Schizophrenia

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31 Schizophrenia

Kenneth Lakritz

Clinical Vignette

This 22-year-old electrician was brought to the emergency room after frequently confronting his parents, friends, and supervisors about being pursued by extraterrestrial aliens. With increasing frequency, he became obsessed with the idea of developing a barrier to electronic emissions that were “emanating from outer space.” He was frightened that these signals were attempting to control his entire life by gaining control of his own body, and subsequently turn him into a baboon. When his parents attempted to be helpful, he found a lawyer and took them to court for persecuting him and invading his privacy.

Up until this time, he had been in perfect health with no outward signs of a thought disorder. He had never required any psychiatric treatment. He had done well in school, served in the armed forces for 4 years, where he learned to be an electrician and received an honorable discharge. Soon after arriving home and starting a civilian job, his parents recognized that a major personality change had occurred. This was characterized by both his paranoia and his withdrawal from most interpersonal relationships, spending almost all of his free time secluded in his room.

Psychiatric examination demonstrated him to be exceedingly tense and fearful. He stated that he was developing a computer system for his personal use that is to prevent alien communications from interfering with his daily activities. Further delusional thoughts were articulated, including his being concerned about a biologic invasion, voices telling him to do scary things, and feelings of being controlled by outside forces that are invading his own brain. Physical examination, cranial MRI, and routine laboratory testing, including drug screen, were unremarkable.

He was involuntarily hospitalized. An atypical antipsychotic drug helped to significantly improve his anxiety. Although this medication did not significantly impact on the presence and frequency of his delusional thinking, these thoughts seemed to be less bothersome to him. However, he was no longer capable of continuing in school and he withdrew from a formal educational environment to spend all of his time at home with his parents.

More than 120 years ago, Emil Kraepelin delineated schizophrenia as a global impairment of psychic functioning. It is distinguished from the affective psychoses by its unremitting course. Schizophrenia typically first occurs in late adolescence or early adulthood; this distinguishes it from the dementias. Sufferers, often initially odd or unsociable, eventually become progressively more isolated and eccentric, commonly failing to care for themselves and sometimes creating a public nuisance. It is quite uncommon for schizophrenia to first appear in midlife. However, when it does occur at this time in life, it overwhelmingly affects women, usually presenting with prominent paranoid symptoms.

During their initial evaluation, these patients overtly express their hallucinations—usually of commanding voices, disordered thinking, and delusional beliefs (Fig. 31-1). When untreated, schizophrenia patients exhibit declining cognitive function, especially early on during their first decade of the illness. Remissions and long-term improvement are eventually possible. Nevertheless, only a minority of schizophrenic patients achieve functional recovery. Most individuals are chronically disabled, accounting for a large proportion of nursing home and some prison populations. Sadly, one of the major consequences of schizophrenia is their very high suicide rate that approaches 10%.

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Figure 31-1 Schizophrenic Disorder.

Schizophrenia affects 0.5–1% of the population; a milder form of the illness, schizotypal personality disorder, is even more common. The pathophysiology continues to be elusive. Familial clustering is obvious, but even identical twins have only ~50% disease concordance, excluding purely genetic explanations. More than 20 candidate genes are identified. Twin studies have refuted theories about defective parenting and “schizophrenogenic mothers.” There are weak associations with winter birth, maternal malnutrition, and prenatal viral exposures, suggesting a stress-diathesis model, combining genetic vulnerability with early environmental insults. Immigrants, especially those who must learn a new language, are at increased risk. Schizophrenia is strongly associated with increased paternal but not maternal age, indicating that new germ-line mutations or epigenetic defects are involved in up to 25% of cases.

Clinical Presentation

Schizophrenic symptoms can be categorized into three large clusters, with only weak associations between the clusters: positive symptoms, negative symptoms, and cognitive disturbance.

The schizophrenic delusions and hallucinations are positive symptoms, which are often more bizarre and illogical than compared with individuals having an affective psychosis. Many experts consider certain “first-rank” symptoms—delusions of passivity or outside control, thoughts being withdrawn from the patient’s brain, thoughts being broadcast by the patient to others, for example—as pathognomonic for schizophrenia. Others maintain that only the long-term course of the illness reveals the diagnosis.

