Over the past several decades, significant progress has been made concerning our understanding of the neural bases of the varied processes that comprise human behavior. Illustrations of such processes include sensation, perception, motor functions, learning, memory, and mood states. As a result of the explosion of knowledge of the neural bases of behavior, inroads have also been made in our understanding of the neural correlates of disorders of thought, mood, and anxiety. However, the acquisition of new knowledge is somewhat tempered by the lack of precise definitions of the different disorders, as well as difficulties in carrying out well-controlled studies in humans. For example, the term "schizophrenia" may not represent a unitary disorder but, instead, may encompass different disease states. As a result, studies may likely be conducted on a heter-ogenous rather than a homogenous population with respect to this disorder. Another major problem in conducting these studies is that it is difficult to dissociate the effects of long-term drug treatment from the behavioral disorder on neural and behavioral functions examined in the patient. Nevertheless, in this topic, we attempt to identify and summarize the current state of knowledge of these behavioral disorders and the rationale for drug and related therapies used in the treatment of these disorders.
Schizophrenia
Behavioral Aspects
Schizophrenia is a disorder characterized by psychosis, which is a dysfunction in the thought process in which the ability to correctly test reality is lacking. The general or primary criteria for schizophrenia include one or more of the following: delusional thought processes (i.e., false beliefs); disturbances in speech, appearance, and behavior; hallucinations (i.e., false perceptions, mostly auditory, such as hearing voices); apathy; a paucity of emotion; and the presence of a catatonic posture. Overall, there is an inability to perceive the world accurately.
Major Subtypes
Paranoid Schizophrenia
Individuals suffering from paranoid schizophrenia are typically preoccupied with hallucinations (mainly auditory, i.e., hearing voices) or delusions, such as persecution, personal exaltation, or having a specific mission.
Disorganized (Hebephrenic) Schizophrenia
Disorganized schizophrenia is characterized by a flat affect, which is mostly inappropriate and incongruous. Consequent speech is often incoherent, disjointed, and rambling. Delusions and hallucinations play a lesser role in this form of schizophrenia.
Catatonic Schizophrenia
Catatonic schizophrenia is characterized by one (or more) of the following: stupor, a decrease in reactivity to the environment, purposeless motor activity, rigidity of posture that may appear bizarre, resistance in responding to instructions, and placing of the body in externally imposed positions. Because of improved treatment options, this type of schizophrenia is currently quite rare.
Undifferentiated Schizophrenia
In undifferentiated schizophrenia, the individual displays one or more of the general criteria listed for the other types of schizophrenia just described but cannot be clearly placed into one of these categories.
Course of Development
In characterizing the development of schizophrenia, three phases may be identified. Prior to the first phase, premorbid signs appear suggesting the possibility of future onset of the disease. These signs could include schizoid behavior (characterized by passive and introverted behavior), where the patient withdraws from social contact. As the disorder evolves, the first phase, the prodromal phase, includes prodromal signs, which typically precede the onset of the first psychotic episode. The patient initially expresses physical complaints, such as muscle pain and headaches, as well as an increased interest in religion, philosophy, and the occult. The patient may also display bizarre thoughts, distorted perception, and unusual speech. In the second or psychotic stage, the patient loses touch with reality. This loss is reflected by positive symptoms, which include hallucinations (such as hearing voices) and delusions (such as a feeling of persecution), and negative symptoms, which include disorganized thinking (expressed by the absence of normal association of thoughts, poor speech, and loss of affect). In the time between psychotic episodes, a residual phase takes place in which the patient is in touch with reality. However, even in the residual phase, the patient displays a flat affect, is withdrawn, and continues to have bizarre or eccentric (deviating from the normal pattern) thinking.
Hereditary Factors
In considering the etiology of schizophrenia, one of the most important discoveries has been the finding of a genetic predisposition to this disease. In a series of well-known studies conducted in the 1930s, the incidence of schizophrenia between identical (monozygotic) and fraternal (dizygotic) twins was compared. In identical twins, the genomes are virtually the same for both siblings, whereas approximately 50% of the genomes are shared by the fraternal twins. The most significant finding of this study was the concordance of the disease between the twins. If one identical twin had schizophrenia, then the occurrence of schizophrenia in the other twin ranged from 45% to 50%. In contrast, if one fraternal twin had schizophrenia, then the occurrence of this disease for the other twin was 10% to 15%.
