10–20 mg/d; quetiapine, 200–1000 mg/d; and risperidone, 2–8 mg/d. Polypharmacy with two antipsychotic drugs should be avoided. If control of positive symptoms is inadequate at these dosages after 6 weeks, it might be useful to increase the dose. However, a switch to clozapine, where the dose can be relatively high with minimal EPS, is often a better strategy, especially after the failure of two adequate antipsychotic trials (e.g., 6 or more weeks at an adequate dose). As with clozapine, augmentation with mood stabilizers, antidepressant drugs or ECT can be attempted on clinical grounds.

Currently, only risperidone is available in a long-acting form. It must be given every 2 weeks and takes 6 weeks before steady state plasma levels are achieved. Therefore, oral risperidone must be continued for at least 3 weeks after the first long-acting risperidone injection, or even longer in some cases. The typical dose of long-acting injectable risperidone is between 35–50 mg every 2 weeks.

Partial D2 Agonists

Aripiprazole is the first partial dopamine agonist which has been approved for the treatment of schizophrenia. The basis of partial dopamine agonism as a block to dopaminergic blockade is that aripiprazole occupies the receptor, but causes significantly less activation of the receptor than the full agonist, dopamine does. The efficacy of aripiprazole is no doubt dependent, in addition, on its serotonergic properties. It is a 5-HT2A antagonist and a 5-HT1A-partial agonist, both of which effects would be expected to minimize EPS. Aripiprazole is generally given once daily, at a dose of 15 mg/d. Sometimes, doses of 20–30 mg are required. Combination with a typical neuroleptic should be avoided as that could interfere with the partial dopamine agonist properties. Aripiprazole produces mild metabolic side effects, comparable to those of risperidone and ziprasidone. It may also be associated with activation when first administered, and can cause nausea.

The management of schizophrenia is often conceived of as occurring in three phases of treatment (acute, continuation, and maintenance).

Acute Phase Treatment

The acute phase of schizophrenia is characterized by fully expressed psychotic symptoms. The acuity of symptoms is often such that hospitalization is necessary for control of acute, life-threatening agitation and combativeness. In order to avoid use of physical restraints, oral antipsychotic medication may be offered; however, oral medication is often refused or, more commonly, cannot be safely administered in an acute situation. For patients who are acutely agitated or likely to harm themselves or others, short-acting injectable antipsychotics, benzodiazepines, alone or in combination, may be considered. Currently, the only atypical antipsychotics available in an acute injectable form are ziprasidone and olanzapine. Several typical neuroleptics are available in this form (haloperidol, 5 mg IM), and are often administered alone or in combination with an injectable benzodiazepine (e.g., lorazepam) and/or an anticholinergic drug (e.g., benztropine or diphenhydramine). It is necessary to isolate such patients in a quiet room, with as much supervision as possible. Parenteral haloperidol may be repeated, as needed, every 2–4 hours. Rarely, ECT will be needed.

Once agitation has been controlled or if injectable medication is not indicated, treatment with an orally administered antipsychotic may be initiated. Ordinarily, the first antipsychotic administered should be chosen from aripiprazole, quetiapine, risperidone, and ziprasidone in a never-treated or medication-free patient who has a history of response to antipsychotic drug treatment (Figure 16–1). Olanzapine, because of its higher burden of metabolic side effects, might be kept in reserve. However, not all patients treated with olanzapine develop metabolic side effects. For patients on one of these drugs for whom a switch is indicated to another of the same class, there is no accepted preferred way to do this. Stopping the current drug as the new drug is introduced may be as safe and effective as rapid or slow cross-titration.

In choosing among the various first-line options, no convincing data suggest superior efficacy in target symptom domains for a particular agent. The clinical decision about which agent to use is based on other factors: side-effect profile, past therapeutic response to agent(s), and patient/caregiver preference. The issue of tolerability due to side-effect burden is no small one, since relapse into acute phase illness is often preceded by unilateral discontinuation of medication.

