CURE FOR SCHIZOPHRENIA A JOURNEY CAN BIOLOGICAL CONTROL SYSTEMS BE THE ANSWER TO CHEMICAL REGULATION?

DOPAMINE AND ITS ROLE

Mushahid M

The Role of Dopamine Receptors in Schizophrenia by: Rupinder Mann for: Biochemistry II (CHEM 4420) 5/29/96 Two million people suffer from schizophrenia at some point in their life, making it one of the most common health problems in the United States. Schizophrenia has also been found to be hereditary. This biological disorder of the brain is a result of abnormalities which arise early in life and disrupt the normal development of the brain. These abnormalities involve structural differences between a schizophrenic brain and a healthy brain. Schizophrenic brains tend to have larger lateral ventricles and a smaller volume of tissue in the left temporal lobe in comparison to healthy brains. The chemical nature of a schizophrenic brain is also different in the manner the brain handles dopamine, a neurotransmitter. Neurotransmitters transmit impulses between neurons. (Brown 1994) The disease schizophrenia can be characterized by disturbances in the areas of the brain that are associated with thought, perception, attention, motor behavior, emotion, and life functioning. The symptoms are divided into negative and positive categories. Negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy. Positron emission tomography (PET) has been used to show that schizophrenics with negative symptoms have reduced brain activity in the prefrontal cortex of the brain. PET measures the blood flow in the brain by measuring particles (positrons) that are emitted from a radioactive chemical injected into the patient. The rate of positron emission is used to evaluate the metabolic rate of nerve cells in particular regions of the brain. PET allows scientists to determine which areas of the brain are being used as people perform certain tasks.

Positive symptoms are frightening, but they are not as disabling in the long term as negative symptoms. These positive symptoms consist of hallucinations, delusions, and bizarre behavior. Single photon emission tomography (SPET) measures a single photon's rate of emission. It has been used to show that during the delusional hearing of voices, the blood flow is greater than normal to Broca's area. This is the part of the brain that has been linked to articulated language. Some subcategories of schizophrenia include hebephrenic, catatonic, and paranoid schizophrenia. Hebephrenic or disorganized schizophrenia is characterized by profuse hallucinations and delusions that often involve deterioration of the body. Catatonic schizophrenia involves motor disturbances, which alternate between immobility and wild excitement. A paranoid schizophrenic has prominent delusions about persecution. (Davison & Neale 1990) A number of these symptoms are thought to be caused by biochemical factors. One of the most prominent of these factors is the excessive activity of the neurotransmitter dopamine. This excessive activity will be explained by the chemistry of the brain and dopamine receptors. Thousands of chemical processes take place in a functioning neuron. The transfer of information is mediated by neurotransmitters that interact with certain receptors. (Sedvall & Farde 1995) When drugs block dopamine receptors in the basal ganglia, the symptoms of schizophrenia are reduced. Amphetamines and other drugs that stimulate the receptors produce schizophrenic symptoms in healthy people. (Brown 1994) Five dopamine receptors, D1, D2, D3, D4, and D5, have been discovered. Each of the receptors contain about 400 amino acids, and they have seven regions spanning the neural membrane. Their function is to bind to dopamine secreted by presynaptic nerve cells. This binding triggers changes in the metabolic activity of the postsynaptic nerve cells. A study was

conducted in which presynaptic dopamine function (measured by the uptake of fluorodopa) was observed by PET in the brains of seven schizophrenic patients and eight healthy people (controls). The fluorodopa influx constant was higher in the schizophrenic patients. Their receptors took up more fluorodopa. In conclusion, these alterations in presynaptic dopamine function constituted a part of the disrupted neural circuits that predispose people to schizophrenia. (Hietala 1995) The dopamine receptors involved in these processes can be separated into the D1 and D2 families. The D1 family contains the receptors D1 and D5. The D1 receptors in the brain are linked to episodic memory, emotion, and cognition. These functions are disturbed in schizophrenic patients. In addition, D1 binding of dopamine was found to be lower in schizophrenic patients as compared to healthy subjects of the same age. The binding was lower as a result of fewer D1 receptors. Certain antipsychotic drugs stimulate D1 regulated pathways, which increases the D1 to D2 activity balance in the brain. This balance can also be regained by the release of dopamine. Not much is known about D5 due to the lack of drugs that are selective for it. The D2 family contains the receptors D2, D3, and D4. D2 is the second most abundant dopamine receptor in the brain. D2 receptor blockade is the main target for antipsychotic drugs, because there is a higher density of D2 in schizophrenic brains. (Sedvall & Farde 1995) A study conducted by Schmauss (1993) found a selective loss of D3 mRNA expression in the parietal and motor cortices of postmortem, schizophrenic brains. This phenomena may be due to either the course of the disease or the therapy given to the patient during the course of the disease. Seeman (1993) found the density of D4 receptors was elevated sixfold in schizophrenic patients.

These dopamine receptors are affected by alterations in the neural cell membranes, which could disrupt communication between cells. Abnormalities in two long-chain fatty acids in the blood cells of people with negative symptoms have been discovered. These substances breakdown into products that are involved in the dopamine system. (Brown 1994) Dopamine is secreted by cells in the midbrain that send their axons to the basal ganglia and frontal lobe. Certain drugs used for schizophrenia bind to the dopamine receptors. This blocks dopamine binding to the receptor. This deactivates the biochemical processes normally initiated by dopamine binding. First dopamine binds to the receptor, and then the receptor autophosphorylates. By phosphorylation, this receptor activates adenylate cyclase, which then makes cAMP. These processes involve the synthesis of cAMP and synaptic action at synapses using dopamine as a transmitter. The dopamine synapses are incapacitated by antipsychotic drugs. Dopamine antagonists are drugs that block dopamine receptors. The brain responds to this receptor blockade by making extra dopamine receptors. This is the postsynaptic cells' attempt to compensate for the weakening of synaptic transmission, which is caused by the drugs. These extra receptors restore the cell's sensitivity to dopamine. The brain also compensates by increasing dopamine synthesis. The increase in dopamine synthesis lasts one to two weeks of medication from the start of therapy, which is the same time required for the medication to become effective. Drugs have been discovered to alleviate the upregulation of receptors and the increased synthesis of dopamine. (Lickey & Gordon 1990) Anti-schizophrenic drugs are called neuroleptics. A dopamine antagonist is chlorpromazine (Thorazine), and reserpine operates by depleting transmitter stores. Ligand-binding techniques, which use neuroleptic drugs labelled with radioisotopes demonstrate that such drugs bind to dopamine

receptors. A correlation exists between this ability to bind dopamine and the dosage required to improve schizophrenic symptoms in patients. This effect could also be directly observed by PET in living subjects . (Sedvall & Farde 1995) Controlling dopamine and dopamine receptors is essential for the treatment of schizophrenia. Because schizophrenia is hereditary, it is important to see progress for the next generation. (Brown 1994) In the future there will be more sophisticated drugs that do not merely suppress symptoms, but also allow for normal cognitive functioning. Although schizophrenics may never be normal, their lives can still be made more tolerable.

INTRODUCTION The last 10 years have witnessed far-reaching changes in the understanding of dopamine (DA) and its possible role in the pathogenesis of schizophrenia. Although the original hypothesis that has so stimulated the study of DA in schizophrenia has proven to be untenable, a role for DA in schizophrenia appears even more likely than it did 10 years ago. The original DA hypothesis of schizophrenia postulated that schizophrenia was characterized by increased DA function (1). This hypothesis was based primarily on the correlation between the ability of neuroleptics to displace DA antagonists in vitro and their clinical potency (2). However, in the last decade it has become increasingly evident that this hypothesis was in need of revision. One of the principal reasons driving the demand for reconceptualizing the original DA hypothesis was the appreciation that some core symptoms of schizophrenia are negative symptoms and cognitive deficits. These symptoms, though amenable to some extent to neuroleptic treatment, are far less responsive to treatment with DA antagonists than are psychotic, positive symptoms. This, in turn, suggests that some of the core symptoms of schizophrenia may be unrelated to increased DA activity. Additionally, knowledge about the DA system has expanded considerably over the last decade and, combined with the above questions, has stimulated further studies into DA and schizophrenia, leading to an increased and refined understanding of its role in that illness. (See Mesocorticolimbic Dopaminergic Neurons: Functional and Regulatory Roles and Dopamine Receptors: Clinical Correlates , for related discussion.)