Negative symptoms are equally important components of the schizophrenic profile. These typically include emotional flatness, social withdrawal, and lack of initiative and self-care (Fig. 31-1). Additionally, the schizophrenic patient usually demonstrates a cognitive disturbance, with deficits in many areas of reasoning, such as working memory and abstract reasoning.

Schizophrenic patients have more than the expected number of neurologic “soft signs.” Specific findings include abnormalities of smooth eye movement pursuit, auditory evoked potentials, and olfactory deficits. At least 50% of schizophrenic patients have gross central nervous system pathology visible on magnetic resonance imaging (MRI), including ventricular enlargement and decreased temporal and frontal lobe volume. Cerebellar abnormalities are also common. Ventricular enlargement appears to correlate with negative symptoms and treatment resistance. The underlying mechanisms explaining brain volume changes in schizophrenia are not yet understood, but the psychosis per se might be related to these changes. Five-year follow-ups on patients with first-episode schizophrenia who underwent brain MRI at inclusion and after 5 years demonstrated an association between longer duration of psychosis, larger gray matter volume decrease, and larger ventricular volume increase. These findings strongly suggest that psychosis contributes to brain volume reductions found in schizophrenia.

Treatment

Therapy of schizophrenic patients is challenging. Part of the difficulty is that patients are often strikingly unaware that they are ill. Because of this, they frequently stop their medications or drop out of treatment. Until neuroleptic medications were introduced in 1953, no effective biological treatments existed. The classic neuroleptic agents that work by blocking dopamine D2 receptors are often effective against positive symptoms, but do not help and may exacerbate negative symptoms.

The first of the atypical neuroleptics, clozapine, was studied as early as the 1960s but was not introduced in the United States for more than 25 years because of its bone marrow toxicity—1% of patients develop potentially fatal agranulocytosis, and clozapine can only be prescribed when there is a mandatory monitoring of hematopoietic functions with regularly scheduled blood counts. Clozapine also causes seizures, metabolic syndrome, and weight gain at higher doses. Despite these problems, clozapine is clearly superior in efficacy to all other currently available antipsychotic drugs. Subsequent atypical or second-generation neuroleptics were developed to mimic clozapine’s mechanism of action—thought to depend on weak D2 antagonism combined with antagonism to the serotonin 5-HT2 receptor—without its inherent toxicity. The newer drugs are all, in varying degrees, less toxic, but none are quite as effective either.

Our current treatments are largely based on the idea that schizophrenia is a disorder of excess dopamine. This idea has some clinical support; dopaminergic drugs can cause or exacerbate psychosis, and antidopaminergic drugs treat psychosis. However, there is little direct evidence for this theory and no one believes that it comprises the entire story.

More recent research has focused on glutamate, especially on the NMDA receptor—in part because NMDA receptor antagonists such as phencyclidine precipitate psychosis. NMDA receptor agonists, such as the antituberculosis drug cycloserine, have been minimally effective. Recently, treatment with N-acetyl-cysteine, which is thought to act through glutamatergic mechanisms, has been promising.

Schizophrenic patients respond poorly to stress. Those living in rural or less industrialized settings tend to have better outcomes. Episodes of relapse correlate with “expressed emotion,” a measure of interpersonal turbulence, in patients’ households. Psychotherapy and educational measures focus on preventing these and other stressors.

Additional Resources

Amador X, David A. Insight and Psychosis: Awareness of Illness in Schizophrenia and Related Disorders. New York, NY: Oxford Univ. Pr.; 2004.

Cahn W, Rais M, Stigter FP, et al. Psychosis and brain volume changes during the first five years of schizophrenia. Eur Neuropsychopharmacol. 2008 Dec 2. Epub ahead of print

Kubicki M, Westin CF, Maier SE, et al. Uncinate fasciculus findings in schizophrenia: a magnetic resonance diffusion tensor imaging study. Am J Psychiatry. 2002 May;159(5):813-820.

Lavoie S. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 2007 Nov 14.

Marom S. Expressed emotion: relevance to rehospitalization in schizophrenia over 7 years. Schizophr Bull. 2005 Jul;31(3):751-758.

Sipos A. Paternal age and schizophrenia: a population based cohort study. BMJ. 329, 2004 Nov 6.

Straub RE, Weinberger DR. Schizophrenia genes—famine to feast. Biol Psychiatry. 2006 Jul 15;60(2):81-83.

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