Essential of Diagnosis
Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated):
delusions
hallucinations
disorganized speech (e.g., frequent derailment or incoherence)
grossly disorganized or catatonic behavior
negative symptoms, i.e., affective flattening, alogia, or avolition
Note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other.
Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement).
Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) 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 two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
Schizoaffective and mood disorder exclusion: Schizoaffective disorder and mood disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.
Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Relationship to a pervasive developmental disorder: If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).
(Adapted, with permission, from Diagnostic and Statistical Manual of Mental Disorders, 4th edn., Text Revision. Washington, DC: American Psychiatric Association, 2000.)
- Diagnostic criteria met, as specified in the box above. Note that these criteria allow the diagnosis in absence of prominent hallucinations or delusions (e.g., there is instead some combination of negative symptoms, disorganized speech, and/or disorganized or catatonic behavior).
- Duration of active psychotic symptoms for at least 1 month, or for a shorter duration if active treatment was initiated.
- Total duration of illness for at least 6 months, including prodrome, acute phase, and residual symptoms.
- Cognitive impairment, characterized by disorganized, illogical, loosely associated or bizarre speech, or by inappropriate or bizarre behaviors.
- The above symptoms are idiopathic in nature.
- Dysfunction in one or more life domains as a result of the above signs or symptoms.
- Lack of insight that symptoms and difficulties that stem from them are products of a mental illness that requires treatment.
- Deterioration in personal appearance and hygiene.
- Depressive and anxiety-based symptoms, including suicidal thinking.
- Abnormal motor activity, including rocking, pacing, grimacing, maintaining uncomfortable postures, stereotypies, and odd mannerisms.
- Poor compliance with treatment.
- Comorbid drug (including nicotine) and alcohol use disorders, and chronic physical health problems.
General Considerations
Schizophrenia is a clinical syndrome historically characterized by a heterogeneous mixture of clinical features referred to as psychosis. These clinical features include hallucinations, delusions, abnormal emotions, cognitive problems, and abnormal behaviors. The clinical diagnosis of schizophrenia is currently made on the basis of these characteristic signs and symptoms, their time course, their adverse impact on functional capacity, and their idiopathic nature (e.g., they are not the psychiatric manifestations of general medical conditions or effects of substances, and are not better accounted for by other diagnoses that feature psychotic symptoms or severe functional or cognitive incapacity).
Even after excluding the secondary causes of psychotic symptoms, the diagnosis of schizophrenia and related disorders remains challenging. For one, the etiology and the neuropathophysiology of schizophrenia is unknown. Second, no single sign or symptom is pathognomonic to schizophrenia. Finally, there is no clinically reliable biological marker, including functional or structural neuroimaging or pattern of genetic heritability.
The concept of schizophrenia as a diagnostic entity is still evolving even though the diagnostic criteria in use today have been unchanged for over two decades. Although it is likely that the schizophrenic syndrome has been described in one form or another since ancient times, the twentieth-century observations of Emil Kraepelin, Eugen Bleuler and Kurt Schneider have contributed most to our current classification of the disorder. Kraepelin was credited with distinguishing manic–depressive illness (now called bipolar disorder) from dementia praecox (the forerunner of schizophrenia) based on relative age of onset (younger in the case of manic–depressive illness), symptom course (episodic for manic–depressive illness, chronic for dementia praecox), vocational/social outcome (better for manic–depressive illness) and level of cognitive impairment (more severe in dementia praecox). Bleuler coined the term “schizophrenia” based on his observation that long-term outcome was quite variable among patients with dementia praecox and on the hypothesis that a split between thought and affect was the central feature of the illness. Bleuler specifically identified four components (also known as Bleuler’s “four A’s”) as the essence of the syndrome: Autism (i.e., a disconnect from reality), Ambivalence (of affect and will), Affectivity (in Bleuler’s words: an “indifference to everything”), and Association (in Bleuler’s words: “the associations lose their continuity”).
