Clinical Manifestations
Schizophrenia is a heterogeneous syndrome characterized by perturbations of language, perception, thinking, social activity, affect, and volition. There are no pathognomonic features. The syndrome commonly begins in late adolescence, has an insidious (and less commonly acute) onset, and, classically, a poor outcome, progressing from social withdrawal and perceptual distortions to a state of chronic delusions and hallucinations. Patients may present with positive symptoms (such as conceptual disorganization, delusions, or hallucinations) or negative symptoms (loss of function, anhedonia, decreased emotional expression, impaired concentration, and diminished social engagement) and must have at least two of these for a 1-month period and continuous signs for at least 6 months to meet formal diagnostic criteria. “Negative” symptoms predominate in one-third of the schizophrenic population and are associated with a poor long-term outcome and a poor response to drug treatment. However, marked variability in the course and individual character of symptoms is typical.

The four main subtypes of schizophrenia are catatonic, paranoid, disorganized, and residual. Many individuals have symptoms of more than one type. Catatonic-type describes patients whose clinical presentation is dominated by profound changes in motor activity, negativism, and echolalia or echopraxia.

Paranoid-type describes patients who have a prominent preoccupation with a specific delusional system and who otherwise do not qualify as having disorganized-type disease, in which disorganized speech and behavior are accompanied by a superficial or silly affect. In residual-type disease, negative symptomatology exists in the absence of delusions, hallucinations, or motor disturbance. The term schizophreniform disorder describes patients who meet the symptom requirements but not the duration requirements for schizophrenia, and schizoaffective disorder is used for those who manifest symptoms of schizophrenia and independent periods of mood disturbance. Prognosis depends not on symptom severity but on the response to antipsychotic medication. A permanent remission without recurrence does occasionally occur. About 10% of schizophrenic patients commit suicide.

Schizophrenia is present in 0.85% of individuals worldwide, with a lifetime prevalence of 1 to 1.5%. An estimated 300,000 episodes of acute schizophrenia occur annually in the United States, resulting in direct and indirect costs estimated at >$33 billion.

Differential Diagnosis
The diagnosis is principally one of exclusion, requiring the absence of significant associated mood symptoms, any relevant medical condition, and substance abuse. Drug reactions that cause hallucinations, paranoia, confusion, or bizarre behavior may be dose-related or idiosyncratic; ß-adrenergic blockers, clonidine, cycloserine, quinacrine, and procaine derivatives are the most common prescription medications associated with these symptoms. Drug causes should be ruled out in any case of newly emergent psychosis. The general neurologic examination in patients with schizophrenia is usually normal, but motor rigidity, tremor, and dyskinesias are noted in one-quarter of untreated patients.

Epidemiology and Pathophysiology
Epidemiologic surveys identify several risk factors for schizophrenia including genetic susceptibility, early developmental insults, winter birth, and increasing parental age. Genetic factors are involved in at least a subset of individuals who develop schizophrenia. Schizophrenia is observed in 6.6% of all first-degree relatives of an affected proband. If both parents are affected, the risk for offspring is 40%. The concordance rate for monozygotic twins is 50%, compared to 10% for dizygotic twins. Schizophrenia-prone families are also at risk for other psychiatric disorders, including schizoaffective disorder and schizotypal and schizoid personality disorders, the latter terms designating individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccentric behavior, and mild perceptual distortions.

Despite evidence for a genetic causation, the results of molecular genetic linkage studies in schizophrenia are inconclusive. Major gene effects appear unlikely. Possible susceptibility genes include: neuroregulin-1 at chromosome 8p21; dysbindin at 6p22.3, proline dehydrogenase at 22q11, and G72 at 13q34. Several of these may be involved in glutamatergic regulation, increasing interest in N-methyl-D-aspartate (NMDA)-mediated glutamate signaling as a possible therapeutic target for treatment. One group has reported risk variants in the 7 nicotinic acetycholine receptor subunit gene and linked it to a specific auditory processing deficit.