IDENTIFICATION SUBTYPES

OF

MULTIPLE

DA

RECEPTOR

The discovery of multiple DA receptors serves as a good illustration of the progress made over the last decade in understanding the DA system. Ten years ago, D2 and D1 were the only DA receptors known, but now D3, D4, and D5 receptors have also been identified. D1 receptors are coupled to adenylate cyclase, have a low binding affinity to [3H]spiperone, and are found predominantly in the cortex of humans (3). D5 receptors resemble D1 (4), but they have a higher affinity for DA than do D1 receptors (5). D2 receptors are negatively coupled to adenylate cyclase, display high binding affinity to [3H]spiperone (6), and are most prominent in the striatal and limbic structures in humans; and their presence, if at all, in the human cortex, is limited (3). The D2 receptor has also been cloned and two D2 isoforms, labeled D2a and D2b, have been identified (7). The D3 receptor has been cloned and is primarily present in the nucleus accumbens with very low levels in the caudate and putamen (8). It also exists in two isoforms (9). [In one study, no linkage was found in four Icelandic pedigrees between schizophrenia and the D3 receptor gene (10).] It bears no resemblance to either the D1 or the D2 system (11). Finally, D4 receptors have been identified displaying a higher affinity for the atypical neuroleptic, clozapine (12). The identification of these various DA receptors has important implications. The high affinity of clozapine to the DA4 receptor, for instance, raises the issue of whether atypical neuroleptics are effective by blocking D4 receptors more effectively than they block D2 receptors. Indeed, it has

been argued that blockade of D4 receptors is related to the efficacy of neuroleptics, whereas blockade of D2 receptors is related to their extrapyramidal side-effect profile (13). The anatomical localization of D3 receptors to limbic regions has intriguing possibilities for the development of antipsychotic compounds.

MODULATION OF THE DA SYSTEM Another discovery of importance in understanding the role of dopaminergic transmission in schizophrenia has been the elucidation of an interaction between cortical and striatal DA systems: An inhibitory regulation of cortical DA systems on striatal DA neurons has been found. When DA neurons are lesioned in the prefrontal cortex (PFC) in rats, increased levels of DA and its metabolites as well as increased D2 receptor binding sites and D2 receptor responsivity are found in striatum (14, 15, 16, 17, 18). Conversely, injection of the DA agonist, apomorphine, in the PFC of rats reduced the DA metabolites, homovallic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), by about 20% in the striatum (19). In a modification to the model proposed by Pycock et al. (14), Deutch (20) proposed that the effect of DA depletion in the PFC on striatal DA activity is particularly revealed after the animal has been stressed. Specifically, when animals were stressed, larger increases in striatal DA activity were found in animals whose mesocortical DA neurons had been lesioned

than in animals with intact PFC DA systems (20). This suggests that the sensitivity of striatal (mesolimbic) DA neurons to physiological (i.e., stress) challenge is enhanced when DA function in the PFC is decreased. These studies therefore indicate that decreasing prefrontal cortical DA activity increases striatal DA turnover, D2 receptor sensitivity, and D2 receptor function, whereas increased DA function in the PFC decreases striatal DA activity particularly in response to stress. Thus, it appears that DA systems in the PFC display an inhibitory modulatory effect on subcortical, striatal DA systems. Decreased activity in the PFC may render the subject particularly sensitive to stress-induced increases in subcortical DA activity. Others suggest an additional link between (diminished) DA activity in the PFC and stress-sensitive changes in subcortical DA activity. It has been hypothesized that the release of DA in subcortical sites is under the control of two independent mechanisms: phasic and tonic DA release (21). Phasic DA release appears associated with behavioral stimuli (stress, for instance), whereas the degree of tonic DA activity determines the magnitude of the phasic response to environmental stimuli. Decreased prefrontal DA activity in schizophrenic patients is hypothesized to reduce tonic DA release, leading to compensatory increases in (for instance) receptor sensitivity, resulting in exaggerated responses to phasic release of DA in response to stress (21). In summary, findings suggesting a regulatory effect for PFC DA systems on subcortical DA function have changed the focus from solely subcortical DA systems to the interaction between the subcortical and cortical DA systems as one of the primary regions of interest in schizophrenia. These findings have farreaching and important implications for the role of DA in schizophrenia: Not only do they suggest the usefulness of

increasing DA activity (in the PFC), but even more importantly, increasing DA function in the PFC may be used as an intervention to prevent (stress-induced) increases in subcortical DA activity (i.e., psychosis) and thus may be considered as maintenance treatment in schizophrenia (see also Schizophrenia and Glutamate).

METHODOLOGICAL ADVANCE Understanding of the DA system in humans has also been enhanced by the development of peripheral measures that reflect central DA function. Measurement of the DA metabolite, homovanillic acid (HVA), in plasma has proven to be such a tool, appearing particularly useful when DA function is putatively manipulated, as during administration of neuroleptics. The HVA found in plasma is produced primarily by brain DA neurons and peripheral noradrenergic (NA) neurons. Secondary sources of HVA are peripheral DA and brain NA neurons. Animal and human studies suggest that brain DA turnover can be reflected by plasma HVA (pHVA) concentrations (22, 23). Although the precise proportion of pHVA deriving from brain HVA has not been fully elucidated (24), measurement of this DA metabolite in plasma of schizophrenic patients appears to be a valid method to investigate DA in this disorder provided certain conditions are met. For example, highly consistent findings have been produced when HVA is measured in plasma prior to and during neuroleptic treatment in schizophrenic patients. All studies found chronic neuroleptic treatment to lower pHVA, and all

found this decrement to relate to treatment outcome (Table 1). Moreover, six out of eight studies found higher pretreatment pHVA concentrations to be related to good neuroleptic treatment response (Table 2). When HVA is measured during the steady state, however, less consistent results have been generated: pHVA differentiates patients from controls only in some studies, and results of studies trying to link pHVA concentrations to specific schizophrenic symptoms, or even to severity of illness, have been inconsistent (Table 3). Thus, while the results when HVA is used as an indication of baseline DA function are conflicting, when HVA is used as an index of change in DA function the results are quite consistent. This may be the result of the relatively large changes in HVA production when DA activity is manipulated as compared to the steady state. For instance, when striatal HVA is reduced (after administration of apomorphine) by about a third, pHVA decreases by about 25% in rodents (22); when HVA increases fourfold (after administration of haloperidol) in striatum, it almost doubles in plasma of rats (25). A single administration of haloperidol roughly doubles pHVA concentrations in human subjects (26). Thus, the changes induced by perturbation of DA function lead to large changes in both central and peripheral HVA concentrations. Possibly, when DA function is manipulated, the changes that occur are profound enough to be detected in metabolite concentrations in plasma. In contrast, when steady-state DA function is assessed, DA metabolite concentrations may be much more prone to multiple confounding factors (27).

MODULATION OF DA SYSTEMS IN ANIMALS

The distribution and development of the DA system in primates have recently been elucidated. This may indirectly help to understand the role of DA in schizophrenia (see ref. 28). In contrast to those in rodents, DA fibers in adult monkeys are widespread in every cortical region, although they are most pronounced in layers I and III (28). Neonatal monkeys, however, display a more uneven distribution of DA fibers— that is, fewer DA axons in layers III–VI. Axonal growth in these layers takes place during the first 2–3 months of life, so that in early adult life the distribution of DA fibers resembles that in adult monkeys. Interestingly, in monkeys that have been socially isolated since birth, the neuronal growth in layers III–VI appears to have been stunted (29), suggesting that early age is critical for the normal development of DA neuronal networks.

MODULATIONS OF DA SYSTEMS IN HUMANS Evidence for Cortical Hypofunction Anatomical Imaging Studies Multiple studies using computerized tomography (CT) have found evidence of enlarged ventricles in schizophrenic patients as compared to healthy controls (for a review see ref. 30). These studies provide only nonspecific evidence of diminished brain tissue. With the advent of magnetic resonance imaging (MRI), evidence of more localized abnormalities have materialized. Decreased volume of the frontal and temporal cortex have been found as well as decreased volume of the hippocampus, although the findings have not been consistent

(see ref. 30). Differences in results may depend on imaging techniques (resolution of MRI scanners) including the slice thickness of the images. The potential significance of these findings can best be viewed in relation to functional imaging studies. Functional Imaging Studies Decreased function of the frontal lobes has been repeatedly demonstrated with both measurements of cerebral blood flow as measured by single photon emission computerized tomography (SPECT) and positron emission tomography (PET) (for a review see ref. 31). In a cognitive task linked to frontal lobe function, the Wisconsin Card Sort Task (WCST), schizophrenic patients failed to show an increase in cerebral blood flow to the same degree as normal controls (32). Facility at this task has been associated with the dorsolateral prefrontal lobe. Similarly, schizophrenic patients showed decreased blood flow and activation of the left mesial frontal cortex on performing the "Tower of London" task (31). This lack of activation and decreased blood flow was similar in drug-naive and medicated patients, but occurred only in patients with high negative symptoms scores (31). Indeed, negative symptomatology has been associated with prefrontal hypometabolism (33). Furthermore, decreased frontal blood flow is not related to medication effects (34). Hence, frontal hypofunction seems a key feature of schizophrenia, particularly to patients with prominent negative or deficit symptoms. However, a critical question is whether the findings of decreased volume and function of the prefrontal cortex in schizophrenia have any relationship to the role of DA in schizophrenia. Obviously, atrophy of the frontal cortex could affect various neurotransmitter systems. Similarly, decreased function of the PFC may be the result of hypofunction of multiple neurotransmitters. However, several lines of evidence