Schneider contributed the concept of first-rank symptoms (e.g., thought insertion, thought withdrawal, thought broadcast, voices arguing or discussing, delusions of control, etc.), which he believed were pathognomonic of schizophrenia and became the forerunner of the notion of positive signs and symptoms. Schneider’s first-rank symptoms are now known not to be specific for schizophrenia, for they may also occur in mania, drug induced states, and other disorders. Nonetheless, these and other signs and symptoms together have undergone extensive empirical testing to be criteria with sufficient diagnostic specificity, reliability, and validity for use in clinical practice
The incidence of schizophrenia ranges from 10 to 40 new cases per 100,000 population, while the age-corrected median point prevalence and lifetime prevalence estimates of the disorder are 4.6 and 4.0 cases per 1000 population, respectively. This figure for lifetime prevalence estimate is lower than the often reported range of 0.5% to 1.0%, which is believed to be an overestimate. Differences between site estimates of incidence and prevalence may be due to a variety of factors, including sex, urbanicity, migrant status, month of birth, recovery, suicide, and other forms of early mortality.
The life expectancy in schizophrenia is lower by about 20% relative to the general population. Increased early mortality among schizophrenics is attributed to increased rates of suicide (10–13% lifetime risk of completed suicide, 18–55% risk for attempted suicide), accidents, and poor physical health. At baseline, schizophrenics appear to be at higher risk for a host of metabolic and cardiovascular disorders, including obesity, diabetes, dyslipidemia, and coronary artery and cerebrovascular disease. Other contributors to the medical morbidity of schizophrenia include unhealthy lifestyle, alcohol and drug abuse, and high rates (70–80%) of chronic heavy smoking. High rates of substance abuse alone contribute to poor physical health, infrequent medical and psychiatric follow up, and poor compliance with medical and psychiatric treatment. In addition, several of the most efficacious treatments for schizophrenia may elevate cardiovascular risk as a result of weight gain, dyslipidemia and glucose elevation.
In spite of the health concerns that accompany schizophrenia, there is a disproportionately low rate of health service utilization among this population. Cognitive dysfunction, paranoid symptoms, apathy, comorbid disorders, poverty and illness-associated stigma may all impede utilization of necessary medical services. Concrete recommendations for health screening and monitoring are provided later (see section “Treatment”).
Schizophrenia is slightly more common in males than in females (male:female risk ratio is 1.4); however, as noted above, the average age of onset of schizophrenia for women is at least 5 years later than for men. Others have found no statistically significant differences in prevalence estimates between males and females. Differences in sex distribution for new-onset cases are especially apparent after the age of 45, where there is a 2:1 sex ratio in favor of women. Compared with men, women with schizophrenia tend to have better premorbid functioning, fewer negative symptoms, more prominent mood symptoms, more complete recovery from episodes, better clinical response to antipsychotic medication, milder long-term course, better social functioning, less comorbid substance abuse and less potential for suicide. Symptoms in females may worsen after menopause.
The age of onset for men appears to be earlier (age 18–25 years) than for women (age 25–35 years). For men, there is a second but much smaller incidence peak between age 30 and 35 years. Onset prior to the age of 10 is considered rare, though when it does occur, symptoms are typically very severe. Onset after the age of 45 (late onset) is also uncommon, and very uncommon after the age of 65 (very late onset). Patients with poor outcome, as indicated by poor response to currently available therapies, have an earlier age at onset than do those who are more responsive to treatment. The average age at onset of neuroleptic-resistant schizophrenia in female patients may be 4–5 years lower than in female patients with neuroleptic-responsive schizophrenia, but male and female patients with neuroleptic-resistant schizophrenia have similar ages at onset: 20–21 years, on average, according to one study.
The prevalence rates of schizophrenia are higher in densely populated urban areas, as well as in industrialized nations. The prevalence of schizophrenia is lower in developing countries compared with developed nations. Patients in developing countries have a more benign illness course than those in developed countries. Especially in Western societies, individuals with schizophrenia are at higher risk for poverty, unemployment, homelessness or inadequate housing, ill health, and poor access to health care. It has been theorized that the limitations posed by the symptoms of schizophrenia result in a downward drift in socioeconomic status, or prevent upward social mobility, or both.
Individuals in lower socioeconomic classes have higher rates of schizophrenia because of the markedly impaired work function of patients with this illness. Lower income is to be expected in the families of schizophrenics because 10% of the parents of schizophrenic patients have schizophrenia themselves, and other parents may have subclinical forms of the illness, including cognitive impairments and Axis II pathology, impairing their earning capacity.