While these findings provided support for the theory of a genetic core, they did not necessarily exclude environmental factors because it was certainly possible that the environmental conditions for the identical twins studied could have been more similar than for fraternal twins. Consequently, other studies were conducted to further separate the environmental and genetic variables. This was achieved by investigators who demonstrated that: (1) the incidence of schizophrenia in twins reared by adoptive parents was similar to the rate for twin siblings reared by their biological parents, and (2) the incidence of schizophrenia was considerably higher in adopted children whose biological parents had schizophrenia.
Thus, the evidence clearly indicates that genetic factors play an important role in the etiology of schizophrenia. Recent studies have suggested that the genetic transmission of schizophrenia involves a combination of genes. Some reports have implicated the short arm of chromosome 19, the X chromosome, and the long arms of chromosomes 5, 11, and 18. Others have implicated chromosome 6 and the long arm of chromosome 22.
It should be pointed out that, while this evidence supports the notion of a genetic factor, psychosocial factors undoubtedly play a role as well. There is an extensive literature (which goes well beyond the scope of this topic) involving psychoanalytic, psychodynamic, and learning theories that provide alternative interpretations of the etiology of this disease.
Brain Abnormalities
Proponents of the view that schizophrenia results from brain dysfunction have suggested that neuropathological processes underlie neuronal loss in specific regions of the brain beginning in utero and continuing in the postnatal period. The rationale for this view is based on the observations that patients with schizophrenia commonly exhibit cognitive and behavioral abnormalities during childhood or adolescence, and those elements of brain pathology have been identified in adults diagnosed with this disorder.
Attention has been given to the possible brain regions affected by maladaptive development in patients with schizophrenia. One of the more impressive findings involved studies using magnetic resonance imaging (MRI) in twins. It was observed that if one twin was normal and the other was diagnosed with schizophrenia, then the lateral ventricles were enlarged only in the twin with schizophrenia but not in the normal one. The enlargement of the ventricles results in damage to structures that lie proximal to the ventricle. These structures include the hippoc-ampal formation, amygdala, cingulate gyrus, and parts of the ventral aspect of the pallidum. Postmortem examination of the brains of patients with schizophrenia revealed decreases in the sizes of the hippocampal formation, amygdala, parahippocampal gyrus, and prefrontal cortex.
The involvement of limbic structures has been suspected because of their role in regulating emotional behavior. The association of the basal ganglia with schizophrenia is based on two factors: The first includes the extensive connections with the prefrontal cortex, and the second is that many patients with schizophrenia exhibit movements characteristic of those associated with diseases of the basal ganglia, even in the absence of drug treatment. The prefrontal cortex has been linked with schizophrenia for a number of reasons. The first is that loss of neurons in the prefrontal cortex has been noted in patients with schizophrenia. Second, the prefrontal cortex has been known to play an important, if not critical, role in cognitive functions, which are significantly affected in these patients. Third, a current leading neurochemical hypothesis, the dopamine hypothesis, focuses on the role of dopamine and its relationship to limbic and cortical structures, including the prefrontal cortex. This hypothesis is discussed in more detail in the next section. It should be pointed out, however, that unequivocal evidence linking specific brain sites to this disorder has yet to be established. The available evidence suggests that, perhaps, schizophrenia results from dysfunction of different groups of neurons located mainly in the forebrain but that may also include brainstem monoaminergic groups as well.
Neurochemical Factors
Extensive research concerning the neurochemistry of schizophrenia has provided evidence that a variety of transmitters may be implicated in this disorder.
Dopamine
The dopamine hypothesis of schizophrenia has prompted considerable research over the past two decades. The theory in its simplest form postulates that schizophrenia results from excess dopaminergic activity. The arguments in support of this hypothesis stem from the following lines of evidence. (1) Antipsychotic drugs, such as chlorpromazine, which have been used effectively for the treatment of schizophrenia by reducing hallucinations, delusions, and bizarre thinking, also block dopamine-D2 receptors. Although five dopamine receptor subtypes (i.e., Dp D2, D3, D4, and D5) have now been cloned, many antipsychotic drugs have a high affinity for D2 receptors, suggesting that the D2 receptor is a major site for the action of these drugs. (2) Chronic administration of high doses of amphetamine (which releases dopamine and other biogenic amines) produces schizophrenia-like symptoms. (3) Specific regions of the brain, such as the prefrontal cortex and limbic system, which have been linked to schizophrenia, receive significant dopaminergic inputs from the mesocortical and mes-olimbic pathways, respectively.
