Schizophrenia

Review by Jose Vega, MD
Column Organized by Evan Schwarz, MD
Division of Emergency Medicine Washington Univeristy

Citation:
Freedman R.  Schizophrenia.  New England Journal of Medicine.  October 2003; 349 (18):  1738-1749.
 

Schizophrenia, the most common psychotic disorder, affects 1 percent of the general population.  The symptoms begin in late adolescence or early 20s in men and 20s and early 30s in women.  The DSM-IV diagnostic criteria for schizophrenia includes:  at least 6 months of sufficiently deteriorated occupational, interpersonal and self-supportive functioning; two or more of the following positive symptoms: delusions, hallucinations, disorganized speech or behavior; or negative symptoms such as affective flattening, alogia or avolition during a 1 month period.  The symptoms can not be accounted for by the presence of a schizoaffective or major mood disorder, autism, or an organic condition.  Positive and negative symptoms vary in intensity over time.  Criminal behavior is not a characteristic of schizophrenia however, patients may commit violent acts due to their hallucinations, delusions, or impaired social skills.  The lifetime prevalence of suicide is 10 percent amongst schizophrenics.

    Multiple genetic and environmental factors are responsible for the symptoms seen in schizophrenia.  One factor is the dopamine theory in which increased dopaminergic neurotransmission causes psychosis.  By decreasing dopaminergic transmission via antipsychotic drugs, the distractibility seen in schizophrenia decreases and improves perceptual abilities.  The theory has several flaws.  First, symptoms are not fully alleviated by treatment.  Secondly, dopamine levels are within normal ranges before and after treatment.  Thirdly, dopamine and its role in the brain is more complex than acting as a simple switch for psychotic symptoms.  Inhibitory interneurons are also affected by a decrease in their number, in enzymes that synthesize the inhibitory neurotransmitter gamma-aminobutyric acid, in neuropeptides cholecystokinin and somatostatin, and in migration of neurons into the cortex from white matter.  There are also genetic findings such as greater concordance among monozygotic twins than dizygotic twins and the high incidence of schizophrenia among adopted children, whose biologic mothers have schizophrenia.  These findings point to a genetic component that accounts for 70 percent of the risk.  The environmental component accounts for the remaining 30 percent, that includes perinatal and childhood brain injury and psychosocial stressors.

    The pharmacologic approach to schizophrenia and its symptoms is centered on neurotransmitters that control the response of neurons to stimuli.  First generation antipsychotic agents such as haloperidol and chlorpromazine block dopamine D2 receptors.  Twenty percent of patients have complete remission of their symptoms, most patients have some response but with continuing symptoms.  Side effects include involuntary movement disorders arising from the extrapryamidal system.  Symptoms include dystonia, akathisia, bradykinesia and tremor.  Akathisia, a state of restlessness, is a major cause of noncompliance with the drug regimen.  It can be treated with propranolol.  Bradykinesia, slowed voluntary movements can be treated with benzotropine.  Tardive dyskinesia, a choreoathetotic movement disorder, develops in 30 percent of patients after several years of treatment.  Orofacial movements are common manifestations.  It slowly resolves after withdrawal of first generation drugs, although it may be irreversible.  When diagnosed early it is usually reversed with a change in medication.  Temperature dysregulation can lead to neuroleptic malignant syndrome, in which the patient’s temperature exceeds 104°F.  Dantrolene, bromocriptine, and rapid cooling can be used to treat the hyperthermia.  Prolonged QT interval is seen in several antipsychotics, in particular thioridazine. 

    Second generation antipsychotic agents block D2 dopamine receptors (like first generation drugs) however they are less tightly bound and the D2 dopamine receptor antagonism is not the sole therapeutic mechanism.  They include clozapine, risperidone, olanzapine, ziprasidone, quetiapine, ariprazole and amisulpride.  Their efficacy is equivalent or exceeds the first generation drugs particularly with respect to negative symptoms.  Side effects include weight gain, DM, hypercholesterolemia, hyperprolactinemia, and seizures.  Movement disorders, including tardive dyskinesia are decreased with the second generation drugs.  Clozapine was the first second generation drug to be used and it also blocks D1, D4 dopamine receptors and norepinephrine and serotonin receptors.  Agranulocytosis is a serious risk associated with clozapine and patients taking the drug must undergo frequent monitoring of leukocyte counts.  They are also at risk for myocarditis.  Agranulocytosis can lead to fevers, malaise and frequent infections in the schizophrenic patient.  For noncompliant patients there are depot injection preparations available.

    The primary mode of treatment of schizophrenia is pharmacologic.  Supportive psychosocial methods are useful in the long-term treatment of schizophrenia.  If the acutely psychotic schizophrenic is delirious, suicidal or homicidal and/or has no support, the patient needs to be hospitalized.