Individuals with schizophrenia are more likely to be single (never married), divorced, or separated relative to age-matched controls. Individuals with schizophrenia who are unmarried tend to have earlier onset of psychosis, poorer premorbid functioning, and more severe illness, relative to those who have married. Conversely, adequate social support in any form and avoidance of high “expressed emotion” environments (over-critical or over-protective) both predict better long-term course.
Schizophrenia affects individuals from all racial and ethnic groups. While schizophrenia was once believed to be more prevalent among nonimmigrant minority groups in the United States, especially African Americans, recent studies have shown that such groups do not appear to be at greater risk for schizophrenia compared with the general population. There is conflicting evidence as to the influence of immigration status on overall risk of developing schizophrenia. The disproportionately high prevalence of schizophrenia observed among first-generation immigrants in Western countries appears to normalize in subsequent generations.
Epidemiologic data consistently show that schizophrenic patients have an increased likelihood of having been born in the late winter and spring months. The seasonal effect has been linked to epidemics of influenza or viral infections that occur more frequently during winter months. A number of epidemiologic studies have attributed the increased rate of schizophrenic births to maternal influenza or other viral infections during the second trimester. Maternal influenza during the second trimester may impair fetal growth and predispose to obstetric complications and lower birth weight in about 2% of individuals destined to develop schizophrenia. Recent epidemiologic evidence based on 2669 cases of schizophrenia in a population cohort of 1.75 million showed significant relative risks of developing schizophrenia with increased urbanization and season of birth. The highest association was for births in the months of February and March, presumably due to the increased risk of viral infection during pregnancy. Other complicating factors such as maternal malnutrition and Rh incompatibility during gestation have been associated with increased vulnerability to schizophrenia.
Kraepelin conjectured that schizophrenia was caused by a biological abnormality, even though the attempts to identify an abnormality (including neuropathological studies by Alois Alzheimer) were unsuccessful. In the middle of the twentieth century, the view that schizophrenia was the result of specific disturbances in child-rearing received considerable attention. In particular, communication deviance between parents and the child who was diagnosed with schizophrenia was considered by some clinicians to be a sufficient cause of schizophrenia. Although communication deviance in families with a schizophrenic child has been demonstrated in a number of studies, evidence that this feature was specific for schizophrenia or causative was unconvincing. Nevertheless, this line of research led to a continual interest in how family (and other caregiver) interactions can contribute to or diminish the stress and coping skills of patients with schizophrenia and, thus, modulate the course of the illness.
The view that schizophrenia is a brain disease now prevails, based on evidence from studies of neurotransmitter systems, histological, and neuroimaging studies of brain structure, and studies of brain function.
Neurochemical Abnormalities
The most widely accepted original hypothesis of the etiology of schizophrenia and of the action of antipsychotic drugs implicates the neurotransmitter dopamine (DA). Dopaminergic neurons arise from two midbrain nuclei: (1) the nigrostriatal tract originates in the substantia nigra, terminates in the striatum, and is involved in modulation of motoric behavior, cognition, and sensory gating; and (2) the mesolimbic and mesocortical tracts originate in the ventral tegmental area and terminate in limbic and cortical structures, respectively, affecting cognitive, motivational, and reward systems. The dopamine 1 (D1) receptor family, which includes D1 and D5 receptors, is present in high concentration in the cortex and striatum. The dopamine 2 (D2) receptor family consists of D2, D3, and D4 receptors and is concentrated in the limbic and striatal regions. Presynaptic DA receptors (i.e., D2 and D3) can consist of either somatodendritic autoreceptors localized to cell bodies in the substantia nigra and ventral tegmental area or terminal autoreceptors limited to axons of these DA cells. The somatodendritic and terminal autoreceptors affect the firing of DA cells and the synthesis and release of DA, respectively.
The DA hypothesis of schizophrenia, as originally postulated, proposed that schizophrenia is due to an excess of DA activity in limbic brain areas, especially the nucleus accumbens, as well as the stria terminalis, lateral septum, and olfactory tubercle (e.g., mesolimbic dopamine hyperactivity). This hypothesis was based on evidence that chronic administration of the stimulant d-amphetamine produced a psychosis that resembles paranoid schizophrenia. d-Amphetamine increases the release of DA and norepinephrine (NE) and inhibits their reuptake. Isomers of d-amphetamine with different effects on the availability of NE and DA in rodents were used to show that increased locomotor activity, which correlates best with psychosis in humans, is due to an increased release of DA rather than NE.