Although the dopamine hypothesis still remains popular, there are some data that are not consistent with this hypothesis. These data include: (1) The absence of a relationship between schizophrenia and dopamine or its acidic metabolite, homovanillic acid, in relevant areas of the brain or in the cerebrospinal fluid (CSF); and (2) the inconsistencies in findings attempting to relate changes in dopamine D2 receptor densities in nonmedicated patients with schizophrenia relative to normal control subjects. In addition, there is also a lack of a clear understanding of the specific dopaminergic mechanism that serves to trigger schizophrenia-like behavior. As previously indicated, earlier views proposed that schizophrenia is associated with excess release of dopamine. Later views represented a modification of this hypothesis by suggesting the presence of any one or more of the following: (1) involvement of either D3 or D4 dopamine receptors, whose actions may be inhibitory rather than excitatory; (2) a reduction in dopamine receptor densities in patients with schizophrenia; (3) hypoactivity of the mesocortical dopamine system with respect to the prefrontal cortex, rather than dopamine hyperactivity in this region as originally thought; or (4) an association of schizophrenia with an increase in activity of the mesolimbic dopamine system with a decrease in the mesocortical system.
Serotonin
Although serotonin has been clearly associated with mood disorders,there is a body of literature that suggests that alterations in serotonin play a role in the development of cognitive impairment as well as positive and negative symptoms associated with schizophrenia. The hypothesis that the etiology of schizophrenia involves deficiencies in serotonin was based largely on studies using lysergic acid diethylamide (LSD), which was believed to antagonize 5-HT receptors and which caused visual hallucinations, a phenomenon remotely related to schizophrenia. Later studies indicated that LSD, instead, contained agonistic properties with respect to the 5-HT2A receptor.
The more significant evidence in support of a serotonin hypothesis stems from drug studies. For example, clozap-ine, which is a potent 5-HT2A and a weak dopamine D2 receptor antagonist, has been shown to be effective in treating the positive symptoms associated with schizophrenia. However, because clozapine has also been shown to have a high affinity for histamine receptors and to cause increased extracellular concentrations of acetylcholine in the frontal cortex (of rats), it is likely that 5-HT interactions with other transmitter systems may account for the positive effects seen with this drug. Additional evidence in support of the serotonin hypothesis include such findings as a decrease in 5-HT2A receptor binding in the prefrontal, cingulate, visual, and temporal cortices of patients with schizophrenia and an increase in the density of 5-HT1A receptors in the cortex and hippocampus in these patients. It is possible that the opposing effects on these receptor subtypes might have synergistic effects on processes associated with the development of schizophrenia. What is left unclear is whether the process of schizophrenia involves an increase or decrease in the release of serotonin. Only further research will help to clarify this issue.
Other Transmitters
Investigators have made attempts to implicate other neu-rotransmitters in schizophrenia. Studies examining the roles of Y-aminobutyric acid (GABA), acetylcholine, and excitatory amino acids have generally been conflicting and difficult to assess. Recent studies have attempted to implicate such neuropeptides as neurotensin and cholecystoki-nin (CCK) in the etiology of this disorder. The primary basis for studying these peptides is that they are commonly co-localized with dopamine in the midbrain and forebrain, including the cerebral cortex. However, the studies to date concerning these peptides have been incomplete and, at times, contradictory. In addition, recent research has suggested that altered glutamate transmission may also be linked to schizophrenia. Suggested treatment conditions include the administration of glutamate agonists.
In summary, the studies conducted over the past few decades suggest that changes in the dopaminergic and, perhaps, serotoninergic systems play important roles in the etiology of schizophrenia. Because schizophrenia is such a complex disorder and these transmitter systems are known to interact with other transmitters, it is likely that a better characterization will be one that is not limited to a single neurotransmitter system.
Drug Treatments
Initially, typical antipsychotic drugs were developed in the 1950′s for the treatment of psychosis, in general, and schizophrenia, in particular. Examples of typical antipsychotic drugs included flupenthixol, chlorpromazine (thorazine), and phenothiazine. Sometime later, a second generation of drugs, called atypical antipsychotics, which are directed mainly on 5-HT and dopamine receptors, were developed for the treatment of schizophrenia. Several such drugs include aripiprazole, which antagonizes 5-HT2 receptors and is an agonist at 5-HT1A and dopamine Ds receptors; clozapine, which has an affinity for dopamine receptors; risperidone, which is a strong dopamine antagonist with affinity for dopamine D2 receptors; and olanzapine, which has an affinity for 5-HT2 receptors.