If circumstances are such that a patient requires treatment with a typical neuroleptic (i.e., prior treatment response to typical rather than atypical drugs in absence of significant EPS, limited formularies, cost considerations, or patient/caregiver preference), treatment is best commenced with an oral drug at low dosage (i.e., 10 mg/d haloperidol equivalent). The dose should not be increased for 4–6 weeks unless psychotic or aggressive symptoms or sleeplessness are severe. Rapid dose increases aggravate the risk of EPS and secondary negative symptoms without added antipsychotic benefit. Routine use of short-acting parenteral medication for newly hospitalized patients is to be avoided unless absolutely necessary.

Long-acting (depot) medication should not be given initially except to those patients noncompliant with other forms of treatment. On the other hand, acute-phase symptoms due to illness relapse in the setting of poor compliance call specifically for consideration of long-acting injectable antipsychotic medication. As previously discussed, long-acting risperidone is the only atypical drug available for such use, whereas haloperidol and fluphenazine are available among the typical drugs. Because of its atypical profile, long-acting risperidone should be the first choice.

Continuation Phase Treatment

Psychotic symptoms respond, usually partially, within the first several days of treatment, or even on the first day in some patients. However, most patients do not achieve a full response at a given dose for 2–6 weeks, and remain vulnerable to early relapse. The purpose of continuation-phase treatment is to monitor patient compliance, therapeutic response, and treatment tolerance. In addition, because a significant lag time may be required to full therapeutic effect at a given dose of drug, it is inadvisable to discontinue a drug prematurely and substitute a different class of neuroleptic agent before the optimal 4–6 weeks of therapy has passed, unless significant side effects develop that are not amenable to treatment. After initial stabilization, continuation treatment ranges in duration up to 6–8 weeks, depending upon treatment response.

In general, the same medication dosage that resulted in control of acute phase symptoms is appropriate for the continuation phase, though the dose may be “fine tuned” during this time in order to minimize adverse effects or bring about a more adequate clinical response. Although some evidence supports intermittent dosing of antipsychotic medication, this strategy has been associated with increased rates of relapse. Continuous dosing is preferred.

The use of several neuroleptics at the same time should be avoided. There is no justification for the concomitant use of two classes of typical neuroleptic drugs (e.g., a parenteral and an oral antipsychotic) unless the patient's route of treatment is being converted from intramuscular to oral. In some instances, particularly when a neuroleptic does not adequately control anxiety and agitation, the adjunctive use of benzodiazepines may be helpful.

Maintenance Treatment

The primary goals of maintenance treatment are prevention of relapse and optimization of psychosocial functioning. Long-term illness management also calls for monitoring and treating medical comorbidities (including the effects of antipsychotic treatment), addressing comorbid psychiatric and substance use disorders, and addressing the important issue of medication compliance.

As is the case with continuation-phase treatment, the dosage used to achieve clinical response in the acute phase is often continued, but may be subject to “fine tuning” for the reasons specified above. Continuous dosing is preferred. Ongoing monitoring of medication compliance must be paramount, as this is still the most common reason for relapse. Noncompliance stems from a number of factors: Denial of illness (poor insight); intolerable side effects; suboptimal management of clinical symptoms; cognitive deficits; and other reasons. Weight gain, EPS (especially akathisia), and sedation can also be distressing to patients. Because many of the adverse effects of medication are dose dependent, problems with compliance may be managed by lowering the dosage, or switching to agents that result in fewer side effects. Pharmacological adjuncts may be required to counter particular adverse effects if dosage adjustment or switching are not clinically feasible. For most patients, treatment with antipsychotic medications will be of indefinite duration.