The second line of evidence relating DA to schizophrenia is that antipsychotic drugs decrease DA activity by receptor depletion (reserpine) and blockade (neuroleptics). The most compelling evidence that linked DA to the positive symptoms of schizophrenia was the finding that chlorpromazine was an effective antipsychotic drug and that it blocked DA receptors in vivo, inhibiting the effect of d-amphetamine on locomotor activity. The discovery that a number of different chemical classes of DA-receptor antagonists are effective as antipsychotic drugs and that there is a high correlation between the drug’s average daily dosage and its affinity for the D2-receptor family led to the view that increased stimulation of these receptors caused schizophrenia.
Decreased dopamine activity in the prefrontal cortex (mesocortical dopamine deficit) may mediate the negative symptoms and cognitive dysfunction associated with schizophrenia.
The concept of increased DA activity as the core deficit in schizophrenia was developed at the time when delusions and hallucinations were central to the diagnosis of schizophrenia, whereas negative symptoms, affective symptoms, and cognitive dysfunction were relegated to a secondary role. The latter aspects of schizophrenia have never been associated with excessive DA activity. As mentioned earlier in this chapter, researchers have proposed that decreased DA activity may lead to cognitive impairment and depression. There is little evidence that blockade of D2 or D4 receptors induces depression or cognitive impairment. Recent studies in primates have implicated the D1-receptor family in the control of working memory, a cognitive function impaired in schizophrenia.
Clinically, factors that challenge the primacy of dopamine imbalance at the expense of other transmitter systems stem from at least two observations. First, drugs that act on other transmitter systems, such as hallucinogens (e.g., lysergic acid, psilocybin) and dissociative anesthetics (e.g., phencyclidine, ketamine), also cause psychotic symptoms. Phencyclidine exposure results in a psychotic syndrome that models schizophrenic psychosis more accurately than amphetamine does (see below). Second, while D2-receptor blockade occurs very quickly after antipsychotic dosing, clinical antipsychotic effects typically require several weeks to ensue.
Furthermore, postmortem studies of patients with schizophrenia have not found consistent abnormalities in the density of any of the five DA receptors or changes in their affinities for DA, with the possible exception of the D3 receptor, which may have an abnormal form. Several research groups have also reported a link between D3 polymorphisms and schizophrenia. There is no reliable evidence, from either postmortem studies or positron emission tomography (PET) studies, for an increase in the density of D2 receptors in schizophrenia. Recent PET studies of the release of DA in the striatum of patients with schizophrenia suggest that the extracellular concentration of DA in this region is increased compared to that in normal subjects. Plasma and cerebrospinal fluid (CSF) levels of homovanillic acid, the major metabolite of DA, are not elevated in patients who have schizophrenia. Some researchers have suggested that DA-receptor sensitization occurs in schizophrenia, but only indirect evidence supports this hypothesis.
Serotonin (5-HT) neurons originate in the midbrain dorsal and median raphe nuclei, which project to the cortex, striatum, hippocampus, and other limbic regions. There are at least 15 types of 5-HT receptors; of these, the most relevant to schizophrenia are the 5-HT1, 5-HT1D, 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptors. Somatodendritic autoreceptors (of the 5-HT1A type) are present on the cell bodies of 5-HT raphe neurons and inhibit firing of serotonergic neurons. Terminal autoreceptors (5-HT1D in humans) regulate the synthesis and release of 5-HT. 5-HT3 receptors stimulate DA release. Postsynaptic 5-HT2A receptors are localized on pyramidal neurons in mesocortical areas. The complex interaction between 5-HT and DA varies by brain region and by types of 5-HT and DA receptor.
An early theory of the etiology of schizophrenia was that it is due to an excess of brain serotonergic activity. This theory was based on the belief that the psychotomimetic properties of lysergic acid diethyl amide (LSD), an indole compound, are due to its 5-HT agonist properties. This led to a search for endogenous indole hallucinogens in the brain, blood, and urine of schizophrenic patients. The enzymes that synthesize and catabolize indoles, of which 5-HT is the most important, were also studied in detail; however, none of the putative abnormalities was confirmed by subsequent careful study.
