E-Note for Adult Medicine
Stat | Lytes | Drugs |  ID  | Heart | Lungs | Kidneys |  GI  | Rheum | Heme-Onc | Endo | Neuro | Derm | Misc. | Resources | Home

Schizophrenia      See Schizophrenia2008.htm  

REF:  NEJM  October 30, 2003; Volume 349:1738-1749 -Robert Freedman, M.D.

Schizophrenia is a chronic, debilitating psychotic mental disorder that affects about 1 percent of people.
No single lesion in the brain appears to be responsible for causing schizophrenia. Rather, multiple genetic  (a significant heritable component that accounts for about 70 percent of the risk) and environmental factors  (accounting for the remaining 30 percent of the risk) contribute to disturbances in brain function and development that result in schizophrenia.

Clinical Characteristics
Schizophrenia has varied and ominous symptoms that generally begin in late adolescence or early adulthood and usually continue throughout life.1 Most patients have a history of behavioral dysfunction — primarily social and learning difficulties.2 Diagnostic features of schizophrenia include auditory hallucinations (generally voices that converse with or about the patient) and delusions (often the paranoid belief that external forces are conspiring against the patient). Patients may have some insight that the voices are internal thoughts and that the delusions cannot possibly be true, but these phenomena remain persistent and troubling. In addition to these overt psychotic, or positive, symptoms, various deficits, or negative symptoms, occur, including an inability to pay attention, the loss of a sense of pleasure, the loss of will or drive, disorganization or impoverishment of thoughts and speech, flattening of affect, and social withdrawal (Table 1). Positive and negative symptoms vary in intensity over time; patients may have predominantly one type at any particular time. Cognitive dysfunction, including a decreased ability to focus attention and deficiencies in short-term verbal and nonverbal memory, is also a core feature of the illness, which predicts vocational and social disabilities for patients.3 Criminal behavior per se is not a concomitant of schizophrenia, but patients may commit violent acts in response to hallucinations or delusions or because of frustration in social interactions.4 The lifetime prevalence of suicide is about 10 percent among patients with schizophrenia.5

Diagnostic Features of Schizophrenia
(Adapted from the criteria of the American Psychiatric Association)

At least 2 of the following characteristic symptoms lasting at least one month:

Dysfunction in work, interpersonal relationships, or self-care throughout most of the illness; a level of functioning markedly below the level the patient had achieved or might reasonably have been predicted to achieve before the onset of illness.

Any of the above symptoms lasting, in full or attenuated form, at least six months.Mood disorder not prominent after the oneset of psychotic symptoms (if pschotic symptoms always occur during mood disturbance severe enough to meet the criteria for bipolar disorder or a majaor depressive disorder, the diagnosis is schizoaffecxtive disorder.)

Illness not due to a medication or other medical conditions or substance abuse.

Illness not part of autism or another pervasive developmental disorder.

Antipsychotic Treatment

First-Generation Antipsychotic (neuroleptic) Agents:

Second-Generation Antipsychotic (neuroleptic) Agents:

Depot IM preparations (every 2-4 week dose)

The most obvious side effects  of the first-generation antipsychotic drugs:
involuntary movement disorders
arising from the extrapyramidal system, many of which mimic the effects of Parkinson's disease and reflect the blockade of dopaminergic transmission between the dopaminergic neurons of the substantia nigra and the dorsal neostriatum.  Symptoms include dystonia, akathisia, bradykinesia, and tremor.

Akathisia, a severe state of restlessness that is difficult to distinguish from agitation, is a major cause of noncompliance with the drug regimen. Treatment with propranolol (20 to 80 mg per day) is useful for controlling akathisia.  Bradykinesia, decreased spontaneous movement and slowed voluntary movement, mimics the effects of depression. Treatment with anticholinergic, antiparkinsonian drugs, such as benztropine/Congentin (2 to 6 mg per day in divided doses), is helpful.  Tardive dyskinesia, a choreoathetotic movement disorder, develops in about 30 percent of patients, generally after several years of treatment.   Orofacial movements such as grimacing are common manifestations. Tardive dyskinesia does not respond to anticholinergic agents; it resolves slowly after the withdrawal of first-generation drugs, but it may be irreversible.

Temperature dysregulation can lead to a severe neuroleptic malignant syndrome, in which the patient's temperature exceeds 40°C (104°F) and brain death ensues.  Preventive measures include hydration and caution in the administration of anticholinergic agents in high-temperature environments, because the agents block perspiration.   Neuroleptic malignant syndrome is treated by rapid cooling, and dantrolene can be administered to inhibit the release of calcium in muscle cells and thus attenuate the metabolic changes caused by the hyperthermia. Dopamine agonists, such as bromocriptine, can be administered to reverse the pathogenic dopamine blockade.

A prolonged QT interval is a side effect of several antipsychotic drugs, and the possibility of this abnormality limits the dose of thioridazine, in particular. To what extent a prolonged QT interval predisposes a patient to the potentially fatal torsade de pointes arrhythmia is unknown, but the incidence of sudden death among patients treated with antipsychotic drugs is 0.015 percent per year — about twice the rate reported in the normal healthy population.

The side effects of second-generation antipyschotic drugs:

Although only clozapine causes agranulocytosis in a substantial proportion of patients, many second-generation drugs produce clinically significant weight gain.
Diabetes mellitus
has been increasingly reported in patients treated for more than five years with second-generation antipsychotic agents, presumably in association with weight gain; there is also some evidence of the development of insulin resistance.   In a few cases, life-threatening ketoacidosis has occurred. Cholesterol levels increase by 10 percent after 14 weeks of treatment with olanzapine.   Ziprasidone and amisulpride at recommended doses cause less weight gain than do other antipsychotic drugs.   Second-generation antipsychotic agents can sometimes induce obsessive–compulsive symptoms, which may reflect antagonism of serotonergic neurotransmission.  


REF:  NEJM  October 30, 2003; Volume 349:1738-1749 -Robert Freedman, M.D.