Coping With Schizophrenia and Psychosis

Coping With Psychosis And Schizophrenia Package

In the first part, you will learn about psychosis and schizophrenia, and how to identify different types of disorders, what the triggers for these disorders are, how to give first aid to someone going through a psychotic episode, what the hospitalization procedures are, and the disabilities that result from various psychotic disorders. The second part is devoted to coping with psychosis, schizophrenia, and its negative symptoms, with an emphasis on embarking on a new path. What post-psychotic depression is, and how to cope with it. What treatment options are available for someone who has experienced psychosis or for a consumer with schizophrenia. How to avoid future psychotic episodes. The layout approach, which refers to what is needed to successfully cope with psychosis. The family as a central support system in the life of the consumer. The place of the spouse in coping with psychosis and, for those who do not have a spouse, how to meet a new partner. Employment as a central factor in coping with psychosis and freeing oneself from feeling trapped, so as not to be dependent on other people. We focus on consumers getting a comfortable job, working on the Internet from home. What stigma is and how consumers and their families can cope with it. Finally, standing up for yourself as part of restoring your lost self-respect.

Coping With Psychosis And Schizophrenia Package Overview

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Evidence for the Activation of Cellular Immunity in Schizophrenia

In schizophrenia, there is evidence that the innate immune system is activated. Thus, the number of monocytes and some of the cytotoxic cells are increased 12 . In addition, the proportion of monocytes and macrophages in the CSF of patients with acute schizophrenia are increased, suggesting that immune activation occurs in the brain as well as in the periphery 13 . Of the pro-inflammatory cytokines that are raised in the CSF, interleukin 6 (IL-6) has been reported to be increased by a number of investigators 14 . IL-6 activates B cells, in addition to playing a key role in the inflammatory cytokine cascade, and therefore contributes to many of the immune changes seen in schizophrenia. If IL-6 plays a role in the psychopathology of schizophrenia, to what extent do changes in this cytokine reflect the clinical status of the patient It is clear that IL-6 is raised in the plasma of schizophrenic patients 15, 16 and that elevated plasma concentrations of this cytokine are related to both...

On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

Obesity is also linked to cardiovascular disease, both conditions occurring frequently in patients with schizophrenia. This is due to the impact of nutrient excess on the vascular endothelial cells. A major function of these cells is to activate nitric oxide synthase to produce the potent, but short-lived, vasodilator nitric oxide. The insulin receptor system-phosphoinositol-3-kinase pathway is a major factor in the control of nitric oxide synthesis in most tissues so that nutrient excess that reduces the activity of this pathway rapidly leads to a reduction in nitric oxide synthesis. Thus, the decrease in nitric oxide, combined with the accumulation of fat in the coronary circulation as a consequence of increased fat synthesis, provides a link between cardiovascular disease, diabetes obesity and inflammation 40 . While it is unlikely that the inhibition of the insulin-sensitive pathway by inflammatory mediators is the only factor of importance, it does emphasize the value of the...

Pharmacotherapy Of Psychosis And Mania I Drugs Used In The Treatment Of Psychoses

The psychotic disorders include schizophrenia, the manic phase of bipolar (manic-depressive) illness, acute idiopathic psychotic illnesses, and other conditions marked by severe agitation. All exhibit major disturbances in reasoning, often with delusions and hallucinations. Several classes of drugs are effective for symptomatic treatment. Antipsychotic agents also are useful alternatives to electroconvulsive therapy (ECT) in severe depression with psychotic features, and sometimes are used in the management of patients with psychotic disorders associated with delirium or dementia or induced by other agents (e.g., stimulants or L-DOPA). The psychoses are among the most severe psychiatric disorders, in which there is not only marked impairment of behavior but also a serious inability to think coherently, to comprehend reality, or to gain insight into the presence of these abnormalities. These common disorders (affecting perhaps 1 of the population at some age) typically include symptoms...

The Dopamine Hypothesis of Schizophrenia and Dopamine Receptors in the Human Brain

As already noted, the paper by Carlsson and Lindqvist 30 is often mistakenly cited as the origin of the dopamine hypothesis of schizophrenia. However, the dopamine hypothesis of schizophrenia was first outlined in 1967 by Van Rossum 33 (see 34 ) as follows fargoing consequences for the pathophysiology of schizophrenia. Over-stimulation of dopamine receptors could then be part of the etiology. With the discovery of the antipsychotic dopamine receptor in vitro, it became possible to measure the densities and properties of these receptors directly not only in animal brain tissues but also in the postmortem human brain and, at a later time, in living humans by means of positron emission tomography. Many, but not all, of these findings directly or indirectly support the dopamine hypothesis of schizophrenia.

Prevalence of Glucose Abnormalities in Schizophrenia

It has been established for over 100 years that glucose abnormalities are more frequent in mentally ill subjects 6 and without doubt predate the emergence of antip-sychotic treatments. The precise prevalence and incidence rates are only starting to be described and are in part dependent on the cohort evaluated and the year of study. Screening for glucose abnormalities has increased since 2000 and data prior to then are less complicated in their interpretation. A lifetime DM prevalence of 15 was reported from the Schizophrenia Patient Outcomes Research Team (PORT) in the USA in data collected dirung the mid-1990s prior to atypicals 7 . The data were stringently collected with subjects being paid for their time spent in interview. In 2002, a prevalence rate of 18 in an outpatient cohort was noteworthy for the clear findings that the prevalence increased with age, as in the general population, with the highest prevalence of > 25 in the 60- to 69-year cohort 8 . In some cohort studies,...