suggest that decreased function of the PFC may be related to decreased activity of mesocortical DA neurons. Relationship Between Cerebrospinal Fluid HVA (CSF HVA) and Function of the PFC Indirect evidence has suggested that cortical hypofunctionality is associated with diminished cortical DA activity. For example, a strong positive correlation was found between the ability to activate the PFC (on the Wisconsin Card Sort Test) and CSF HVA concentrations (32). Indeed, cognitive deficits attributed to activity of the frontal cortex, such as WCST performance, were associated with lowered CSF HVA concentrations, suggesting a relationship between decreased DA function and impaired frontally mediated cognitive function (35). Moreover, blood flow in the prefrontal cortex increases in schizophrenic patients after administration of the DA agonists amphetamine (36) and apomorphine (37), suggesting that the hypofrontality found in schizophrenic patients can be redressed by increasing DA activity in the PFC. The increase in prefrontal blood flow after amphetamine also correlated significantly with improved performance on the WCST (36), indicating that increasing DA activity improves a cognitive deficit linked to diminished prefrontal cortical activity. Effect of DA Agonists on Negative Symptoms If negative symptoms were related to decreased function of the mesocortical DA system, one would expect treatment with DA agonists to improve negative symptoms of schizophrenia. Various studies have attempted to improve schizophrenic symptoms by increasing DA activity. Most have failed to find clinically meaningful effects (see ref. 38). However, recently the DA reuptake inhibitor, mazindole (2 mg/day), improved negative symptoms as compared to placebo (39). In that study,

mazindole or placebo were added to neuroleptic treatment after patients had been stabilized on neuroleptic for 4 weeks. However, well-controlled large studies are needed to explore the efficacy of increasing DA activity in the negative symptoms of schizophrenia, although the data reviewed here certainly encourage such an approach. Conclusion In summary, evidence suggests that the negative symptoms and some of the cognitive deficits of schizophrenia may be related to decreased PFC function which, in turn, based on indirect evidence, may be associated with decreased mesocortical DA activity. Evidence for Subcortical Hyperfunction Increased DA activity of the subcortical, striatal DA neurons has been the basis of the original DA hypothesis. Although unlikely to be the only, or even the main, dopaminergic abnormality in schizophrenia, some evidence does suggest that increased striatal or mesolimbic DA activity is related to some schizophrenic symptoms. Increased activity in those areas is suggested by anatomical and functional imaging studies and more indirectly by measurement of pHVA. Anatomical Imaging Studies Only very recently have imaging studies been able to focus on volumetric measurement of the subcortical structures with the availability of high-resolution MRI scanners with section thickness of 3 mm. Increased volume of the left caudate nucleus has been described in a study comparing 44 schizophrenic patients with 29 healthy controls (40). This effect may be medication-related, because it was not found in

neuroleptic-naive patients but, instead, appeared only after patients had been receiving neuroleptic treatment. Functional Imaging Studies In vivo measurement of D2 receptor affinity in humans, using PET, has provided conflicting results. An increase in D2 receptor numbers in striatum of 10 neuroleptic-naive schizophrenic patients has been reported, using [11C]methylspiperone as a D2 ligand (41). In contrast, D2 receptor density was not different in 15 (42) and 18 (43) similarly drug-naive schizophrenic patients as compared to normal controls when studied with [11C]raclopride. Similarly, when [76Br]bromospiperone was used to compare D2 receptor density in 12 schizophrenic patients (who were either drugnaive or at least 1 year drug-free) with 12 controls, no group differences in D2 receptor density were found (44). Interestingly, the more acutely ill patients had higher D2 receptor density in the striatum than did the more chronically ill patients and higher than the control subjects, suggesting that DA2 receptor density may be state-dependent. Part of these conflicting data may be due to the ligand used. For instance, methylspiperone, but not raclopride, binds potently to 5HT2 receptors. Moreover, the methods with which PET data were analyzed varied across studies. In addition, as the study using [76Br]bromospiperone suggests, differences in patient population may partly explain the different D2 receptor densities found in schizophrenic patients. Finally, the ligands used occupied different populations of DA receptors, and they may therefore point toward an increase in number in only the receptors occupied by methylspiperone but not raclopride. pHVA and the Mechanism of Action of Neuroleptics

The relationship between pHVA concentrations and neuroleptic treatment response suggests an association between the effects of neuroleptics on DA activity and treatment outcome (Table 1). Neuroleptics initially increase (45) and subsequently decrease pHVA concentrations (49!popup(ch113, 50, 51, 52, 53). Both the initial increase and the subsequent decrease by neuroleptics are associated with clinical response. Interestingly, increased pretreatment pHVA concentrations (49, 50, 52, 53), 54 but also see refs. 45) and 55) are predictive of good treatment response to neuroleptics. Conversely, clinical decompensation after discontinuation of neuroleptic is associated with increases in pHVA levels (56, 57, 58). Thus, pHVA studies suggest that neuroleptics initially increase and subsequently decrease DA activity. This is consistent with studies in rodents where, in the nigrostriatal (A9) and mesolimbic (A10) DA systems, a single dose of a neuroleptic increases DA neuron firing (59) while chronic (3–4 weeks) neuroleptic administration decreases DA neuron firing in A9 and A10 below pretreatment levels. Interestingly, atypical neuroleptics—that is, antipsychotics that do not induce extrapyramidal side effects, such as, for instance, clozapine— are anatomically more selective in their effect on DA neuronal firing than typical neuroleptics in that they decrease DA activity in A-10 only (59). On the basis of these data, it has been proposed that decreased activity in A9 is responsible for induction of extrapyramidal side effects, while in A10 it leads to the antipsychotic effects of neuroleptics (59). The effects of clozapine on pHVA are less clear-cut than those of typical neuroleptics. Clozapine treatment decreased pHVA concentrations with larger decrements associated with good treatment response (60). However, in another study the effect of clozapine on pHVA was less robust, although treatment responders tended to show a decrement in pHVA while nonresponders did not (57). A complicating factor in examining

clozapine's effect on pHVA concentrations is the fact that, unlike typical neuroleptics such as haloperidol (Davidson, unpublished results) and fluphenazine (60), it increases plasma norepinephrine (NE) concentrations. Because about one-third of NE is metabolized into HVA in the peripheral nervous system (24), the clozapine-induced increase in plasma NE (pNE), may partially overshadow a possible lowering effect of clozapine on pHVA. Consequently, measurement of pHVA as a reflection of clozapine's effect on (central) DA turnover may be compromised by its concomitant opposite effect on NE metabolism. Therefore, a relationship between symptom improvement on clozapine and its effects on pHVA could be obscured by this potent effect of clozapine on pNE. pHVA and Positive Symptoms Studies examining a relationship between steady-state pHVA and schizophrenic symptoms have been less consistent than studies examining the effect of neuroleptic treatment on pHVA (Table 3). Four studies have found a positive correlation between pHVA levels and clinical severity (27, 46, 61, 62), while three studies did not (47, 53, 63). The most likely explanation for the different results across studies is the number of pHVA samples taken as a basis for the correlational studies. The studies employing more than one sampling of pHVA found significant positive correlations between pHVA and severity of symptoms, whereas studies using one single measurement of pHVA did not. The studies producing significant correlations between pHVA and severity of schizophrenic symptoms averaged two (27), three (46), four (61), or thirteen (62) pHVA samples, whereas the studies that produced negative findings assessed pHVA only once (47, 53, 63). Repeated pHVA measurements in the same individual therefore appears to increase the signal/noise ratio for pHVA by reducing the intra-

individual variance in pHVA concentrations Schizophrenia and Glutamate). Postmortem Studies

(see

also

Although HVA and DA concentrations in postmortem brains of schizophrenic patients consistently show patient–control differences, the localization of these differences are not consistent. Increased HVA concentrations in schizophrenic patients have been found in caudate and nucleus accumbens (64) and cortex as compared to normal brains. The difference in caudate was attributable to prior medication history, while the finding in accumbens only applied in the medication-free patients. Similarly, although DA was found to be increased in nucleus accumbens in schizophrenic patients compared to controls (65), another study found increased DA in the caudate of schizophrenic patients, but not in nucleus accumbens (66). Finally, increased DA has been found in the amygdala of schizophrenic patients, mostly in the left hemisphere (67). These inconsistencies may be due to differences in medication status of the patients studied, varying analytical and statistical methods used, and, finally, genuine variability in the location of DA abnormalities in schizophrenia. Receptor affinity studies have found increases in D2, but not D1, receptors in the striatum of schizophrenics (68, 69, 70, 71, 72; see Table 4). Although these results could have been a result of prior medication use, most studies show that those patients who were neuroleptic-free for at least 1 year prior to study or were drug-naive still have increased striatal D2 receptors. Moreover, a bimodal distribution of D2 receptor numbers in brains of schizophrenic patients indicates that neuroleptics do not uniformly increase D2 receptor numbers (68). That neuroleptic treatment alone cannot explain the increased D2 receptor affinity in schizophrenia is also suggested by