Schizophrenia is also associated with gestational and perinatal complications, including Rh factor incompatibility, fetal hypoxia, prenatal exposure to influenza during the second trimester, and prenatal nutritional deficiency. Studies of monozygotic twins discordant for schizophrenia have reported neuroanatomic differences between affected and unaffected siblings, supporting a “two-strike” etiology involving both genetic susceptibility and an environmental insult. The latter might involve localized hypoxia during critical stages of brain development.

A number of structural and functional abnormalities have been identified in schizophrenia, including (1) cortical atrophy and ventricular enlargement; (2) specific volume losses in the amygdala, hippocampus, right prefrontal cortex, fusiform gyrus, and thalamus; (3) progressive reduction in cortical volume over time; (4) reduced metabolism in the thalamus and prefrontal cortex; (5) abnormalities of the planum temporale; and (6) changes in the size, orientation, and density of cells in the hippocampus and prefrontal cortex, and decreased numbers of cortical interneurons. These observations have suggested that schizophrenia may result from a disturbance in a cortical striatal–thalamic circuit resulting in abnormalities in sensory filtering and attention.

Schizophrenic individuals are highly distractible and demonstrate deficits in perceptual-motor speed, ability to shift attention, and filtering out of background stimuli. Event-related evoked potential studies of schizophrenia have defined a specific reduction in P300 amplitude to a novel stimulus, which implicates an impairment in cognitive processing. Impaired information processing is also found in unaffected family members.

The dopamine hypothesis of schizophrenia is based on the discovery that agents that diminish dopaminergic activity also reduce the acute symptoms and signs of psychosis, specifically agitation, anxiety, and hallucinations. Amelioration of delusions and social withdrawal is less dramatic. Thus far, however, evidence for increased dopaminergic activity in schizophrenia is indirect, although decreased D2 receptor occupancy by dopamine has recently been shown in drug-naive patients. An increase in the activity of nigrostriatal and mesolimbic systems and a decrease in mesocortical tracts innervating the prefrontal cortex is hypothesized, although it is likely that other neurotransmitters, including serotonin, acetylcholine, glutamate, and GABA, also contribute to the pathophysiology of the illness. Possible involvement of excitatory amino acids is based on the genetic data cited above and finding that NMDA receptor antagonists and channel blockers, such as phencyclidine (PCP) and ketamine, produce characteristic signs of schizophrenia in normal individuals; cycloserine, an NMDA receptor agonist, can decrease the negative symptoms of psychosis.

Treatment
Antipsychotic agents are the cornerstone of acute and maintenance treatment of schizophrenia, and are effective in the treatment of hallucinations, delusions, and thought disorders, regardless of etiology. The mechanism of action involves, at least in part, blockade of dopamine receptors in the limbic system and basal ganglia; the clinical potencies of traditional antipsychotic drugs parallel their affinities for the D2 receptor, and even the newer “atypical” agents exert some degree of D2 receptor blockade. All neuroleptics induce expression of the immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cortices. The clinical efficacy of newer atypical neuroleptics, however, may involve D1, D3, and D4 receptor blockade, _ß1- and _ß2- noradrenergic activity, and/or altering the relationship between 5HT2 and D2 receptor activity, as well as faster dissociation of D2 binding.

Conventional neuroleptics differ in their potency and side-effect profile. Older agents, such as chlorpromazine and thioridazine, are more sedating and anticholinergic and more likely to cause orthostatic hypotension, while higher potency antipsychotics, such as haloperidol, perphenazine, and thiothixene, are more likely to induce extrapyramidal side effects. The model atypical antipsychotic agent is clozapine , a dibenzodiazepine that has a greater potency in blocking the 5HT2 than the D2 receptor and a much higher affinity for the D4 than the D2 receptor. Its principal disadvantage is a risk of blood dyscrasias. Unlike other antipsychotics, clozapine does not cause a rise in prolactin level. Approximately 30% of patients have a better response to these agents than to traditional neuroleptics, suggesting that they will increasingly displace the older-generation drugs. Clozapine appears to be the most effective member of this class and has demonstrated superiority to other atypical agents in preventing suicide; however, its side-effect profile makes it most appropriate for treatment-resistant cases. Risperidone , a benzisoxazole derivative, is more potent at 5HT2 than D2 receptor sites, like clozapine, but it also exerts significant 2 antagonism, a property that may contribute to its perceived ability to improve mood and increase motor activity. Risperidone is not as effective as clozapine in treatment-resistant cases but does not carry a risk of blood dyscrasias. Olanzapine is similar neurochemically to clozapine but has a significant risk of inducing weight gain. Quetiapine is distinct in having a weak D2 effect but potent 1 and histamine blockade. Ziprasidone causes minimal weight gain and is unlikely to increase prolactin, but may increase QT prolongation. Aripiprazole also has little risk of weight gain or prolactin increase but may increase anxiety, nausea, and insomnia as a result of its partial agonist properties.