In spite of recent advances in antipsychotic treatment, a significant proportion of patients are left with persisting symptoms, especially negative and neurocognitive symptoms. Even under the best of circumstances, however, positive symptoms frequently persist, though in a less acute form. Incompletely treated symptoms are associated with significant psychiatric and physical health-related morbidity, and with an increased risk of relapse and rehospitalization. Thus, management during maintenance phase must endeavor to achieve as optimal a treatment response as possible. If at least a partial response to a well-executed antipsychotic trial has been achieved, remaining options include watchful waiting (since some treatment effects may take longer to appear), upwardly adjusting the drug dosage, using adjunctive medication, or switching to another medication, assuming that other factors that contribute to suboptimal treatment response have been ruled out (Table 16–12). For typical neuroleptics, clinical evidence indicates that the dose–response profiles eventually either plateau, or the side-effect liability begins to outweigh therapeutic benefit as doses are increased. For atypical antipsychotics, the dose–response interactions have been less well studied, though there is some evidence in favor of high-dose strategies for olanzapine and other atypicals.

The evidence for augmenting nonclozapine atypical antipsychotics is generally lacking. Serial trials of antipsychotic monotherapy are preferred. For treatment-refractory patients, a trial of clozapine monotherapy is clearly indicated (discussed later). However, when dosages of antipsychotic medication cannot be raised, when the risk of losing the partial response already achieved outweighs the potential benefit of switching medication, or when no other options are feasible, augmentation may be considered for specific target symptoms or psychiatric comorbidities that antipsychotic monotherapy cannot address. When an adjunct is being considered, great care must be taken to review all medications, in order to anticipate unwanted drug interactions and other risks of combining medications. Specific clinical subgroups for whom adjuncts have at least some support include patients with aggressive behavior (valproate, benzodiazepines), anxiety (benzodiazepines, antidepressants), substance use problems (naltrexone), prominent affective symptoms (valproate, lithium, antidepressants), positive symptoms (benzodiazepines), negative symptoms (antidepressants) and cognitive difficulties (antidepressants, buspirone). These strategies, again, are based on anecdotal reporting and, in cases where the evidence is stronger, clinical responses can be highly variable or even worse, especially in the case of benzodiazepines.

Treatment-Refractory Schizophrenia

Treatment-resistant schizophrenia is variously defined. Failure of two well-carried-out therapeutic trials of antipsychotic from any pharmacological class is a generally accepted definition. The atypical antipsychotic, clozapine, is the only drug with proven efficacy for treatment-resistant patients. It remains the gold standard in this subgroup. Approximately 30–60% of all schizophrenic patients who fail to respond to typical antipsychotics respond to clozapine. Data concerning the usefulness of other atypical antipsychotics at conventional doses are not convincing, though higher-than-usual doses of other atypical antipsychotics may be of benefit. As was previously discussed in regard to other atypicals, there are several potentially useful adjuncts for addressing a partial antipsychotic response to clozapine, though none have a particularly strong empirical basis. To date, the most evidence is for ECT. While the rationale for the use of augmenting therapies would be the strongest for clozapine, given its status as a treatment of last resort, the potential for dangerous adverse effects with certain drug combinations is considerable. Thus, the need for caution may be even greater when augmenting clozapine partial response than for other agents.

Psychotherapeutic Interventions

Although antipsychotic drugs are the mainstay of treatment of schizophrenia, significant residual symptoms often remain, even with optimal management. Furthermore, the rate of nonadherence to pharmacological treatment is high. Both of these facts make it imperative for every clinician to explore nonpharmacological modalities of treatment. Such treatments are aimed at improving compliance with drug therapy, supporting the patient, fostering independent living skills, improving psychosocial and work functioning, and reducing caretaker burden.

The major forms of psychotherapeutic interventions for schizophrenia are cognitive–behavioral therapy (CBT), personal therapy, compliance therapy, acceptance and commitment therapy, and supportive psychotherapy. The CBT, originally developed for the treatment of depression and anxiety, has been modified for the treatment of schizophrenia. The goals of CBT in the treatment of schizophrenia include belief modification, reattribution, and normalizing of psychotic experiences. A recent meta-analysis of CBT trials in schizophrenia reported a modest effect size (0.37) for the reduction of positive symptoms. A variation of CBT is acceptance and commitment therapy, which does not aim to change thoughts and feelings, but to “just notice” and accept them. Personal therapy focuses on affective dysregulation and aims to achieve recovery in several stages of decreasing acuity, making it a long-term therapeutic effort. Compliance therapy is short term and uses motivational interviewing to improve medication adherence in the acute stage of the illness (often at the time of hospitalization).