postmortem studies in other patient groups treated with neuroleptics: Patients with Alzheimer's disease and Huntington's disease who had been treated with neuroleptics prior to death showed increases in striatal DA receptors of only 25% as compared to controls, whereas schizophrenics had greater than 100% increases (68). Thus, the available data indicate that D2 (but not D1) receptor density is increased in schizophrenia, and that this finding cannot be accounted for by medication history alone. D4 receptors have also been reported to be elevated in postmortem schizophrenic brain in subcortical regions (73). Because a selective D4 ligand was not used in this study, subtraction of two different ligands was used to infer the D4 receptor number. The differences found between schizophrenic and controls was quite robust, but awaits confirmation (see all Cytochrome P450 Enzymes and Psychopharmacology). Conclusion Increased striatal DA activity has not been demonstrated directly in schizophrenia. Postmortem and in vivo receptor binding studies provide some, but not consistent, evidence that striatal DA function is increased, while studies examining pHVA prior to and after neuroleptic treatment only provide an indirect suggestion that modulatory DA activity in schizophrenia can alter symptomatology. pHVA appears to be a useful indicator of central DA activity, and studies examining pHVA justify the following conclusions: (a) Increased DA turnover is related to good response to neuroleptic treatment, and (b) neuroleptic treatment decreases DA turnover, and this effect is related to treatment response. Temporal Lobe Function and Dopamine

An increasing number of MRI studies indicate abnormalities in the temporal lobes (more pronounced on the left side) in schizophrenic patients. Decreases of 10% in total temporal lobe volume (74) or 20% of temporal lobe gray matter have been found, present at first episode (75). Interestingly, the abnormalities of the temporal cortex in schizophrenia appears to be associated with specific positive symptoms, such as auditory hallucinations (76) and thought disorder (77). Additional, indirect evidence that the temporal lobes are associated with (positive) schizophrenic symptoms is the discovery that stimulation of the superior temporal gyrus (left and right) elicits auditory experiences (78) and that psychotic symptoms in temporal lobe epilepsy patients appear related to anatomical abnormalities in the medial temporal lobe (established at postmortem examination) (79). Although speculative, since increased D2 receptor binding has been found in the temporal cortex of brains of schizophrenic patients (80), the abnormalities found in the temporal cortices of schizophrenic patients and its association with some of the schizophrenic symptoms may be related to dysfunctional DA systems in those areas. These findings are particularly provocative in light of the fact that hippocampal lesions to rat pups produces subcortical hyperdopaminergia and an enhanced stress response at adulthood (81). Frontal Cortical DA Function and Negative Symptoms Negative Symptoms and Cortical Function The negative or deficit symptoms—that is, decreased social interaction, apathy and avolition—are considered to be core symptoms of schizophrenia. Indeed, Bleuler proposed that deficit state symptoms represent pathognomonic signs of schizophrenia and are at the root of the poor social and work function that characterize people with chronic schizophrenia.

Primate studies suggest that insufficient frontal cortical functioning is responsible for poor social skills: Monkeys with frontal lobe ablations not only have an inability to suppress irrelevant stimuli, poor concentration, and impaired delayed response testing, but also exhibit the poor social function that is reminiscent of deficit state symptoms which characterize schizophrenia (82). Only a handful of studies have directly attempted to link decreased activity of the PFC in schizophrenia with negative symptoms. Decreased activation of the PFC as measured by SPECT was only found in schizophrenic patients with predominantly negative symptoms (31). Furthermore, negative symptoms were associated with decreased frontal blood flow as assessed by PET (33). Although preliminary, these data do suggest a link between negative symptoms and impaired cortical function in schizophrenia. There are data indicating that frontal lobe dysfunction can be associated with psychotic symptoms. Evidence of frontal lobe damage leading to abnormal behaviors strikingly similar to some of the more persistent symptoms observed in schizophrenia can be found in anecdotal and case series describing (a) patients with frontal lobe injury and (b) primates with frontal lobe ablations (e.g., see ref. 83). Although there is great individual variation in the severity and constancy of the symptoms that emerge in patients even with severely damaged frontal lobes, some of these bear a remarkable resemblance to the deficit state symptoms in schizophrenia. For example, orbitofrontal and anteromedial lesions can produce flattened affect. That negative symptoms are associated with decreased DA function (in the mesocortical DA system) is suggested indirectly. pHVA concentrations levels were lower in chronic,

treatment refractory schizophrenic patients than in normal subjects (62). Treatment with the DA reuptake blocker, mazindole (35), or with the DA agonist, SKF393939 (84), appears to ameliorate negative symptoms in some schizophrenic patients. Although indirect, these data imply that decreased DA activity can modulate negative symptoms in schizophrenia. Negative Symptoms and Decreased Frontally Mediated Cognitive Function Schizophrenic patients perform poorly on cognitive tests that are thought to depend on activation of the PFC, such as the WCST (e.g., see ref. 32) and the "Tower of London" (31). Animal studies suggest that some of these cognitive deficits may be due to decreased mesocortical DA activity: (a) Surgical ablation of the PFC or selective destruction of mesocortical DA neurons in monkeys impaired performance of the spatial delayed-response task, a test thought to depend on activation of the frontal cortical areas in monkeys (85); (b) iontophoretically applied DA in area 46 [corresponding to the dorsolateral aspects of the PFC (DLPFC) in humans] improved performance in the delayed-response task in monkeys (86); and (c) administration of D1 antagonists dose-dependently produced deficits in performance during the delayed response task, while the selective D2 antagonist raclopride did not (86). Because the terminals of the mesocortical DA system consists of the D1 (and likely D5) receptor subtype (87), these findings suggest that the mesocortical DA system is important for memory and retrieval functions in high-order primates, and by inference in humans as well. These data are consistent with the notion that the decreased cognitive performance on frontally mediated tasks in schizophrenia may be the result of decreased activity of the mesocortical (D1/5) system. Indeed, single-dose administration of DA agonists, such as apomorphine and

amphetamine, ameliorate cognitive performance on frontally mediated tasks (36). Studies examining the effect of selective D1/5 agonists on cognitive function in schizophrenia have yet to be conducted. Andreasen et al. (31) and Wolkin et al. (33) demonstrated that these cognitive deficits occur predominantly in negativesymptom schizophrenics. By inference, the cognitive deficits and negative symptoms in schizophrenia may both be related to decreased mesocortical DA function. Therapeutic Implications DA1 Agonists: Increasing DA Function in Cortex? The persistent symptoms of schizophrenia appear to be the deficit state symptoms rather than the positive symptoms and appear to be related to decreased DA function in the cortex rather than being related to increased DA activity in the subcortical regions. Thus, it is not surprising that these symptoms are resistant to treatment with DA antagonists. Indeed, one would expect these symptoms to be amenable to treatment with DA agonists with cortical selectivity. Because mesocortical DA neurons are primarily of the D1 and D5 type, it can be hypothesized that selective D1 or D5 agonists would be particularly helpful for these symptoms. Moreover, consistent with the finding by Jaskiw et al. (88) that increasing prefrontal cortical DA activity reduces striatal DA activity, D1 or D5 agonists would be expected to decrease the hypothesized increased DA activity in subcortical DA neurons and thus be useful (in combination with traditional D2 antagonists) in the treatment of acute psychoses as well. Preliminary data from treatment of nonresponsive patients treated with mazindole or SKF39393 are consistent with this notion (39, 84).

To treat both positive and negative symptoms of schizophrenia, a balance between increasing DA activity at D1/5 receptors and decreasing it at D2, D3, or D4 receptors may be needed. Studies examining such combination treatments, using selective D1 agonists and D2, D3, or D4 antagonists, have yet to be conducted, but promise to be scientifically and possibly practically fruitful. 5HT2 and 5HT3 Antagonists: Roles in Regulating DA Function It would be overly simplistic to hypothesize that the pathophysiology of schizophrenia is only dopaminergic in nature. Several authors have suggested that it may be abnormalities in the interaction between monoaminergic systems in general and between serotonin (5HT) and DA systems in particular (38), rather than abnormalities in any one system, that is relevant to the pathophysiology of schizophrenia. Indeed, it is particularly difficult to discuss DA without mentioning its interactions with 5HT. Both neurotransmitter systems are highly intertwined, anatomically and functionally, with 5HT having an inhibitory modulation on DA function (89). Moreover, human studies consistently find high correlations in CSF between the DA and 5HT metabolites HVA and 5-hydroxyindolic acid (5HIAA), respectively (see ref. 90). This appears to be the result of a functional interaction, with 5HIAA "controlling" HVA (90), and is not due to a shared transport mechanism (91). Blockade of 5HT receptors diminishes extrapyramidal side effects induced by DA antagonists. Indeed, ritanserin, a selective 5HT1c/2 antagonist, significantly reduced extrapyramidal side effects when added to neuroleptic treatment in schizophrenic patients in several placebocontrolled, double-blind studies (92). Thus the addition of 5HT2 antagonism to DA2 receptor blockade may lead to