The notion that the effects of LSD and other indole hallucinogens, such as psilocybin and N,N′-dimethyltryptamine, provide an adequate model of schizophrenia was also rejected because the primary effect of these drugs is to cause visual hallucinations. The potency of these agents as hallucinogens is highly correlated with their 5-HT2A-receptor affinity. The thought disorder, auditory hallucinations, and bizarre behavior usually present in schizophrenia are generally absent in normal individuals given these agents. However, ingestion of these agents can cause an exacerbation of positive symptoms in schizophrenic patients.
Neuroleptic drugs are not particularly useful in decreasing the effects of the indole hallucinogens. Newer antipsychotic drugs such as clozapine, olanzapine, risperidone, quetiapine, and sertindole are potent antagonists of the 5-HT2A receptor. Some of the advantages of these drugs may result from their greater potency as 5-HT2A-receptor antagonists, relative to D2-receptor blockade. The most likely advantages of these drugs, related to their higher affinity to 5-HT2A versus DA receptors, are their low D2-induced extrapyramidal symptoms (EPS) profile and their ability to improve negative symptoms. Increased stimulation of 5-HT2A receptors may be important in the etiology of negative symptoms and EPS. Although this concept of the role of 5-HT in schizophrenia is no longer considered viable, alternative theories of the role of 5-HT are of interest and are discussed in subsequent sections.
Clinical and experimental evidence has supported a complex role for glutamate in the etiology of schizophrenia. The original evidence for an abnormality of the glutamatergic system was a decreased level of glutamate in the CSF of patients with schizophrenia. Subsequent studies have revealed decreased expression of glutamatergic receptors, such as the N-methyl-d-aspartate (NMDA) and AMPA/Kainate receptors. Evidence indicates that decreased glutamatergic activity is the result of decreased levels of glutamate receptors of the NMDA subtype. Consistent with the role of glutamate in schizophrenia, three noncompetitive antagonists of NMDA receptors (phencyclidine [PCP], ketamine, and MK-801), and three competitive antagonists (CPP, CPP-ene, and CGS 19,755), can produce a range of positive and negative symptoms and cognitive dysfunction in normal control subjects closely mimicking the clinical signs and symptoms of schizophrenia. Exposing schizophrenic patients to these agents results in marked intensification of core schizophrenic symptoms.
Neuroleptics can block some of the clinical effects of PCP. The ability of the 5-HT2A– and D2-receptor antagonists, such as clozapine and olanzapine, to block the clinical effects of these NMDA-receptor antagonists is unknown. However, the preclinical effects of PCP, such as disruption of sensory gating, can be blocked by selective 5-HT2A-receptor antagonists, such as MDL100,907, and by clozapine. Several compounds that enhance NMDA receptor function (e.g., glycine, d-serine, d–cycloserine) have been reported to alleviate negative and positive symptoms in patients with schizophrenia when administered in conjunction with typical neuroleptic drugs. It has also been suggested that increased levels of glutamate can have neurotoxic effects on various neurons; however, there is no conclusive evidence for neurodegenerative change in schizophrenia.
The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia. After initial reports of decreased GABA levels in CSF, recent postmortem studies have implicated a decreased function of GABAergic neurons in schizophrenia. The most replicated finding is a decreased expression of the messenger RNA for glutamic acid decarboxylase (GAD), the enzyme necessary for the synthesis of GABA. The 67 kDa isoform of GAD has been reported as decreased in the cerebral cortex and hippocampus of schizophrenic subjects. Subsequent studies have identified gene and protein expression changes in specific subsets of GABAergic neurons in the cerebral cortex, such as parvalbumin-positive GABAergic neurons in the prefrontal cortex, which play a crucial role in the modulation of pyramidal cell firing and the synchronization of cortical activity.
Structural Brain Abnormalities
The neuropathological exploration of schizophrenia is experiencing a renaissance and has been complemented recently by neuroimaging studies of the cortical gray and white matter, and subcortical regions.
The study of the cerebral cortex remains at the center of schizophrenia research. Ever since Kraepelin’s original conceptualizations of dementia praecox as a disorder of uniquely human qualities (such as volition and insight), most studies of brain structure have focused on the prefrontal cortex, primarily its dorsolateral aspects (i.e., dorsolateral prefrontal cortex [DLPFC]). Recently, the medial temporal lobe, especially the hippocampus, has attracted significant interest, originally because of the reports of psychotic symptoms in patients with medial temporal lobe lesions. Other regions of interest include the anterior cingulate cortex and the superior temporal gyrus. Improved neuroimaging methods allow for the in vivo measurement of regional brain volumes, the estimation of cortical thickness, and the shape analysis of cortical and subcortical structures. Two important morphometric findings have been replicated, with achieve significant effect sizes in meta-analyses. First, the lateral and third ventricles are enlarged. Second, the volumes of several cortical regions are decreased in the medial temporal lobe.