Is D2High the Unifying Mechanism for Schizophrenia

Throughout the years between 1963 and the present, the overall strategy has been to identify the main target of antipsychotic medications and then to determine whether these antipsychotic targets are overactive in schizophrenia or in animal models of psychosis. Has this strategy worked The answer is yes. First, the primary target for antipsychotics, the dopamine D2 receptor, has been identified, and, second, many avenues indicate that D2High (the high-affinity state of the D2 receptor) may be the unifying mechanism for schizophrenia. In particular, the following facts on dopamine receptors validate the 45-year search for a basic unifying mechanism for schizophrenia 2. The brain imaging by Hirvonen et al. 66 shows that the D2 density is elevated in healthy identical co-twins of patients who have schizophrenia. This finding suggests that the elevation of D2 receptors is necessary for psychosis. At the same time, however, the findings of Hirvonen et al. also illustrate that in addition...

Schizophrenia Alleviating the Cognitive Deficit and Regulating Sensorimotor Gating Through a2 and a3 Gabaa Receptors

A large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, i.e., abnormal functional integration of brain processes. This dysconnectivity could arise from aberrant wiring of connections during development or from aberrant synaptic plasticity. Among the various clinical symptoms of the disease, the cognitive deficits are associated with a deficit in EEG g band

Why Are Low Doses of Clozapine or Remoxipride Effective in Treating lDOPA Psychosis

The psychosis caused by l-DOPA or bromocriptine in Parkinson's Disease can be readily treated by low doses of either clozapine68-72 or remoxipride.73 The average dose for clozapine is 55 mg day, while that for remoxipride is 150 mg day, much lower than that used in schizophrenia for either drug (Figure 1). These lower doses follow directly from the well-known fact that 90 to 99 of brain dopamine has been depleted in Parkinson's disease. Hence, there is virtually no endogenous dopamine to compete against clozapine or remoxipride. The low dose of clozapine corresponds to a low spinal fluid concentration of clozapine and norclozapine, estimated to be of the order of 60 nM (given that the unbound clozapine is 20 of the total plasma clozapine11). Under these conditions, the fraction of D2 receptors occupied would be about 60 .* This D2 occupancy by clozapine may be even lower, possibly 20 , if the estimated free concentration of clozapine in plasma ( 10 nM) is used from four Parkinson...

Using Pharmacology of Disrupted and Persistent LI to Model Domains of Pathology in Schizophrenia

Disrupted and persistent LI can be seen as two poles of dysfunctional attentional control, namely, a failure to inhibit attention to irrelevant stimuli and a failure to re-deploy attention when previously irrelevant stimuli become relevant. The former would likely give rise to the aberrantly increased salience perception and distracti-bility that are associated with psychotic symptoms, whereas the latter would result in the cognitive inflexibility and impaired attentional shifting that are associated with negative cognitive symptoms. Indeed, both disrupted and excessively strong LI are found in schizophrenia patients, the former associated with acute psychosis and the latter associated with predominance of negative symptoms. Based on their distinct pharmacological profiles, LI abnormalities produced by amphetamine, haloperidol, NMDA antagonists, and scopolamine have been suggested to represent four domains of pathology in schizophrenia (Table 2). Amphetamine- and scopolamine-induced...

The 5HT2C Receptor in Schizophrenia and Its Relation to Other 5HT Receptors and 5HT Mechanism

The serotonin-2C (5-HT2C) receptor is one of several of the 14 distinct 5-HT receptors that has been implicated in schizophrenia as a target for antipsychotic drugs to diminish psychosis, to diminish side effects of some antipsychotic drugs (e.g., catalepsy), or to improve cognition, a major need in the treatment of schizophrenia. The 5-HT2C receptor has also been of interest as the basis for adverse side effects of antipsychotic drugs, particularly weight gain (Kroeze et al. 2003). While this is an impressive array of potential relevance to schizophrenia, it pales in comparison with that for the 5-HT2A receptor, i.e., the 5-HT receptor that has received the most attention of any 5-HT receptor in this regard (Meltzer and Huang 2008). There is considerable evidence that 5-HT1A and 5-HT7 receptors are also important for schizophrenia, especially for cognition, or that they modulate antipsychotic drug action (Meltzer and Huang 2008). To a lesser extent, the 5-HT3, 5-HT4, 5-HT5, and 5-HT6...

Overlap Between Schizophrenia and Bipolar Disorder

Schizophrenia is best thought of as a syndrome rather than a discrete disease. Its boundaries with a number of other psychiatric disorders are not clearly delineated, and there is no pathognomonic symptom or biomarker that defines it. It is characterized by a variety of disturbances in reality testing, cognition, affect, volition, and mood, which vary in intensity from one patient to another and over time, with or without treatment. It is usually first diagnosed in the middle of the second to the middle of the third decade of life, earlier in males than females, but may appear even earlier or later in some individuals. It is highly heritable although not entirely so, with environmental factors contributing to onset and modifying its course. These factors are broadly conceptualized as stress, with maternal influenza in the second trimester and secular famine contributing as well. Strikingly, only half of monozygotic twins are concordant for schizophrenia. Multiple genes of small...