decreased extrapyramidal side-effect potential of DA receptor blockade. Although more speculative, it has also been suggested that blockade of 5HT2 (38) or 5HT1c (89) receptors mediates, in part, the superior clinical efficacy of clozapine. Another interesting relationship is the one between 5HT3 systems and DA function. For instance, 5HT3 antagonists fail to alter basal DA activity, but they reverse the increase in DA release that results from behavioral and biological stressors (93, 94). This may have important implications for the treatment of schizophrenia and schizophrenia spectrum disorders. If 5HT3 antagonists prevent stress-induced increases in DA activity, these drugs would be particularly useful in the prevention of relapse in schizophrenic patients and may also have a role in patients that are prone to display psychotic decompensations, such as borderline personality disorders. FUTURE DIRECTIONS The explosion in knowledge concerning DA in general, and its possible role in modulating the symptoms of schizophrenia in particular, offers rich ground for drug development and for further elucidating the biology of schizophrenia and its symptomatology. The following seem to be particularly exciting directions. 1. The development of drugs with selectivity for frontal cortical regions could be a viable approach to the treatment of the negative or deficit symptoms of schizophrenia. Dopamine D1 or D5 receptors would be most appropriate targets. 2. The development of specific D4 antagonists will be an important test of the centrality of this DA receptor subtype in

alleviating the positive symptoms of schizophrenia, and it will further our understanding of the relatively unique properties of clozapine. 3. The role of the corticostriatal glutamatergic pathway and its likely role in mediating the reciprocal relationship between cortical and subcortical dopaminergic activity needs to become a target for investigation both in antemortem and postmortem protocols. With the generation of new antibodies for the glutamatergic receptors, the latter may be a particularly worthwhile pursuit. 4. The importance of stress in precipitating subcortical hyperdopaminergia following lesions to the cortex has obvious implications for understanding the initiation of schizophrenic symptoms. Studies in schizophrenic patients that attempt to rigorously document stressful events in a longitudinal context, and correlate them with changes in dopaminergic parameters as well as with symptom fluctuation, would be particularly informative. 5. Some link must be sought between the morphometric abnormalities that have been found in postmortem examination of schizophrenic tissue and the bidirectionality of dopaminergic systems. With the inevitable conduct of the above investigations, real advances in testing the validity of current conceptualizations regarding DA and schizophrenia will finally be made. Schizophrenia is a major therapeutic challenge of modern medicine, and one of the last frontiers of brain research. The illness is defined by delusions, hallucinations, disorganized

behavior, and cognitive difficulties such as memory loss. It occurs in 1% of the world population and usually first appears in early adulthood. Although antipsychotic medications have dramatically improved the lives of patients with schizophrenia, the causes of the illness remain unknown. Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis. As originally put by Van Rossum in 1967 (ref. 1, p. 321), "When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could be part of the aetiology ... [emphasis added]." Indeed, this speculative sentence by Van Rossum foreshadows the title of the important work by Abi-Dargham et al. (2) in this issue of PNAS: "Increased baseline occupancy of D2 receptors by dopamine in schizophrenia." The discovery of the antipsychotic/dopamine receptor (3, 4), now commonly known as the dopamine D2 receptor, led to repeated confirmation that it is the primary site of action for all antipsychotics (3-5), including clozapine and quetiapine (6). All these drugs have different potencies at the receptor. The potency depends on the drug's dissociation constant at D2, which, in turn, relates to the rate of release of the drug from the D2 receptor. For example, the dopamine D2 receptor releases clozapine and quetiapine more rapidly than it does any of the other antipsychotic drugs (7, 8). Given the tight correlation between the clinical potency and the D2-blocking action of the antipsychotic medications, dopamine overactivity could be the common denominator in the psychotic element of schizophrenia. This possibility has been actively investigated. Dopamine overactivity can be presynaptic (an excess of dopamine release from dopamine

nerve terminals) or postsynaptic (an increase in the density of D2 receptors or an increase in postreceptor action). The innovative report by Abi-Dargham et al. (2) sheds light on both pre- and postsynaptic aspects by using an indirect method to measure the levels of endogenous dopamine in patients and controls. Although numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia (9), the majority of the postmortem tissues examined have come from patients who have been treated with antipsychotics, raising the probability that the drugs themselves contributed to the elevation of D2 receptors. To measure the density of D2 receptors in never-medicated patients with schizophrenia, D2-selective ligands have been used with in vivo brain imaging methods (10-12). The results have not been consistent. Data with [11C]methylspiperone show elevated D2 receptors in schizophrenia (ref. 10, but see also ref. 12), whereas data with [11C]raclopride do not show such elevation (ref. 11 and discussed later in this paper). One major reason for this discrepancy is the quantitatively different effects of endogenous dopamine on [11C]methylspiperone and [11C]raclopride (see references in ref. 7). Hence, one way to resolve this discrepancy is to measure D2 receptors after partial depletion of endogenous dopamine in patients. The work of Abi-Dargham et al. (2) provides this resolution. Fig. 1 summarizes the principle used by AbiDargham et al. Fig. 1 (Top) illustrates that the radiobenzamide (S)-()-3-[123I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2pyrrolidinyl)methyl]benzamide ([123I]IBZM) binds to the same number of D2 receptors in control and schizophrenia individuals. That is, the "binding potential" was the same in both sets of subjects. However, after partial depletion of endogenous dopamine by oral ingestion of -methylparatyrosine

over 2 days, the binding of [123I]IBZM rose by 19% in schizophrenia but only by 9% in control subjects (Fig. 1, Bottom). In fact, when Abi-Dargham et al. examined the number of D2 receptors after partially removing the obscuring effect of endogenous dopamine, the D2 receptors were significantly elevated in schizophrenia patients as compared with control subjects. When the authors examined the data by subgroups, the results of increased receptors reached significance for previously medicated patients, but exhibited only a trend for patients who had never been medicated with antipsychotic drugs. Despite this lack of statistical significance in this latter group of patients, the empirical findings of AbiDargham et al. indicate that an increase in dopamine D2 receptors must occur, because it is not possible for patients to show a greater increase yet not have a higher number of D2 receptors. Thus, the paper by Abi-Dargham et al. provides support for both an increase in the level of dopamine as well as an increase in the number of D2 receptors in schizophrenia, compared to control subjects. View larger version (45K): [in this window] [in a new window] Fig. 1. Method and findings of Abi-Dargham et al. (2) to reveal an increased occupancy of dopamine D2 receptors in schizophrenia. (Top) The number of dopamine D2 receptors, measured by the [123I]IBZM binding potential (green triangles with I), were the same in the brain striata of control and schizophrenia subjects. The levels of synaptic dopamine (pink triangles with D), which is higher in patients compared to control subjects, normally occupies most of the D2 receptors, masking the difference between control and schizophrenia individuals. (Bottom) After partial depletion of endogenous brain dopamine by oral ingestion of -methylparatyrosine over

2 days, the binding of [123I]IBZM rose in both the control and schizophrenia subjects, but that for the patients rose significantly higher.

Schizophrenia, as compared with control subjects, also is associated with an increased releasability of dopamine (13, 14). A high release rate of dopamine reduces the binding of radiobenzamides to tissues (15, 16), but enhances the binding of radiospiperone (17, 18). Competition with endogenous dopamine, as well as dopamine-induced internalization of the D2 receptors, may account for the lessened binding of radiobenzamides to the tissue (13, 14), because the benzamides are generally water-soluble and have less ready access to vesicle-associated receptors. Radiospiperone compounds, by contrast, are highly lipid-soluble and readily permeate cell membranes to reach internalized receptors. In addition to the two schizophrenia-associated factors of increased D2 receptors and increased dopamine release, there is a third factor. Dopamine D2 receptors exist in monomer, dimer, and oligomeric forms (19). The D2 monomer, but not the D2 dimer, is selectively labeled by a photolabel of radiospiperone (19). This finding is in contrast to a benzamide photolabel (for nemonapride), which readily binds to both monomers and dimers of D2 (19). This important distinction between benzamides and butyrophenones may explain why more D2 receptors are detected in schizophrenia (as compared to controls) by radiospiperone, even without depletion of endogenous dopamine. This finding is illustrated in Fig. 2, where the control individual has three D2 receptors, two in the dimer form and one in the monomer form. It is proposed that in schizophrenia, under the influence of increased release of endogenous dopamine, all three exist in the monomer form.

Thus, radioraclopride binding would show no difference, but the binding of radiospiperone would be higher in the schizophrenia brain (as compared to controls) because of an increased number of monomers. View larger version (56K): [in this window] [in a new window] Fig. 2. Possible model to account for the increased number of dopamine D2 receptors in schizophrenia seen with [11C]methylspiperone but not with [11C]raclopride. It is known that the photolabel of spiperone ([125I]azidophenethylspiperone) primarily or selectively labels monomers of D2 receptors, whereas the benzamide photolabel ([125I]azido-iodo-nemonapride) unselectively labels monomers, dimers, and oligomers of D2 receptors (see text). These findings suggest that even if there is no increase in the total population of D2 receptors in schizophrenia, an increase in the proportion of monomers caused by the increased level of dopamine in schizophrenia (see Fig. 1) would result in an increase in the binding of [11C]methylspiperone (red triangle with S) in schizophrenia but not with [11C]raclopride (white triangle with R).

