Schizophrenia is characterized by positive (reality distortion and disorganization), negative, cognitive, and mood symptoms.7 The types and severity of symptoms differ among patients and change over the course of the illness. Positive symptoms typically reflect an excess or distortion of normal functions. In contrast, negative symptoms reflect a decrease or loss of normal functions. Positive symptoms include the psychotic dimension, or distortions in thought content (delusions) and perception (hallucinations), as well as the disorganization dimension, or disorganization in speech and behavior. The resulting positive symptoms also include the inability to self-monitor behavior, which results in grossly disorganized or catatonic behavior. Delusions, or systematic, fixed, false beliefs, usually involve themes of persecution, reference, somatization, religiosity, or grandiosity. Hallucinations are sensory perceptions with no apparent stimulus. They occur in any sensory system (such as auditory, visual, olfactory, gustatory, or tactile) but usually auditory hallucinations are the norm. Auditory hallucinations are commonly experienced as voices, distinct from the person’s own thoughts, and out of the range of normal experience. Disorganized thinking is usually evaluated by an individual’s speech, and is frequently characterized by frequent derailment or loose associations, invented words, tangential ideas, and, when most severe, incomprehensible speech. Grossly disorganized behavior can range from childlike silliness to unpredictable agitation, and impairs the individual’s ability to complete tasks of daily living. When individuals display catatonic motor behaviors, they show a decrease in reactivity to environmental events, to such an extreme that they can maintain a rigid posture and resist efforts to be moved. The positive symptoms¹³ of schizophrenia are thought to result from excessive dopamine D₂ receptor activity in the brain. Negative symptoms are considered to be restricted affect, or avolition and asociality. Negative symptoms represent deficits in functioning and can be more difficult to recognize than positive symptoms. Negative symptoms¹³ of schizophrenia are considered to be associated with dopamine D₁ receptor activity in the brain. Poor cognitive functioning in schizophrenia includes difficulties with memory, attention (e.g., poor concentration, distractibility, selective attention), and decision making.

According to the workgroup responsible for developing DSM-5,³ the active phase of schizophrenia is characterized by two or more of the following symptoms that must be present for a significant portion of time during a 1-month period (or less if successfully treated): (1) delusions; (2) hallucinations; (3) disorganized speech; (4) grossly abnormal psychomotor behavior; and (5) negative symptoms. At least one of these symptoms should include delusions, hallucinations, or disorganized speech. In addition, for a significant portion of the time since the onset of the disturbance, schizophrenia is also characterized by social/occupational dysfunction in one or more major areas: work, interpersonal relations, or self-care. All of these are markedly below the level achieved before the onset of the illness (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement). Regarding duration, typically continuous signs of the disturbance exist for at least 6 months, with at least 1 month of symptoms (or less if successfully treated) that meet criteria for the active phase (delusions, hallucinations, disorganized speech), 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 by two or more of the active-phase symptoms in an attenuated form (e.g., odd beliefs, unusual perceptual experiences). Finally, for an individual to receive the diagnosis of schizophrenia, the diagnoses of schizoaffective disorder and mood disorder with psychotic features must be ruled out. In addition, symptoms cannot be due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.⁷

Schizophrenia has been divided into five subtypes in DSM-IV-TR:² paranoid; disorganized; catatonic; undifferentiated; and residual. In each subtype there is predominant symptomatology at the time of evaluation; these can change over time, such as at a subsequent diagnosis. In addition, an individual may have symptoms characteristic of more than one subtype. DSM-V may introduce a different classification of subtypes. The paranoid and disorganized types are the least severe (in that order). The undifferentiated type is essentially a catch-all category for individuals who do not meet criteria for any of the other subtypes. The residual type indicates that the disturbance has continued, but the active-phase symptoms are no longer met.

When untreated, schizophrenia is associated with increased mortality, impaired vocational and social functioning, and reduced quality of life.5 Unfortunately, the extent to which treatment does actually improve life span and psychosocial functioning is not specifically clear. Because antipsychotic medications do decrease the likelihood of relapse, they are encouraged.