The Dopamine Hypothesis Of Schizophrenia

The dopamine hypothesis of schizophrenia is supported by several observations. First, the D2 receptor is the common target of antipsychotic drugs (Figures 1 and 2). Second, additional support for the dopamine hypothesis comes from the finding that the density of dopamine D2 receptors is elevated in postmortem schizophrenia tissues75 as well as in schizophrenia patients, as measured by 11C methylspiperone,76,77 but not by 11C raclopride.78 Hence, if the two benzamides (nemonapride and raclopride) have similar properties, the findings of Wong et al.76,83 may suggest that the D2 monomers (labeled by 11C methylspiperone) are elevated in schizophrenia, but that the total population of monomers and dimers of D2 (labeled by 11C raclopride) are the same as in control subjects (Figure 10). The elevation of D2 monomers in schizophrenia75,76 may arise from the fact that the dopamine in the synaptic space in postmortem schizophrenia tissues is virtually absent,75 as indicated by the lack of...

The Role of DA and 5HT in Psychosis

The discovery of chlorpromazine, the first antipsychotic drug, in 1952, and, shortly thereafter, the central role of dopamine (DA) receptor blockade in its action and the role of DA in the etiology of delusions following chronic amphetamine administration led to neglect of the critical importance of cognitive dysfunction for schizophrenia, a serious error, which has been corrected over the last 20 years. Since delusions and hallucination both responded well to chlorpromazine, and amphetamine is known to enhance synaptic DA levels, the etiology of these two symptoms was linked to enhanced dopaminergic function (Angrist and Gershon 1974). We have reviewed the history of the development of the theory of the role of 5-HT in the etiology of schizophrenia elsewhere (Meltzer et al. 2003). The pivotal discovery that lysergic acid diethylamide (LSD) ingestion produces visual hallucinations, followed by the findings of similar effects of mescaline and 4-iodo-2,5-dimethoxyamphetamine (DOI), all...

HT2C Receptor and Dopamine Function in Schizophrenia

Abnormalities in dopaminergic function in the limbic regions (nucleus accumbens and the extended amygdala), frontal cortex, cingulate cortex, and hippocampus have been considered important causes of psychosis (limbic) and cognitive dysfunction (cortical-hippocampal) in patients with schizophrenia. The data supporting the role of DA in these components of the illness suggest enhanced dopaminergic activity in the limbic region as the basis for psychosis and hypodopaminergic function in the cortico-hip-pocampal regions as the basis for cognitive impairment and negative symptoms. As psychosis, negative symptoms, and cognitive impairment in schizophrenia represent separate dimensions of the illness, i.e., they are virtually completely uncorrelated in severity, course, and response to available treatments, they more than likely result from independent processes, even if some of the pathways involved are the same (Meltzer 1992). Regardless of the ultimate cause(s) of the hyperdopaminergic...

Editing and Alternative Splicing of the 5HT2C Receptor in Schizophrenia

There has been some investigation of the relevance of editing of the 5-HT2C receptor for schizophrenia. In a study of brain tissue from frontal cortex of only five controls and five subjects with schizophrenia, reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (p 0.001), and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were found in the schizophrenia group. Since the unedited 5-HT(2C-INI) couples more efficiently to G proteins than the other isoforms do, the authors suggested enhanced 5-HT2CR-mediated effects might be present in schizophrenia (Sodhi et al. 2001). However, Dracheva et al. (2003) found no differences in editing or alternative splicing of the 5-HT2C receptor in a comparison of 15 elderly patients with schizophrenia and 15 matched controls. Sodhi et al. (2005) have also suggested that chronic treatment with antipsychotic drugs might alter editing of the 5-HT2C receptor (Sodhi et al. 2005).

HT2C Receptors Cognitive Impairment in Schizophrenia

Number of mechanisms that fine-tune DA release in these two brain regions crucial for cognition, has been linked to the cognitive deficits in schizophrenia that are the principal cause of enduring disability in schizophrenia (Green 2006). The dentate gyrus of the hippocampus has been identified as an important locus of deficits in working, long-term verbal, and spatial memory in schizophrenia (Takao and Miyakawa 2009). The dentate gyrus is also a key region for neurogenesis, a process that may be disturbed in schizophrenia, along with plasticity at the synaptic level (Reif et al. 2007). In 5-HT2C null mice, Tecott et al. (1998) found that long-term potentation was impaired in the medial perforant pathway of the dentate gyrus. This was suggested to be the basis for impairment of performance by these mice in the Morris water maze, a measure of spatial learning and reduced aversion to a novel environment. No general deficit in learning or spatial discrimination was noted. The PCP model...

Genetic Studies Of D1 Receptors In Schizophrenia

Polymorphisms in the human D1 dopamine receptor genes are summarized in Table 2. Two polymorphisms of restriction fragment length were recognized by Eco R1 and Taq I.4950 There were 13 polymorphisms in the DNA sequence, including 4 silent mutations in the coding region observed only in patients with schizophrenia.45,46 (Table 2). However, neither linkage49-51 nor association43,44,52,53 studies using the two restriction fragment length polymorphisms or DNA variations in the promoter, 5' UTR and 3' UTR, revealed any positive findings of D1 receptors with schizophrenia (Table 3). Ten variations in the DNA sequence have been reported in the human D5 dopamine receptors.47,48 (Table 2). There were no statistically significant findings in the linkage54 or association study47 with schizophrenia (Table 3). Consequently, it is unlikely that genes of the D1 subfamily (D1 and D5) play a major role in the genetic predisposition of schizophrenia.