The dopamine hypothesis has been much criticized. For instance, although therapeutic doses of most antipsychotics occupy 60% to 80% of the D2 receptors in patients, clozapine and quetiapine have been apparent exceptions, exhibiting clinical efficacy with only 10% to 45% occupation of D2 receptors (see references in ref. 7). It therefore has been suggested that the dopamine hypothesis of schizophrenia be extended into a serotonin-dopamine hypothesis. However,

recent work on imaging both D2 and serotonin-2 receptors in patients taking antipsychotics fails to find evidence for a contribution from the occupation of serotonin receptors (20). For example, the threshold for clinical antipsychotic action remains at 65% occupation of D2 receptors in first-episode patients, whether one uses haloperidol, which has no serotoninreceptor blocking action, or risperidone or olanzapine, which block all serotonin-2 receptors but at doses far below those needed for clinical efficacy. Similarly, the threshold for extrapyramidal signs, which is 80% D2 occupancy, remains unaltered despite the presence of 100% block of serotonin-2 receptors for risperidone or olanzapine. It should also be noted that therapeutic doses of clozapine and quetiapine transiently occupy high levels of D2 receptors in patients, but the effect lasts for only the first few hours (6). Thus, the D2-occupying properties of clozapine and quetiapine are remarkable only for their short duration of action; they otherwise support the dopamine hypothesis of schizophrenia, as originally outlined by Van Rossum (1). There is more to schizophrenia than psychosis. The psychological abnormalities and cognitive difficulties in schizophrenia precede and outlive the psychosis. The hypothesis of dopamine dysregulation is the best explanation for the psychotic episode in schizophrenia; the pathophysiology of other psychological and cognitive abnormalities in schizophrenia remains unclear. A combination of susceptibility genes (21) and other factors contributes to schizophrenia, and the net result dysregulates the dopamine neurotransmission system, leading to high release of dopamine, more D2 receptors, and an apparent predominance of monomer forms of D2. This dopamine dysregulation leads to the psychotic episode. Further research needs to uncover underlying mechanisms that predispose the brain to the dysregulation of the dopamine system (22). Until then, the dopamine hypothesis

remains the main path to the origin and treatment of clinical signs and symptoms of psychosis in schizophrenia. Schizophrenia First, let's discuss what schizophrenia is not. People who have schizophrenia do NOT have multiple personalities. In 1911, Eugen Bleuler, first used the word "schizophrenia." Although the word schizophrenia does come from the Greek words meaning "split" and "mind," people with schizophrenia do not have split personalities. This misunderstanding has caused many people to misuse the term schizophrenia. The "split mind" refers to the way that people with schizophrenia are split off from reality; they cannot tell what is real and what is not real. Contents of this Page Who has schizophrenia? Symptoms Causes Treatment References Who has schizophrenia? Schizophrenia is one of the most common mental illnesses. About 1 of every 100 people (1% of the population) is affected by schizophrenia. This disorder is found throughout the world and in all races and cultures. Schizophrenia affects men and women in equal numbers, although on average, men appear to develop schizophrenia earlier than women. Generally, men show the first signs of schizophrenia in their mid 20s and women show the first signs in their late 20s. Schizophrenia has a tremendous cost to society, estimated at $32.5 billion per year in the US (statistic from Brain Facts, Society for Neuroscience, 2002).

What are the symptoms of schizophrenia? The behavior of people with schizophrenia is often very strange and shocking. This change in behavior, when people cannot tell the difference between what is real and what is not, is called "psychosis" or a "psychotic episode." The American Psychiatric Association has published guidelines that are used to classify people with mental disorders. The most recent guidelines are contained in a book called the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (known as DSM-IV for short). The DSM-IV describes several symptoms that a person MUST have before he or she is classified as having schizophrenia. These symptoms include two or more of the following behaviors for a duration of at least one month: Delusions - bizarre, false beliefs These beliefs seem real to the person with schizophrenia, but they are not real. For example, a person may believe that aliens or spies are controlling his or her behavior, mind and thoughts. Sometimes these delusions can be paranoid in nature. People with paranoia have an unreal fear or suspicion that someone is "out to get them." Delusions may also be of grandiosity. In these cases, people believe that they are someone important, such as a president, king or prime minister. Hallucinations - bizarre, unreal perceptions of the environment These hallucinations can be: Auditory (hearing voices) - sometimes the "voices" tell a person to do something Visual (seeing lights, objects or faces) Olfactory (smelling things) Tactile (for example, feelings that bugs are crawling on or under the skin)

Disorganized Thinking/Speech Abnormal thoughts are usually measured by disorganized speech. People with schizophrenia speak very little; others have speech that is disjointed. Sometimes the person will change the topic midway through a sentence. Negative Symptoms - the absence of normal behavior Delusions, hallucinations and abnormal speech indicate the presence of abnormal behavior. Negative symptoms include social withdrawal, absence of emotion and expression, reduced energy, motivation and activity. Sometimes people with schizophrenia have poor hygiene and grooming habits. Catatonia - immobility and "waxy flexibility" Catatonia is a negative symptom where people become fixed in a single position for a long period of time. "Waxy flexibility" describes how a person's arms will remain frozen in a particular position if they are moved by someone else. When people show any of these five symptoms, they are considered to be in the "active phase" of the disorder. Often people with schizophrenia have milder symptoms before and after the active phase. There are three basic types of schizophrenia. All people who have schizophrenia have lost touch with reality. The three main types of schizophrenia are: Disorganized Schizophrenia (previously called "hebephrenic schizophrenia") - lack of emotion, disorganized speech Catatonic Schizophrenia - waxy flexibility, reduced movement, rigid posture, sometimes too much movement Paranoid Schizophrenia - strong delusions or hallucinations

What occurs in the brain? A common finding in the brains of people with schizophrenia is larger than normal lateral ventricles. The lateral ventricles are part of the ventricular system that contains cerebrospinal fluid. The picture below shows magnetic resonance image (MRI) brain scans of a pair of twins: one with schizophrenia, one without schizophrenia. Notice that the ventricles (red arrows) are larger in the twin with schizophrenia. (Image courtesy of NIMH Clinical Brain Disorders Branch.)

A reduced size of the hippocampus, increased size of the basal ganglia, and abnormalities in the prefrontal cortex are seen in some people with schizophrenia. However, these changes are not seen in all people with schizophrenia and they may occur in people without this disorder. What are the causes of schizophenia? There are probably multiple causes for schizophrenia and scientists do not know all of the factors that produce this mental disorder. Genetics Schizophrenia does "run in the family." In other words, schizophrenia has an important genetic component. Evidence for a genetic component comes from twin studies. Monozygotic twins (identical twins) are those with exactly the same genetic makeup; dizygotic twins (fraternal twins) are those who share only half of their genetic makeup. If genetics was the ONLY factor in developing schizophrenia, then both monozygotic twins should always develop this illness. Twin Studies

Twin studies have shown that the tendency for both monozygotic (identical) twins to develop schizophrenia is between 30-50%. The tendency for dizygotic (fraternal) twins to develop schizophrenia is about 15%. The tendency for siblings who are not twins (such as brothers of different ages) is also about 15%. Remember, schizophrenia is found in the general population at a rate of about 1%. Therefore, because the tendency for monozygotic twins is NOT 100%, genetics cannot be the only factor. However, because the tendency for monozygotic twins to have schizophrenia is much greater than the tendency for dizygotic twins, genetics DOES play a role. Adoption Studies Some studies have looked at the family background of people who were adopted at an early age and who later developed schizophrenia. One study (Kety et al., 1968) found that 13% of the biological relatives of the adoptees with schizophrenia also had schizophrenia, but only 2% of the relatives of "normal" adoptees had schizophrenia. These studies support the role of genetics in schizophrenia. To learn more about the role of genetics in schizophrenia, see the Genetics and Mental Disorders page at the National Institute of Mental Health. Environment Nongenetic factors that may influence the development of schizophrenia include: family stress, poor social interactions, infections or viruses at an early age, or trauma at an early age. Somehow the genetic makeup of individuals combines with nongenetic (environmental) factors to cause schizophrenia. Neurotransmitters Many studies have investigated the possible role of brain neurotransmitters in the development of schizophrenia. Most

of these studies have focused on the neurotransmitter called dopamine. The "dopamine theory of schizophrenia" states that schizophrenia is caused by an overactive dopamine system in the brain. There is strong evidence that supports the dopamine theory, but there are also some data that do not support it: Evidence FOR the Dopamine Theory of Schizophrenia: Drugs that block dopamine reduce schizophrenic symptoms. Drugs that block dopamine have side effects similar to Parkinson's disease. Parkinson's disease is caused by a lack of dopamine in a parts of the brain called the basal ganglia. The best drugs to treat schizophrenia resemble dopamine and completely block dopamine receptors. High doses of amphetamines cause schizophrenic-like symptoms in a disorder called "amphetamine psychosis." Amphetamine psychosis is a model for schizophrenia because drugs that block amphetamine psychosis also reduce schizophrenic symptoms. Amphetamines also make the symptoms of schizophrenia worse. Children at risk for schizophrenia may have brain wave patterns similar to adults with schizophrenia. These abnormal brain wave patterns in children can be reduced by drugs that block dopamine receptors. Evidence AGAINST the Dopamine Theory of Schizophrenia: Amphetamines do more than increase dopamine levels. They also alter other neurotransmitter levels. Drugs that block dopamine receptors act on receptors quickly. However, these drugs sometimes take many days to change the behavior of people with schizophrenia. The effects of dopamine blockers may be indirect. These drugs may influence other systems that have more impact on the schizophrenic symptoms.