When effective, antipsychotic medication can be expected to diminish or remit hallucinations or reduce their impact on functioning.³⁴ The ability to reason should improve; ambivalence, delusions, and suspiciousness should be greatly reduced; agitation and confusion should be relieved; and social behavior should improve. Antipsychotic medications are designed to have specific effects on targeted neurotransmitters. Newer antipsychotic medications, typically called second-generation agents (SGAs) (atypical), are intended to generally manage psychosis as well as both positive and negative schizophrenia symptoms.⁵ Older antipsychotic medications, traditionally called first-generation agents (FGAs) (conventional), were less effective in managing negative schizophrenia symptoms. They mainly acted as dopamine antagonists, blocking the dopamine receptors (D₂). This action diminishes the amount of dopamine received by the receptor sites (Figure 48-5).

All FGAs and SGAs appear to be equally effective in reducing the positive symptoms and disorganization associated with schizophrenia, hence blocking the dopamine D₂ receptor.5,34 Neither antipsychotic agent appears to improve the cognitive symptoms in patients with schizophrenia; in fact, findings suggest that they worsen cognitive impairment.⁵ Although the maximum drug response may not be reached for many months, patient response over the first 2 to 4 weeks of antipsychotic medication use will typically predict long-term response. Antipsychotic response will vary as a result of the stage of illness, with first-episode patients responding faster and at a higher rate than those at later stages.⁵ In addition, both FGAs and SGAs play a substantial role in decreasing the likelihood of relapse.

FGAs and SGAs differ most notably in their side effect profiles and their potential for interacting with other medications. FGAs (e.g., chlorpromazine) had relatively nonspecific neurotransmitter effects and numerous side effects, the most difficult being extrapyramidal symptoms (EPS). Haloperidol was the first FGA that had significantly less anticholinergic and hypotensive side effects. By 1990, SGAs became widely available; the SGAs have generally shown a lower risk of EPS but a higher risk of other metabolic adverse effects. The first SGA, clozapine, was quickly followed by a generation of new atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone), each promising still fewer side effects, better relief of both positive and negative schizophrenic symptoms, and minimal risk of EPS, specifically those associated with tardive dyskinesia. Some worrisome side effects are clinically significant weight gain, glucose dysregulation, and dyslipidemia.^35,36 Experts have speculated that hyperglycemia may have to do with dopamine receptor involvement in the regulation of insulin secretion. Numerous explanations for weight gain as a major side effect of antipsychotic medication continue to be developed and tested. The glutamate neurobiological model³⁷ of psychosis and schizophrenia, an alternative to the dopamine model, may be the basis for the next new generation of antipsychotic medications.

The glutamate deficit³⁷ model attempts to focus attention on the cause of excessive dopamine receptor activity rather than the excessive activity itself. γ-Aminobutyric acid (GABA) is the most important inhibitory brain neurotransmitter. GABA synthesis depends on and is controlled by the enzyme glutamic acid decarboxylase (GAD). GAD activity is modulated by the glutamate receptor NMDA. GAD dysregulation is thought to lead to insufficient GABA activity and, consequently, excessive dopamine activity. Reduced GAD activity has been observed in the dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia. The interesting observation for pharmacologic researchers is that a broad range of different drugs has been shown to be capable of affecting GAD activity. Although the glutamate deficit model is not new, the model still may lead to a class of antipsychotic medications unlike any previous generation.

Dopamine D₂ continues to remain the lead neurotransmitter target of the atypical antipsychotics.³⁴ Researchers found that the most common side effects of antipsychotic medication could be reduced if the drug’s impact on dopamine D₂ receptors was not excessive. Lower receptor occupancy, less receptor affinity, and faster release³⁸ of the receptor were methods shown to be associated with fewer side effects. More recently, the aim for effective antipsychotic medication is to stabilize rather than reduce dopamine activity. The newest SGAs, such as aripiprazole, paliperidone, iloperidone, asenapine, and lurasidone, show greater affinity for serotonin receptors (negative symptoms) and moderate affinity for dopamine and norepinephrine receptors (positive symptoms).^5,38 Effective antipsychotic medications have significant dopamine effects; however, schizophrenia symptoms are highly complex and likely to involve other neurotransmitters, particularly serotonin and norepinephrine (Table 48-2).

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