Postmortem Studies Of D1 Receptors In Schizophrenia

An increased formation of c-AMP induced by D1 agonist (SKF 38393) was observed in the caudate nucleus of postmortem brains of schizophrenics. Receptor binding studies, except for a report by Hess et al.,59 failed to find any changes in densities of D1 receptors in the basal ganglia (Table 4). There were also no alterations in the mRNA levels of D1 receptors.64,65 Hess et al.,59 however, demonstrated that D1 in the caudate nucleus was significantly reduced by 43 , and there was a marked increase in the D2 receptor density. They speculated that the alteration in the D2 D1 dopamine receptor ratio might reflect the imbalance between the receptors, which could be associated with the subsequent psychopathology of schizophrenia. Increased D2 receptors in the striatum

Clinical Studies of D1Related Drugs in Schizophrenia

Results of open clinical trials of selective D1 antagonists in acute psychotic states are summarized in Table 6. A selective D1 antagonist, SCH 39166, was withdrawn prematurely in half of the patients of each trial because of deterioration of psychotic symptoms and refusal to take the drug. The trials did not reveal any significant effects on positive symptoms of schizophrenia, while an effect on negative symptoms was observed in one study73 and an improvement in the brief psychiatric rating scale (BPRS) scores was observed in two schizoaffective disorders, but not in schizophrenics.74 The lack of apparent antipsychotic effects of D1 antagonists could not be attributed to inadequate dosage of the drug, as single oral doses of 100 mg SCH 39166 induced around 70 D1 receptor occupancy in the basal ganglia.76 Another selective D1 antagonist, NNC 01-0687, was given to 14 chronic schizophrenic patients, and 9 patients completed the clinical trial.75 Some improvement of psychotic symptoms as...

Alteration Of 5ht Receptors In Schizophrenia

The involvement of alteration of 5-HT transmission in the pathophysiology of schizophrenia is supported by numerous postmortem studies, which have been reviewed elsewhere40-43 (Table 1). The most consistent abnormalities of 5-HT markers in schizophrenia are a reduction in cortical 5-HT Alterations in 5-HT Receptors in Schizophrenia Postmortem Studies Alterations in 5-HT Receptors in Schizophrenia Postmortem Studies

Treatment Strategies for Agitation and Psychosis in Dementia

Summary This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents anticonvulsant agents (carbamazepine and valproic acid) anxiolytic agents (benzodiazepines and buspirone) antidepressants (trazodone and selegiline) serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline) cholinergic therapy and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4...

Schizophrenia and Clinical Outcome

Schizophrenia is a brain disorder with protean manifestations. It has a lifetime prevalence of 1 , with a relatively early age of onset - late adolescence and early adulthood. It is characterized by psychotic symptoms ('positive' symptoms such as hallucinations and delusions), impaired thinking and bizarre behaviour sometime during the course of the illness. Many patients have 'negative' symptoms that are just as, if not more, troublesome as positive symptoms, and include decreased emotional arousal and social drive, paucity of mental activity, motor retardation and decreased ability to experience pleasure. While positive symptoms are often episodic in nature, and generally responsive to treatment, negative symptoms tend to be persistent and treatment-resistant. Treatment of this disorder includes long-term administration of antipsychotic agents, rehabilitation, family and community support, and education. However, in spite of current best treatment efforts, the clinical outcome of...

Importance of Membrane EFA in Schizophrenia

Since the dynamic functional state of all membranes, including neuronal, is dependent on their composition, even small changes in key EFA that make up phospholipids, such as AA and DHA, can lead to a broad range of membrane dysfunction involving receptor binding, neurotransmission, signal transduction and prostaglandin synthesis. Further, AA is itself a second messenger. Thus, deficits in membrane EFA may explain many biological, physiological and clinical consequences observed in schizophrenia (see review by Horrobin, 1996).

Alterations in Phospholipids and PUFA in Schizophrenia

Early studies, reviewed by Rotrosen and Wolkin (1987), reported a variety of alterations in plasma or red blood cell (RBC) membrane phospholipid concentrations in psychotic patients. These findings included variable alterations in levels of phosphatidylcholine, phosphatidylserine and phosphatidylinositol, but consistent reductions in phosphatidylethanolamine levels. The variability in the findings may be due to differences in diagnostic methods and laboratory methodology. Further, the previous results may have been confounded by the recent finding of a bimodal distribution of RBC AA and DHA in chronic schizophrenic patients, in contrast with the unimodal distribution seen in normal controls (Glen et al., 1994 Peet et al., 1994). While a majority of previous studies were done in chronic schizophrenic patients, studies of patients with recent-onset schizophrenia also show decreased RBC phosphatidylethanolamine (Keshavan et al., EFA concentrations have been investigated only recently....

Why Focus On Smoking In Patients With Schizophrenia

Patients with schizophrenia smoke at much higher prevalence rates (70-80 ) than the general population (25 to 30 ).1-5 This is true even when patients are identified in their first psychotic episodes, before they have been institutionalized or treated with antipsychotic medications.6 Smokers with schizophrenia also smoke more heavily than smokers in the general population, or smokers with other psychiatric illnesses.78 The increased prevalence of smoking, and the heavy smoking, suggest that nicotinic mechanisms are involved in the pathophysiology of schizophrenia. Smoking takes its cost in this population. Mortality rates for patients with schizophrenia are two to four times that of the general population, and patients with schizophrenia die, on average, ten years earlier than would otherwise be expected. The prevalence rates for respiratory and cardiovascular disease are significantly elevated among patients with schizophrenia in some studies twice as high as seen in age-matched...

Nicotineresponsive Elementary Phenotypes In Schizophrenia

Schizophrenia is a complex genetic disorder i.e., the illness does not have a pattern of inheritance resulting from a single genetic abnormality.10 Two nicotine-responsive neurophysiological abnormalities, one in auditory sensory gating and the other in smooth pursuit eye movements, are currently under investigation as potential elementary phenotypes representing gene effects that, in combination with other specific gene effects, may result in the development of schizophrenic illness.1112 These neurophysiological abnormalities appear to be transmitted as autosomal dominant characteristics in some families with high occurrence rates for schizophrenia, and they are both normalized by nicotine administration. The subjective experience of this normalization may contribute to the drive to smoke among patients with schizophrenia. In nearly all neuronal systems, when stimuli are repeated, the electroencephalo-graphic response to the second stimulus is less than that to the first. The first...