At the cellular level of cortical organization, abnormalities of cell number, protein expression, and gene expression have been reported. The well-established finding of decreased cortical volume in schizophrenia is not mirrored, as in most neurological disorders, by reports of marked neuronal loss. Some investigators have interpreted the lack of marked cell loss and the lack of an associated increase in the number of glial cells as evidence against a neurodegenerative and in favor of a neurodevelopmental abnormality.
Some studies provide evidence of a decreased prominence of dendrites and axons (referred to, in aggregate, as neuropil), resulting in an increased density of cortical neurons. This is complemented by emerging evidence for decreased oligodendrocyte functioning, i.e., of the glial cells crucial for the myelination of fiber pathways.
The application of sophisticated methods of protein and gene expression in postmortem brain tissue has provided researchers with the opportunity to study subtle abnormalities of cellular architecture, not detected by the standard neuropathological examination of brain tissue. Such studies have demonstrated deficits in cortical and hippocampal neurons, such as subtypes of GABAergic neurons in the prefrontal cortex.
Longitudinal neuroimaging studies have shown convincingly that the changes in cortical structure are visible at the time of the first episode of schizophrenia, and not simply the effect of longstanding illness or treatment. Furthermore, some studies provide evidence that abnormalities of brain structure can be found in individuals who are at high risk of developing schizophrenia, but have not yet become symptomatic. Finally, neuroimaging studies reveal that some of the abnormalities found in schizophrenia are present also in unaffected first-degree relatives. Taken together, there is a compelling evidence for structural abnormalities of the cortex and hippocampus in schizophrenia.
Initial reports indicated a significant decrease of mediodorsal thalamic nucleus volume and neuronal population. Some reports specifically implicated those neurons of the mediodorsal thalamic nucleus that establish strong reciprocal connections with the DLPFC. Recent rigorous, larger studies, however, have not been able to replicate the finding of thalamic neuronal loss.
The basal ganglia have been studied extensively in schizophrenia, as they are a projection site of dopaminergic fibers from the substantia nigra. While several studies have demonstrated an increased release of dopamine into the striatum (especially during periods of acute psychosis), there is little evidence for an abnormality in basal ganglia volume, cell number, or protein and gene expression.
Recent studies reveal abnormalities of glial cells and myelinated fiber pathways in schizophrenia. The cellular abnormalities include a decreased number of oligodendroglia and a decreased expression of myelin-related genes. Either abnormality could lead to a disturbance of myelinated fiber pathways in the brain. Neuroimaging studies of fractional aniostropy, a measure of the alignment and organization of fiber bundles in the brain, have indeed revealed such patterns of cortical disconnection. They appear to affect regions in the prefrontal cortex as well as several large-scale networks of brain regions, such as the frontal and temporo-parietal brain regions subserving language function.
Functional Brain Abnormalities
There is little doubt that the core features of schizophrenia (i.e., the positive and negative symptoms and the significant decline in social functioning) are caused by abnormalities of brain function. The extensive literature on neuropsychological deficits in schizophrenia is supported by more recent reports of the neural basis of such deficits.
Most patients with schizophrenia show significant deficits on standard neuropsychological tests. While some investigators have proposed that such deficits are selective (e.g., for verbal memory or attention), meta-analyses reveal abnormalities in most aspects of cognition in schizophrenia. The deficits of cognition are present in the early stages of the illness. Cohort studies of subjects, who later develop schizophrenia reveal significant cognitive deficits before the onset of the illness. While schizophrenia as a whole is characterized by cognitive deficits, their severity varies and predicts the level of functioning in the community.