Conventional antipsychotic agents are effective in 70% of patients presenting with a first episode. Improvement may be observed within hours or days, but full remission usually requires 6 to 8 weeks. The choice of agent depends principally on the side-effect profile and cost of treatment or on a past personal or family history of a favorable response to the drug in question. Atypical agents appear to be more effective in treating negative symptoms and improving cognitive function. An equivalent treatment response can usually be achieved with relatively low doses of any drug selected, i.e., 4 to 6 mg/d of haloperidol, 10 to 15 mg of olanzapine, or 4 to 6 mg/d of risperidone. Doses in this range result in >80% D2 receptor blockade, and there is little evidence that higher doses increase either the rapidity or degree of response. Maintenance treatment requires careful attention to the possibility of relapse and monitoring for the development of a movement disorder. Intermittent drug treatment is less effective than regular dosing, but gradual dose reduction is likely to improve social functioning in many schizophrenic patients who have been maintained at high doses. If medications are completely discontinued, however, the relapse rate is 60% within 6 months. Long-acting injectable preparations are considered when noncompliance with oral therapy leads to relapses. In treatment-resistant patients, a transition to clozapine usually results in rapid improvement, but a prolonged delay in response in some cases necessitates a 6- to 9-month trial for maximal benefit to occur.

Antipsychotic medications can cause a broad range of side effects, including lethargy, weight gain, postural hypotension, constipation, and dry mouth. Extrapyramidal symptoms such as dystonia, akathisia, and akinesia are also frequent with traditional agents and may contribute to poor compliance if not specifically addressed. Anticholinergic and parkinsonian symptoms respond well to trihexyphenidyl, 2 mg bid, or benztropine mesylate, 1 to 2 mg bid. Akathisia may respond to beta blockers. In rare cases, more serious and occasionally life-threatening side effects may emerge, including ventricular arrhythmias, gastrointestinal obstruction, retinal pigmentation, obstructive jaundice, and neuroleptic malignant syndrome (characterized by hyperthermia, autonomic dysfunction, muscular rigidity, and elevated creatine phosphokinase levels). The most serious adverse effects of clozapine are agranulocytosis, which has an incidence of 1%, and induction of seizures, which has an incidence of 10%. Weekly white blood cell counts are required, particularly during the first 3 months of treatment.

The risk of type 2 diabetes mellitus appears to be increased in schizophrenia, and atypical agents as a group produce greater adverse effects on glucose regulation, independent of effects on obesity, than traditional agents. Clozapine, olanzapine, and quetiapine seem more likely to cause hyperglycemia, weight gain, and hypertriglyceridemia than other atypical antipsychotic drugs. Close monitoring of plasma glucose and lipid levels are indicated with the use of these agents.

A serious side effect of long-term use of the classic antipsychotic agents is tardive dyskinesia, characterized by repetitive, involuntary, and potentially irreversible movements of the tongue and lips (bucco-linguo-masticatory triad), and, in approximately half of cases, choreoathetosis . Tardive dyskinesia has an incidence of 2 to 4% per year of exposure, and a prevalence of 20% in chronically treated patients. The prevalence increases with age, total dose, and duration of drug administration. The risk associated with the newer atypical agents appears to be much lower. The cause may involve formation of free radicals and perhaps mitochondrial energy failure. Vitamin E may reduce abnormal involuntary movements if given early in the syndrome.

Drug treatment of schizophrenia is by itself insufficient. Educational efforts directed toward families and relevant community resources have proved to be necessary to maintain stability and optimize outcome. A treatment model involving a multidisciplinary case-management team that seeks out and closely follows the patient in the community has proved particularly effective.