Evidence for Free Radicalmediated Pathology in Schizophrenia

It was proposed over 40 years ago that toxic radicals had a role in the aetiology of schizophrenia (Hoffer et al., 1954). Only in the last two decades Alterations in the antioxidant defence system do not necessarily indicate the presence of oxidative stress and possible membrane lipid damage. Evidence of peroxidative damage, such as measures of lipid peroxidation by-products, is required. This type of evidence in schizophrenia, while limited, has been consistent. There is substantial evidence that oxidative stress can directly lead to the type of specific membrane defects described earlier, and that AA is particularly susceptible to oxidative damage (Katsuki and Okuda, 1995). One intriguing finding in schizophrenic patients of an inverse relation between RBC AA concentration and thiobarbituric acid-reactive substances (an index of lipid peroxidation) supports the proposed relations between oxidative stress and membrane pathology (Peet et al., 1994). There is abundant evidence that...

Clinical Implications of Membrane Deficits and Oxidative Stress in Schizophrenia

Are that the specific pathophysiology in schizophrenia remains unknown. However, there are several intriguing associations between clinical features of schizophrenia and the biochemical measures at issue. For example, in the prefrontal cortex, a key area implicated in schizophrenia, there is evidence for both phospholipid abnormality (e.g. Pettegrew et al., 1993) and impaired free radical metabolism (Levon et al., 1996). Since PUFA are preferentially vulnerable to free radical insult, it is conceivable that decreased membrane EFA levels also exist in these areas. Prominent negative symptoms have been associated with low levels of RBC AA levels (Glen et al., 1994) and low levels of GSH-Px (Buckman et al., 1990). Positive symptoms have been associated with low RBC AA levels (Peet et al., 1995) and correlated with SOD activity (Khan and Das, 1997). We have observed a significant correlation between positive symptoms and plasma GSH-Px (Yao et al., 1998b), and an inverse correlation...

EFA Supplementation in Schizophrenia

Early studies of EFA supplementation, based on its efficacy in animal models (Costall et al., 1984), were aimed at treating tardive dyskinesia (TD), a motor abnormality associated with chronic antipsychotic treatment. Several studies reported decreased TD severity in open clinical and blind placebo-controlled trials (Nohria and Vaddadi, 1982 Kaiya, 1984). However, in a double-blind placebo-controlled study of EFA supplementation, Vaddadi et al. (1989) showed that EFA alone did not improve TD, though it did produce a significant improvement in Weschler memory scale scores and psychopathology scores in a group of psychiatric (primarily schizophrenic) patients. Similar results were obtained by other investigators (Soulairac et al., 1983 Bourguignon, 1984 Wolkin et al., 1986). The failure of these EFA trials to improve movement disorder could be due to using a low dosage, inadequate length of the trial, small number of patients, as well as chronicity and irreversibility of TD (Vaddadi,...

Antipsychotic Drugs Smoking And Schizophrenia

Antipsychotic drugs ameliorate the psychopathology and course of schizophrenia. Recent research has begun to examine how antipsychotic drugs affect smoking among patients with schizophrenia, how they affect nicotine-responsive phenotypes, and how these effects relate to the drugs' effects on psychopathology and cognitive psychomotor performance. There are substantial advantages to studying smoking among hospitalized inpa-tients with schizophrenia 1) patients with schizophrenia have high rates of noncom-pliance with clinical or investigational procedures without the close supervision that the inpatient setting can provide 2) the inpatient environment is stable, and patients are largely protected from stressful events or concurrent substance abuse that may alter their response to nicotine and, 3) the protective containment of the inpatient environment permits rapid detection of and attention to any adverse reactions developing in relation to novel interventions under study. Two-hour...

C 5HT2A Agonism LSD and Model Psychosis

The observation of an LSD-induced psychosis in healthy subjects was the first indication of a potential relationship between serotonin function and schizophrenia. The early reports in the 1950s emphasized the clinical similarities between LSD-induced psychosis and schizophrenia.113 These were followed by numerous studies which carefully examined the differences, such as the prevalence of visual as opposed to auditory hallucinations, the absence of thought disorder, and the preservation of affect and insight.114 However, these differences were lessened when the comparison involved early as opposed to chronic schizophrenics115 and when cross-cultural differences in schizophrenic symptomatology were examined.116 One study117 attempted to compare LSD effects to the different subtypes of schizophrenia and found similarities between the drug group and the paranoid but not the undiffer-entiated patients. Interestingly enough, the authors described a higher rate of overlap of symptoms for...

WAY 163969 A 5HT2C Agonist Treatment for Schizophrenia

The 5-HT2C-selective receptor agonist, WAY-163909 12 1,4 diazepino 12 indole ,was reported to be active in various animal models of schizophrenia (Marquis et al. 2007). At doses of 1.7-30 mg kg IP, it decreased apomorphine-induced climbing and behaved like an atypical in that it did not cause catalepsy. Similar to 5-HT2A antagonists, e.g., M100907, WAY 163909 (0.3-3 mg kg subcutaneous SC ) was reported to be more effective in inhibiting PCP-induced locomotor activity than d-amphetamine with no effect on spontaneous activity. WAY 163909 (1.7 to 17 mg kg IP) reversed MK-801 5H-dibenzo a,d cyclohepten-5,10-imine (dizocilpine maleate - and DOI prepulse inhibition of startle (PPI) and improved PPI in DBA 2N mice. Like all known antipsychotic drugs, WAY 163909 reduced conditioned-avoidance responding, an effect blocked by the 5-HT2B 2C receptor antagonist SB 206553. At very high doses, WAY 163909 (10 mg kg SC) selectively decreased extracellular levels of DA in the nucleus accumbens without...