Other psychosocial approaches include illness education, cognitive remediation, and social skills training. Providing education and support to family members is a crucial component of comprehensive treatment. Family treatment that ameliorates expressed emotion reduces the likelihood of relapse, especially if the patient's response to antipsychotic medication is less than optimal.

In most mental health systems, case management has been developed to provide low-cost support for patients living in the community, many of whom were formerly institutionalized. Case managers help patients find housing; manage financial resources; get access to psychiatric clinics, rehabilitation services, and crisis intervention; and comply with medication regimens. Such assistance enables patients to live in settings with no or minimal mental health worker provided supervision. Some mental health systems assign patients at especially high risk of rehospitalization to a multidisciplinary team that is available around-the-clock, an approach termed “assertive community treatment.”

Finally, many communities offer supported employment programs, whereby patients are assessed for skills and are matched with an appropriate job with on-site support and training from a work coach familiar with the special needs of patients with schizophrenia. The goal of supported employment is similar to that of sheltered work programs—assisting patients to obtain employment.

As indicated above, the course of schizophrenia is highly variable; however, the typical pattern is of relative remissions with residual symptoms and dysfunction, punctuated by periodic symptom exacerbation. About 10% of patients eventually recover, while an additional 20% have a good outcome. One third of treated patients have a stable but only intermediate outcome, while the remaining one third have a deteriorating course.

Thus, a significant proportion of treated patients (about 40%) continue to manifest psychotic symptoms. Even low-grade residual symptoms can be enough to impede functional capacity (e.g., to work, sustain meaningful relationships, maintain adequate self-care, and live independently). Therefore, in spite of advances in the treatment of the disorder, more is needed before patients with schizophrenia can enjoy a quality of life comparable to that of the general population.

Predictors of Better Long-Term Course

Predictors of better long-term course are summarized in Table 16–13. Even under these circumstances, return to a full premorbid level of functioning is rarely observed, and milder residual deficits persist as indicated above. The long-term prognosis for independent living is unfavorable.

Predictors of Poorer Long-Term Course

Predictors of poorer long-term course are summarized in Table 16–13. Taking into account the different syndromal domains of schizophrenia, negative symptoms, and cognitive dysfunction are more closely tied than positive symptoms to functional disability and problems with independent living. This is probably due to the combination of illness-specific factors and the limitations of available treatment, the latter of which may successfully address combativeness, agitation, neurovegetative problems and other positive symptoms but provide less benefit for negative symptoms, social dysfunction, impeded cognition, and poor insight. On the other hand, negative symptoms and cognitive dysfunction are more responsive to the atypical antipsychotic drugs than to the typical neuroleptics.

More than half of patients with schizophrenia have poor insight. Many are unaware that their symptoms are attributable to mental illness. Even if appropriate treatment is initiated, the rates of relapse are high, especially in the context of poor treatment compliance, the most common form of which is “partial” noncompliance rather than outright treatment refusal or discontinuation.

Early Mortality

Early mortality is frequently encountered among schizophrenic patients, roughly 1.5–2.0 times more often than in the general population. Excess mortality is attributed not only to illness-related psychopathological symptoms and cognitive dysfunction, but also to medical comorbidity, accidents, and suicide. The standardized mortality ratios for “natural causes,” accidents, and suicide among patients with schizophrenia are approximately 1.1, 2.2, and 8.4, respectively. The lifetime risk for suicide among patients with schizophrenia is 10–13%. At some point during their lifetime, 18–55% of patients attempt suicide.

Successful treatment of the disorder, therefore, requires attention not only to psychopathological domains such as positive and negative symptoms, but also to cognition, functional capacity, treatment compliance, affective/anxiety symptoms, psychosocial support, comorbid conditions (psychiatric and substance related) and general medical care. Advances in pharmacological and psychosocial treatment, and increased attention to medical problems and the other special needs of schizophrenic patients, offer hope to many.