New drugs for schizophrenia, for example, clozapine, block receptors for both serotonin and dopamine. Treatment of Schizophrenia Medication Drugs to treat schizophrenia are called antipsychotic medications. This type of drug was first developed in the 1950s. They have proved to be highly successful in treating the symptoms of schizophrenia. The different types of antipsychotics work best on different symptoms of the disorders and are not addictive. The drugs are not a cure for the disease, but they do reduce the symptoms. Antipsychotic Drugs Generic Name Trade Name Comments Aripiprazole Abilify New antipsychotic medication that may work on dopamine and serotonin systems. Chlorpromazine Thorazine The first antipsychotic medication developed Chlorprothixene Taractan Clozapine Clozaril Does not have "tardive dyskinesia" (see below, side effects) as a side effect, but there is a 1-2% chance of developing a low white blood cell count Fluphenazine Prolixin A phenothiazine type drug Haloperidol Haldol Loxapine Loxantane NOT a phenothiazine type drug Mesoridazine Serentil Molindone Moban Olanzapine Zyprexa Blocks serotonin and dopamine receptors Perphenazine Trilafon Quetiapine Seroquel Blocks some serotonin and dopamine receptors; Introduced in 1997 Risperidone Risperdal Blocks some serotonin and dopamine receptors

Thioridazine Mellaril Also used as a tranquilizer Thiothixene Navane Trifluoperazine Stelazine Also used to control anxiety and nausea Possible Side Effects of Antipsychotic Drugs Parkinson's disease-like symptoms - tremor, muscle rigidity, loss of facial expression Dystonia - contraction of muscles Restlessness Tardive dyskinesia - involuntary, abnormal movements of the face, mouth, and/or body. This includes lip smacking and chewing movements. About 25-40% of patients who take antipsychotic mediations for several years develop these side effects. Weight gain Skin problems Counseling Antipsychotic medications often do not reduce all of the symptoms of schizophrenia. Also, because people with schizophrenia may have become ill during the time when they should have developed technical skills and a career, they may not have the ability to become useful members of society. Therefore, psychological therapy, family therapy and occupational training may be used along with antipsychotic medication to help these people get back into the community.

ScienceDaily (Apr. 25, 2007) — New research helps bridge an important gap in understanding schizophrenia, providing the best evidence to date that defects in the brain's white matter are a key contributor to the disease, which affects about 1 percent of people worldwide. The findings, to be published online by the Proceedings of the National Academy of Sciences during the week of April 23, also demonstrate how two of the dozen or more genes previously linked with schizophrenia may contribute to the disease. Prior genetic studies had linked schizophrenia to the genes for neuregulin 1 (NRG1), a growth factor involved in brain development, and erbB4, a receptor on brain cells through which NRG1 exerts its action. But until now it hadn't been shown that alterations in these genes lead to psychiatric disorders. Working in a mouse model, researchers led by Gabriel Corfas, PhD, Kristine Roy, PhD, and Joshua Murtie, PhD, in the Children's Hospital Boston Neurobiology Program now demonstrate, for the first time, that alterations in NRG1erbB signaling induce pathologic changes in the brain's white matter. They further show that these changes lead to alterations in biochemical signaling and to behaviors suggestive of mental illness.

"We show that causing a defect in white matter is sufficient to cause biochemical and behavioral changes resembling those seen in neuropsychiatric disorders," says Corfas, the study's senior author. "I think this will provide a new way of thinking about the causes of, and possibly, therapies for schizophrenia." The findings could also have implications for bipolar disorder, which has also been linked with NRG1 and also involves white matter defects, he adds. Working with mice, the researchers blocked NRG1-erbB signaling in oligodendrocytes --the cells that form the fatty sheath, known as myelin, which insulates nerve fibers. These myelinated nerve fibers make up the brain's white matter. When NRG1-erbB signaling was blocked, the mice had more oligodendrocytes than normal mice, but these cells had fewer branches and formed a significantly thinner myelin sheath around nerve fibers. As a result, the nerve fibers conducted electrical impulses more slowly, the researchers found. The mice also had changes in the nerve cells that make and use dopamine, a key chemical in the brain that transmits messages from one nerve cell to another. The dopamine system has long been known to be altered in schizophrenia, and is the target of many antipsychotic drugs. "Changing the white matter in the brain apparently unbalanced the dopamine system, something that also occurs in patients with neuropsychiatric disorders," says Corfas. Finally, mice whose NRG1-erbB signaling was blocked showed behavioral changes that appeared to be consistent with mental illness. They explored their environment less than normal mice and had reduced social interaction, thought to be a

manifestation of so-called "negative" schizophrenic symptoms such as decreased initiative and social withdrawal. The mice also showed behaviors suggestive of anxiety, a symptom seen in patients with schizophrenia and bipolar disorder, and increased sensitivity to amphetamine, also seen in many schizophrenia patients. Is it possible to modify NRB1-erbB signaling with drugs, or otherwise protect oligodendrocytes (and white matter) as a way of treating or preventing schizophrenia? "This is something that should be investigated," says Corfas. "People are thinking about ways to repair white matter as a treatment for multiple sclerosis, which is also a disease of white matter. That research could now be used in thinking about neuropsychiatric disorders." Schizophrenia is typically diagnosed in late adolescence or early adulthood, but it is almost always preceded by subtle affective, cognitive or motor problems, Corfas adds. "We need to investigate whether the white-matter defects emerge early, before psychotic symptoms are evident," he says. "If they do, that raises the possibility of early diagnosis and preventive treatment." The idea of schizophrenia arising from white-matter defects may also help explain the timing of its emergence, Corfas notes. Recent evidence suggests that myelination of the prefrontal cortex (a brain area that has been implicated in schizophrenia) occurs not only during infancy and toddlerhood, but also during late adolescence or early adulthood -- just when schizophrenia strikes. "We now need to go back to patients with schizophrenia and see whether those with variants of the NRG1 and erbB4 genes

have differences in their white matter," Corfas says. "It may be that there are different kinds of schizophrenia, arising from alterations in different genes, and that directed treatments could be developed for the different forms." Corfas and colleagues also plan to investigate other genes linked with schizophrenia, studying whether they interact with NRG1-erbB signaling and how they may alter brain function. The research was funded by the National Institute of Neurological Disorders and Stroke (NINDS), the National Multiple Sclerosis Society, the National Institute of Mental Health (NIMH), NARSAD: The Mental Health Research Association, and an NIH Development Disability Research Center Grant. Adapted from materials provided by Children's Hospital Boston, via EurekAlert!, a service of AAAS. Need to cite this story in your essay, paper, or report? Use one of the following formats: APA MLA Children's Hospital Boston (2007, April 25). Understanding Schizophrenia: How Genetics, White-matter Defects, Dopamine Abnormalities And Disease Symptoms Are Associated. ScienceDaily. Retrieved February 9, 2008, from http://www.sciencedaily.com/releases/2007/04/070423185615.ht m When NRG1-erbB signaling was blocked, oligodendrocytes from the brain's frontal cortex had a less complex structure than normal, forming fewer branches. Shown are threedimensional reconstructions of oligodendrocytes from a normal

mouse (left) and a mutant mouse (right). (Credit: Image courtesy Joshua Murtie, Ph.D., Children's Hospital Boston.) Ads by Google Advertise here Parkinson's Disease Parkinson's Disease: Everything You Need To Know In One Place. www.AllAboutParkinsons.com Schizophrenia Top Results For Schizoprenias. aboutschizophrenias.com Discuss Schizophrenia Join the Mental Health Forum Discussions taking place now! www.mentalhealthforum.net I Cured My Gum Disease Stop Gum Disease in its Tracks with this Powerful All Natural Solution www.gumdisease-treatment.com Liver Health Visit The NHS Hepatitis C Site For Liver Health Information www.hepc.nhs.uk Related Stories Research On Nerve Cell Circuitry Reveals Clue About Schizophrenia (Nov. 8, 2004) — Animal research at Wake Forest University Baptist Medical Center has found how one of the genes linked to schizophrenia might function to cause the disease. The work was reported today at the annual ... > read more Pivotal Brain Processor Decreased In Schizophrenia; Lower Levels Could Explain Disruption In Mental Function (Aug. 15, 2002) — Levels of a pivotal signal processor in the brain are reduced significantly in people with schizophrenia, a study by scientists at UC Irvine, Weill Cornell Medical College and Rockefeller University ... > read more