Role of Leptin in Inflammation and Its Possible Connection to Obesity in Schizophrenia

However, the adipocytes and macrophages are responsible for the increase not only of the pro-inflammatory cytokines but also for leptin and resistin. The increase in leptin exerts a strong negative feedback on insulin sensitivity thereby enhancing insulin resistance 43 . This situation is compounded by the impact of the glucocorticoids on the regulation of leptin hypercortisolemia, a common feature of schizophrenia and other major psychiatric disorders, stimulates the release of leptin and thereby further enhances insulin resistance 44 . As has been mentioned previously, premature death due to cardiovascular disease is a common occurrence in both schizophrenia and depression. IL-6 is increased in both schizophrenia and major depression and is known to induce hepatic C-reactive protein that has been implicated in cardiovascular disease 45 . In addition to such changes, obesity is associated with a decrease in circulating adiponectin. Adiponectin is a cardioprotective...

Effects of 5HT2C Inverse Agonists in Animal Models of Psychosis

(PCP) or MK-801, and blockade of the disruption of prepulse inhibition by indirect or direct DA agonists or NMDA receptor antagonists. Atypical and typical antipsy-chotic drugs are active in all these models, with atypical antipsychotic drugs, apparently because of their 5-HT2A antagonist properties, preferentially effective in blocking NMDA-receptor blockade-mediated hyperlocomotion. Pretreatment of rats with the 5-HT2C 2B receptor antagonist SB 221284 (0.1-1 mg kg, intraperitoneal (IP) ) or with the selective 5-HT2C receptor antagonist SB 242084 (1 mg kg, IP), at doses shown to block mCPP- induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Both 5-HT2C antagonists enhanced the ability of PCP to increase the efflux of DA from the nucleus accumbens while having no effect on their own in that regard (Hutson et al. 2000). These results demonstrate that blockade of 5-HT2C receptors...

Role Of Free Radicals In Brain Disease A Schizophrenia

There are several reports that spine numbers, and thus synapses, in the cortex and striatum in schizophrenic brain are reduced by 50 (28-30,70). There are also reports that certain brain areas have loss of neuropil (30,82,93). It is not clear, however, if this is because they were never formed properly or were pruned excessively. It is possible that this finding represents an imbalance in the dynamic process that controls the formation and deletion of synapses. I have put forward the hypothesis (88) that this dynamic process is disordered in schizophrenia because of an imbalance between excessive neurotoxic free radical production (including catecholamine o-semiquinones) and defective neuroprotective antioxi-dant mechanisms on the basis of the following evidence 1. Antioxidant defenses have been reported to be weak in schizophrenia and oxidative stress to be present. Abdalla et al. (1) found an increase in superoxide dismutase and a decrease in glutathione peroxidase, which would...

Effects of Typical and Atypical Antipsychotics on Sleep in Schizophrenia Patients

Typical antipsychotic drugs including haloperidol, thiothixene, and flupentixol have been shown to reduce stage 2 sleep latency and to increase total sleep time and sleep efficiency. Stage 4 sleep and SWS remained unchanged, whereas REM latency was significantly increased (Taylor et al. 1991 Nofzinger et al. 1993 Wetter et al. 1996 Maixner et al. 1998). Olanzapine given to schizophrenia patients or healthy subjects reduced stage 2 sleep latency and wake time after sleep onset, whereas total sleep time and sleep efficiency were enhanced. Concerning sleep architecture, stage 1 sleep was decreased, whereas stage 2 and SWS were augmented. On the other hand, olanzapine tended to disrupt REM sleep as judged by the reduction of REM sleep duration and the increase of REM latency (Salin-Pascual et al. 1999 Sharpley et al. 2000 Muller et al. 2004). The limited information on risperidone tends to indicate that the compound improves sleep maintenance and increases SWS in schizophrenia patients...

Effect of Meta Chlorophenylpiperazine a 5HT2C Agonist as a Challenge Agent in Schizophrenia

There are conflicting data on the effect of the acute administration of mCPP, a mixed 5-HT2A 2C agonist, to patients with schizophrenia, with one study reporting a decrease in psychotic symptoms (Kahn et al. 1992) three others, a mild exacerbation of positive symptoms (Iqbal et al. 1991 Krystal et al. 1993) and two, no significant effect (Maes and Meltzer 1996 Koreen et al. 1997). The reasons for these discrepancies are unclear. It is not related to route of administration, severity of symptoms, or gender. Maes and Meltzer (1996) also reported no differences in the mCPP-induced prolactin, cortisol, or temperature responses in patients with schizophrenia who were neuroleptic free at the time of study. Clozapine has been reported to antagonize the cortisol response to mCPP in patients with schizophrenia, consistent with its 5-HT2C antagonist properties (Kahn et al. 1994 Owen et al. 1993). Two studies reported no difference in the cortisol or adrenocorticotropic hormone (ACTH) response...