Depression and Other Mood Disorders
Under ordinary conditions, individuals experience various emotions in which moods may vary from depressed to normal and elevated states. One of the basic differences between so-called "normal" individuals and those who experience a "mood disorder" is that the normal individual feels in control of his or her emotions, whereas one who is suffering from a mood disorder feels that he or she has lost control of his or her emotions. Disorders of mood states may take different forms, such as unipolar (depression or dysthymia), and bipolar, (mania, depression, cyclothymia) disorders. These disorders reflect disturbances in the emotional state of the patient, which is often highly distressful and results in difficulties in being able to function.
Major Depressive (Unipolar) Disorder
Because of the behavioral complexity of the disorder and the variations it may take in different individuals, it is probable that major depression reflects several (if not more) disease states. Nevertheless, there are features of major depression that appear, in general, to be common among individuals. The patient typically feels sad, helpless, guilty, and has low esteem. There is a lack of motivation, decreased appetite, and weight loss, and sleep patterns are poor. Feelings of anxiety are present as well as suicidal ideation.
Major depressive disorder may include other characteristics. A few of these are identified here. Some patients express denial of the disorder and will seek out a general practitioner rather than a psychiatrist in response to physical symptoms that appear to be vague. This is called masked depression. Depressive disorders may also be seasonal, called seasonal affective disorder, which appears to occur more frequently during the winter months when there are fewer hours of sunlight. As indicated earlier, there is also an increased risk for suicide. A variety of factors appear to contribute to suicidal tendencies. These include a previous serious suicide attempt, family history of depression, and, in particular, having a parent who committed suicide. Other factors include a serious medical condition, such as cancer; substance abuse; divorce; age (e.g., male over 65 years and adolescents); being at the initial stages of recovery from severe depression; impulsiveness; a feeling of hopelessness; and having psychotic symptoms along with severe depression.
Bipolar Disorder
Bipolar disorders are characterized by distinct episodes of both elevated mood and depression and have been subdivided into bipolar I and bipolar II disorders. Bipolar I disorder is characterized by depression and clear-cut manic symptoms present during the course of the disease. Some of the manic symptoms include a tendency to be quick to anger and easily bothered (i.e., impulsive and irritable responses); a lack of modesty in dress; assaultive behavior; delusions of grandeur and power; intense feelings of happiness and well-being, elevated, irritable, or expansive mood; a decreased need for sleep; inflated self-esteem; talkativeness; distracted behavior in which attention is given to trivial stimuli; an increased involvement in activities considered pleasurable but that can have significant negative consequences, such as sexual indiscretions and buying sprees. In bipolar II disorder, depression is coupled instead with hypomania, an elevated mood that does not negatively affect function.
Dysthymia And Cyclothymia
The major feature of dysthymic disorder is the continued presence of a mildly depressed state lasting most of the day and for most days, extending for a period of 2 years with no discrete episodes of the illness (as is the case with bipolar disorders). The patient may display irritability, anger, guilt, withdrawal from society, or a lack of both activity and productivity.
The major feature of cyclothymic disorder is that it basically reflects a mild form of bipolar II disorder in which there are episodes of mild depression and hypomania over a 2-year period. However, in contrast to bipolar II disorder, there are no clear-cut discrete episodes associated with cyclothymia.
Hereditary Factors
Research studies suggest that genetic factors may play significant roles in both depression and bipolar disorders. One line of evidence is based on the observations that first-degree relatives of major depressive disorder probands (i.e., the patient or family member bringing a family under study) are much more likely to have this disorder than similar relationships in a control population. Parallel findings have been reported with respect to individuals suffering from bipolar disorder. Moreover, with respect to depression, the concordance rate for monozygotic twins is much higher than for dizygotic twins. However, studies attempting to link specific chromosomal variations with this disorder have not yielded uniform results, and, accordingly, further studies are required to support a genetic factor as determined from chromosomal analysis.
Brain Abnormalities
In general, the findings from studies attempting to identify specific regions of the brain linked to depression and related disorders have been inconclusive, but studies using positron emission tomography and MRI scans have provided evidence of possible prefrontal cortical involvement. It should be pointed out that this region of the cortex has both direct and indirect projections to the hypothalamus, amygdala, and midbrain periaqueductal gray. These are areas of the brain that are significantly involved in the regulation of emotional behavior. That the prefrontal cortex is involved in depressive disorders is supported by studies showing that lesions of this region enhance aggression and disrupt thought processes and the making of rational decisions. It remains for future research to determine the extent to which dysfunctions involving other regions of the brain contribute to depressive disorders.