Changes In Brain Density Can Help Predict Schizophrenia (Dec. 11, 2006) — Changes in brain density could be used to predict whether an individual who is at risk for schizophrenia is likely to develop the condition or not. A study published today in the open access journal ... > read more First Mouse Model Of Schizophrenia Developed (Jul. 31, 2007) — Researchers have genetically engineered the first mouse that models both the anatomical and behavioral defects of schizophrenia, a complex and debilitating brain disorder that affects over 2 million ... > read more Innovative, Multicenter Study Of Schizophrenia Will Follow Disease Traits In Hunt For Genetic Causes (Jun. 3, 2003) — Specific information processing abnormalities and brainrelated circuit dysfunction in schizophrenia patients may be the keys to finding the genetic basis of this puzzling, devastating mental illness ... > read more U Of T Researcher Links Schizophrenia, Gene Mutations (Feb. 21, 2005) — The supersensitivity to dopamine that is characteristic of schizophrenia can be caused by mutations to a wide variety of genes, rather than alterations to just two or three specific genes, says a ... > read more Abnormalities Of The Mouth Associated With Schizophrenia (Mar. 14, 2007) — Recent research quantifies, for the first time, how schizophrenia is apparently associated with a broader hard palate and abnormalities in the teeth. This knowledge may lead to improved early ... > read more New Dopamine Brain Target Discovered; Potential Breakthrough For Schizophrenia Treatment (Jan. 23, 2007) — A team of Canadian researchers, lead by Dr. Susan George and Dr. Brian O'Dowd at the Center for Addiction and Mental health, discovered a Gq/11-coupled signalling unit that triggers a calcium signal. ... > read more

Progress in Dopamine Research in Schizophrenia: A Guide for Physicians Edited by Arvid Carlsson, M.D., Ph.D., and Yves Lecrubier, M.D., Ph.D. Abingdon, Oxfordshire, U.K., Taylor & Francis Group, 2004, 128 pp., $29.95 (paper). RAJIV TANDON, M.D. Tallahassee, Fla. For the past half-century, the dopamine hypothesis has dominated thinking about the neuropharmacological underpinnings of schizophrenia and antipsychotic action. Despite the absence of any definitive evidence of specific dopaminergic abnormalities in schizophrenia and only indirect support for a specific role of dopamine antagonism in its treatment, discussions about the pathophysiology and treatment of schizophrenia continue to focus on dopamine. There is, in fact, no single dopamine hypothesis of schizophrenia and antipsychotic action. Ideas about the

pathophysiology of schizophrenia have evolved from too much dopamine somewhere in the brain (1960s–1970s) to increased activity at the D2 dopamine receptor (1970s–1980s) to the current concepts of too much dopamine somewhere (the "emotional" mesolimbic circuit) and too little dopamine elsewhere (the "thinking" mesocortical circuit), or too much dopamine sometime (stimulated "phasic" increase) and too little dopamine most of the time (tonic deficiency). In the context of an abundance of often confusing findings from numerous areas of research, what is the current state of our understanding of the role of dopamine in the pathophysiology and treatment of schizophrenia? This superbly edited pocketbook clearly describes the current status of dopamine research in schizophrenia and antipsychotic action. The relationship of cognitive dysfunction in schizophrenia to dopamine susceptibility genes and prefrontal dopamine signaling is described in the light of recent findings, and information about the role of genetic variation in predicting individual antipsychotic treatment response is considered. The role of dopamine in different brain circuits is summarized in the context of interactions with other neurotransmitters (particularly glutamate and serotonin) and the functions that these circuits subserve. The specific role of dopaminergic neurotransmission in normal information processing, reward-reinforcement, and attribution of salience is described. How observed dopaminergic abnormalities in schizophrenia can explain its complex psychopathology is then considered: pathologically increased stimulated phasic dopamine activity can explain the positive symptoms of schizophrenia (paranoia, delusions, and hallucinations), and decreased tonic dopamine activity can explain negative and cognitive symptoms of the illness along with the greater occurrence of substance abuse. The first half of this handbook succinctly connects current research about the role of

dopaminergic abnormalities in the etiology and pathophysiology of schizophrenia to the psychopathology of the illness in a logical and coherent manner. The second half of the book elucidates current thinking about how specific antidopaminergic actions of medications are relevant to their antipsychotic effects and what pharmacological attributes might explain differences between typical and atypical antipsychotics with regard to their spectrum of efficacy in the treatment of schizophrenia and their propensity to cause neurological and endocrine adverse effects. There is a detailed consideration of amisulpride, which is described as a "distinctive atypical antipsychotic agent because of its uniquely high selectivity for dopamine receptors." This chapter should be of particular interest to American readers who are unfamiliar with amisulpride because of its lack of availability. The final chapter considers current challenges in the treatment of schizophrenia and possible future strategies to meet these challenges. I highly recommend this 100-page pocketbook to anyone with an interest in understanding the current state of dopamine research in schizophrenia and antipsychotic action without wading through volumes. Adapted and abridged from the proceedings of a recent symposium in which many international experts in dopamine research in schizophrenia participated, this concise handbook contains simple yet nonbanal explanations of complex topics and combines brevity with relatively comprehensive coverage of an important topic in an easy-to-read format.

Schizophrenia

Aetiology As schizophrenia is a complex brain disorder, it likely results from the interplay of genetic, behavioural, developmental and other factors. The exact cause of this group of illnesses is not known but stress, trauma and viral infection at an early age are factors thought to be involved. Schizophrenia can run in families and it is likely that the disease has a genetic component – if one twin of an identical pair has schizophrenia, there is a 46% chance that the other twin will also suffer from a schizophrenic disorder. It is not known how many genes are involved or how the genetic predisposition is transmitted. In addition, recent evidence suggests that schizophrenia may result when neurons in the brain form inappropriate connections during foetal development. It may be that an intrauterine starvation or infection causes such inappropriate connections to form and these may lie dormant until puberty when substantial neuron reorganisation occurs in the brain. Identification of specific genes involved in the development of schizophrenia will provide important clues as to what goes wrong in the brains of people with the disease and this will guide the development of improved treatments. Stress imposed by life events or family circumstances appears to be an important external event associated with schizophrenia. The onset of illness is often associated with a distressful period in life and it may be that stress can trigger the onset of illness in those people with a genetic predisposition to the disease. An imbalance in the concentrations of dopaminergic and glutamatergic systems in the brain is also thought to play a role

in the development of schizophrenia. The dopamine hypothesis states that the behavioural patterns typical of schizophrenia are a result of overactivity of dopamine in certain regions of the brain. Serotonin is also important in schizophrenia and it may be that the serotonin system interacts with the dopamine system to modify the way in which it operates. The serotonin receptors which are important in the treatment of schizophrenia are 5-HT1, 5-HT2 and 5-HT3. What Happens in the Brain? The areas of the brain implicated in schizophrenia are the forebrain , hindbrain and limbic system . It is thought that schizophrenia may be caused by a disruption in some of the functional circuits in the brain, rather than a single abnormality in one part of the brain. Although the brain areas involved in this circuit have not been defined, the frontal lobe, temporal lobe, limbic system,(specifically the cingulate gyrus , the amygdala and the hippocampus ) and the thalamus are thought to be involved. The cerebellum , which forms part of the hindbrain, also appears to be affected in people with schizophrenia. neurotransmitters are implicated in the development of schizophrenia. The dopamine hypothesis of schizophrenia postulates that schizophrenia is caused by an overactive dopamine system in the brain; excessive dopamine and reduced striatal activity can disrupt all aspects of motor, cognitive and emotional functioning and can result in an acute schizophrenic psychosis. An excessive dopamine concentration in the brain of people with a schizophrenic disorder was originally thought to be associated with increased activity of the D2 class of dopamine receptors in the prefrontal cortex . Recent studies indicate that reduced numbers of the D1 class of

dopamine receptors may contribute to the rise in dopamine concentration. Other neurotransmitters, including serotonin, glutamate, gamma aminobutyric acid and acetylcholine may also be involved in the pathogenesis of schizophrenia. It may be that due to the careful orchestration between neurotransmitter systems, an imbalance in one neurotransmitter affects others which are not causally involved in the pathogenesis of disease. Several structural changes are found in the brains of people with schizophrenia, most of which occur in the forebrain. Reductions in the volume of grey matter in the frontal lobe, and decreased brain volume and activity, have been repeatedly noted among people with a schizophrenic disorder. The ventricles are commonly found to be larger than normal, as are the basal nuclei , while the hippocampus and amygdala are often smaller. The disease is also associated with alterations in blood flow to certain areas of the brain.

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