Bipolar disorder and schizophrenia

Interestingly, GSK-3 has been implicated in the origins of schizophrenia. Both the Wnt receptor Frizzled-3 (Fz3) and PKB protein have been associated with schizophrenia51 53 (Figure 1.2). Although the Fz3 association is only genetic, PKB polymorphisms have been found to directly reduce PKB expression. Treatment with the anti-psychotic haloperidol increases activity of the kinase PDK-1, an upstream activator of PKB. As PKB inhibits GSK-3 activity, these observations suggest that GSK-3 may be elevated in schizophrenic patients. Early reports on the use of lithium suggest that it may be active against schizophrenic patients, but with the availability of many anti-psychotic drugs it is not in common usage.

Immune Changes in Schizophrenia

The concept that a dysfunctional immune system plays a role in the etiology of schizophrenia can be traced back to the 19th century when it was estimated that approximately one-third of psychotic patients in Europe were suffering from neurosyphilis, a condition that has largely disappeared following the introduction of antibiotics in the 20th century. However, in the last century, it was observed that viral infections such as rubella and the influenza virus were also associated with the symptoms of schizophrenia, at least in some patients 6 . Perhaps the most compelling evidence for a link between schizophrenia and a dysfunctional immune system has been provided by Lindholm et al. 7 who demonstrated that a locus at chromosome 6p22 was linked to both schizophrenia and to the genes of the human lymphocyte (HLA) system. This system is crucially involved in combating viruses which might account for the increased vulnerability of schizophrenic patients to viral infections. Another...

Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

A number of different groups measuring the HPA axis at rest have observed hypercor-tisolaemia and elevated ACTH levels in schizophrenia though this is not a universally reported finding 3-9 . There are probably a number of reasons why this is the case but the 3 most likely are differences in methodology, patients were receiving antip-sychotic medication at the time of testing, or patients had been abruptly withdrawn from medications in order to produce a 'medication-free' scenario. Antipsychotics dampen activity of the HPA axis and such actions may occur via or independently of their actions on various monoaminergic systems 10 . Support that schizophrenia itself may be associated with increased HPA axis activity has come from endocrine and neuroimaging studies in drug-naive first-episode patients (10 larger pituitary volume) and high-risk subjects (who showed a 20 increase of developing psychosis with each further 10 increase in pituitary size) 11 . Dynamic challenges of the HPA axis...

Antipsychotic Drug Effects In An Animal Model Of Schizophrenia

As noted previously, the ability of antipsychotic drugs to stimulate dopaminergic transmission, particularly within the frontal cortex, has received a great deal of attention, in part, because of the notion that schizophrenic patients may have reduced cortical dopamine transmission.50,52 The concept of reduced cortical dopamine transmission and associated cognitive and behavioral effects has long been central to neurobiological hypotheses of schizophrenia49,51,61 and to animal models of the disorder.50,62 Recently, we have characterized the behavioral and neurochemical consequences of subchronic exposure to the psychotomimetic A-methyl-d-aspartate glutamate receptor antagonist phencyclidine (PCP) in an attempt to model some of the primary behavioral and neurobiological pathophysiology of schizophrenia. Our results indicate that repeated, intermittent exposure to PCP produces persistent decreases in frontal cortical dopaminergic transmission and associated performance deficits on tasks...

Drug Treatment Of Psychoses

SHORT-TERM TREATMENT The antipsychotic drugs are effective in acute psychoses of unknown etiology, including mania, acute idiopathic psychoses, and acute exacerbations of schizophrenia. The best studied indications are for the acute and chronic phases of schizophrenia and in acute mania. Antipsychotic drugs also are used empirically in many other neuromedical and idio-pathic disorders with prominent psychotic symptoms or severe agitation. Usually 2-3 weeks or more are required to demonstrate obvious beneficial effects in schizophrenia patients maximum benefit in chronically ill patients may require several months. In contrast, improvement of some acutely psychotic or manic patients can be seen within 48 hours. Aggressive dosing with high doses of an antipsychotic drug at the start of an acute episode of psychosis has not been found to increase either the magnitude or the rate of therapeutic responses. However, parenteral agents in moderate doses can bring about rapid sedation and may...

Epigenetic Targets in GABAergic Neurons to Treat Schizophrenia

GABAergic Malfunction in the Limbic System Resulting from an Aboriginal Genetic Defect in Voltage-Gated Na+-Channel SCN5A is Proposed to Give Rise to Susceptibility to Schizophrenia VII. Linkage of Propranolol Cognitive Effects with Correction of a Limbic System Defect that Results in Failure of Habituation in Schizophrenia (see Gruzelier, 1978) 135 VIII. Susceptibility to Schizophrenia may Result from Mutation of the Na+ Channel-Coding SCN5A Gene, Which Occurs at Uniquely High Levels in Neural Components of the Limbic System 137 XI. The GABA System and Schizophrenia 141 References 144

Schizophrenia

The literature on pain among patients with schizophrenia has suggested that these patients demonstrate an insensitivity or indifference to pain associated with serious medical conditions. A number of experimental paradigms have demonstrated that patients with schizophrenia tend to have reduced pain sensitivities and higher thresholds for pain compared with patients who do not have schizophrenia (Dworkin 1994). Reduced pain sensitivity was found to be a familial trait present among healthy relatives (i.e., without schizophrenia) of patients with schizophrenia (Hooley and Delgado 2001). A number of mechanisms for these findings have been postulated. Higher pain thresholds have been correlated with higher levels of endogenous opioids in the cerebrospinal fluid in patients with schizophrenia as compared with those without schizophrenia. These endogenous opioids might mitigate awareness of and sensitivity to pain. In addition, alteration of cortical evoked potentials during noxious...