Behavioral, neuroimaging, and electrophysiological studies have shown convincingly that several functions of the prefrontal cortex are impaired in schizophrenia. These include abnormal DLPFC function during the storage of information as well as the retrieval of information from working memory. Abnormal anterior cingulate cortex function is found when inhibiting responses to sensory stimuli. Functional neuroimaging studies using PET and functional magnetic resonance imaging (fMRI) reveal a complex pattern of abnormal DLPFC activation in schizophrenia. While patients show a decreased activation of the DLPFC compared to healthy control subjects (referred to as hypofrontality) during some cognitive tasks, they show normal or increased DLPFC activation on other tasks. Task performance, which is typically lower in schizophrenia, explains some of the variable patterns. When the performance on tasks of DLPFC function is equilibrated between subjects, subjects with schizophrenia typically show an increased pattern activation. This has been interpreted as a sign of decreased cortical efficiency, since greater DLPFC activation (i.e., more activity in the same number of cortical neurons or the same degree of activity in a larger number of neurons) is required for the same level of task performance. Some have speculated that such patterns could be the result of abnormal dopaminergic modulation of cortical neurons, while others have proposed decreased cortical inhibition and impaired cortical synchronization as the cause.
Some aspects of hippocampal function during the encoding and retrieval of memory are abnormal in schizophrenia. There are patterns of increased hippocampal activity at baseline and during passive viewing of stimuli, and a decreased ability to modulate hippocampal responses during the retrieval of previously stored information. The impairment of hippocampal function appears to be particularly pronounced when the relationship between previously learned items has to be recalled.
The reception and integration of sensory information is abnormal in schizophrenia. An extensive electrophysiological literature has documented abnormalities in early sensory processing. These abnormalities involve the thalamic nuclei, the primary sensory cortices, and the multimodal cortices.
Several other brain regions, including thalamus, basal ganglia, and cerebellum have been shown to be impaired during the performance of cognitive tasks in schizophrenia.
Genetic Hypothesis
It has been known for many years that the risk of schizophrenia is increased if another family member is affected (Table 16–1). Family, twin, and adoption studies of schizophrenia have revealed a high degree of heritability, approximately 80%. Heritability is the proportion of phenotypic variance accounted for by genetic effects. It refers to variance in the population and does not translate into a straightforward risk assessment for an individual. Furthermore, high heritability does not exclude a role for nongenetic factors. This is evidenced by the fact that, despite the high heritability of schizophrenia, the concordance rate in monozygotic twins is only 50%, pointing to the importance of environmental factors. Taken together, there is convincing evidence that a combination of risk genes contributes to the development of schizophrenia. However, it is also apparent that schizophrenia is not completely determined by genes (as in an autosomal dominant condition with full penetrance, such as Huntington disease).
Lifetime Expectancy (%) | |
|---|---|
If no relative has schizophrenia | 1 |
If the following relative has schizophrenia: | |
One Parent | 10 |
Both Parents | 46 |
Sibling | 10 |
Child | 6 |
For twin if cotwin has schizophrenia: | Proband-wise concordance (%) |
Dizygotic twin | 14 |
Monozygotic twin | 46 |
The exact genetic mechanism of schizophrenia remains elusive. The introduction of molecular biological techniques has resulted in many reports of linkages between the diagnosis of schizophrenia and polymorphisms in the human genome. However, linkage to particular chromosomal regions has been hard to confirm in independent replication studies, most likely due to a combination of small genetic effects, inadequate sample sizes, and the use of marker maps of insufficient density. Two recent meta-analyses have attempted to overcome the issue of limited power in individual studies. Both analyses provided support for the existence of susceptibility genes on chromosomes 8p and 22q, but they differed with regard to specific regions on chromosomes 1q, 3p, 5q, 6p, 11q, 13q, 14p, and 20q.
Recently, the detailed mapping of chromosomal regions has led to the identification of several genes that are being examined (Table 16–2). Several genes code for proteins known to affect pathways relevant to schizophrenia. For example, the newly found protein neuregulin 1 (NRG1), which is coded for by gene G72 on chromosome 13q34, and the enzyme d–amino acid oxidase (DAAO) are all in a position to affect glutamatergic neurotransmission. On the other hand, a mutation in the gene coding for catechol-O-methyl transferase (COMT), the catabolic enzyme of dopamine, is associated with impaired brain function in schizophrenia. Thus, there is now compelling evidence for specific risk genes for schizophrenia. This could lead to a better understanding of disease mechanisms and the identification of targets for drug development.
There is clear evidence that genetic factors influence the risk of developing schizophrenia.
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