Dopaminergic Receptors

Four types of D2 receptors have been identified. The two subtypes of D2 receptors (the short and long forms, D2S and D2L, respectively) are derived from alternative splicing of the D2 gene. Although a seemingly identical pharmacological profile for these receptors exists, there are undoubtedly (yet to be discovered) physiological differences between the two subtypes. D2 receptors mediate their cellular effects via the Gi Go proteins and thereby several effectors (see Figure 1-4B). In addition to the well-characterized inhibition of adenylyl cyclase, D2 receptors in different brain areas also regulate PLC, bring changes in K+ and Ca2+ currents, and possibly regulate phospholipase A2. D2 receptors are located on cell bodies and nerve terminals of DA neurons and function as autoreceptors. Thus, activation of somatodendritic D2 receptors reduces DA neuron firing activity, likely via opening of K+ channels, whereas activation of nerve-terminal D2 autoreceptors reduces the amount of DA...

Cholinergic Receptors

From a clinical standpoint, Freedman et al. (1997) demonstrated that in a cohort of patients with schizophrenia, abnormal P50 auditory evoked potentials were linked to a susceptibility locus for this disease on chromosome 15. Notably, this is where a nicotinic receptor subunit is found, providing indirect support for the long-standing contention that the high rates of cigarette smoking in patients with schizophrenia may represent (at least in part) an attempt to correct an underlying nicotinic receptor defect.

Alprazolam Definition

Alprazolam is a high-potency, short-acting anxiolytic benzodiazepine medication used in the treatment of anxiety, panic, and phobic disorders. It has some antispas-modic and anticonvulsant effects. It is not antidepressant. It is sometimes used in conjunction with antipsychotic medication in acute psychotic episodes. Unwanted effects include sedation, headaches, paradoxical excitement, confusion, cognitive and psychomotor impairment, and confusion in the elderly. Long-term use may induce dependence with withdrawal reactions. Recreational use and abuse can occur alprazolam is a scheduled substance.

Role of Pharmacotherapy

Schizophrenia is characterized by a variety of symptoms, including hallucination, delusion, and psychomotor excitement. A dopamine receptor antagonist, chlorpromazine, was introduced in the treatment of this illness in 1952 and has shown its effectiveness, which has made the dopami-nergic system a primary target of research on the patho-genesis of schizophrenia as well as potential mechanisms of antipsychotic action of this type of drugs. This has led to the prototype of the dopaminergic hypothesis for schizophrenia where the increase and decrease in the dopaminergic neural transmission is attributed to its symptoms and treatment effects of antipsychotic drugs, respectively. Although this hypothesis has been revisited and further developed, the dopaminergic system cannot fully account for the mechanisms underlying this illness. Recently, other neural systems such as glutamater-gic and cholinergic systems have also come to the front line of this line of research. Dopamine was the first...

Transporters as Targets for Drug Discovery

In addition to regulating monoaminergic chemical transmission, transporters also play a role in controlling synaptic concentrations of amino acid neurotransmitters. Two such transporters for the CNS active amino acid glycine, GlyT1 and GlyT2 from the NSS family were identified in the early 1990s 47-49 . Since that time there has been significant interest in GlyT1 inhibition as a therapy for schizophrenia with the proposed additional benefit of improved cognition. Although there is substantial pharmacological evidence to support this therapeutic hypothesis, clinical proof of concept is yet to be determined. However, a number of interesting compounds have now progressed to clinical trials and hence the validity of GlyT1 as a target for schizophrenia, as well as differentiation between the different structural classes of inhibitors, is likely to be clarified in the next decade. In their review Walker et al. (vide infra) review the current medicinal chemistry landscape for the glycine...

Receptor Looking for a Therapeutic

The clinical relevance of 5-HT2C receptor editing has been linked in association studies to suicidality (Niswender et al. 2001), schizophrenia (Sodhi et al. 2001), anxiety (Hackler et al. 2006), depression (Iwamoto et al. 2005), and spatial memory (Du et al. 2007). However, these data need confirmation, as is common in the field. 5-HT2C receptors have been shown to modulate mesolimbic dopaminergic function, where they exert a tonic inhibitory influence over dopamine neurotransmission (Di Giovanni et al. 1999 Bubar and Cunningham 2007) and, therefore, the interest in this receptor as a therapeutic target for treating abuse (Bubar and Cunningham 2006). The 5-HT2C receptor is also believed to mediate, in part, the effects of antidepressants, e.g., mirtazapine or agomela-tine (Cremers et al. 2007), possibly by stimulating neurogenesis, as well as that of atypical antipsychotics (Herrick-Davis et al. 2000). 5-HT2C receptors are expressed in the amygdala, and functional magnetic resonance...

Pharmacogenetics In Clinical Research And Drug Development

The need for more disease understanding and greater clarity and understanding of optimal patient drug treatment options is recognized by the NIMH and currently incorporated as part of the NIMH Treatment Research Initiative. This program includes 3 large real-life clinical trials studying the effectiveness of drugs for unipolar depression (STAR*D Sequence Treatment Alternatives to Relieve Depression http www.edc.gsph.pitt.edu stard), schizophrenia (CATIE Clinical Antipsychotic Trials of Intervention effectiveness www.catie.unc.edu) and bipolar disorder (STEP-BD Systematic Treatment Enhancement Program for Bipolar Disorder www.stepbd.org) (Rush et al. 2003 CATIE, 2003). These clinical studies aim to determine the most appropriate treatment strategies for patients with mood and psychotic disorders. The findings from these studies have the potential to have a major impact on prescribing recommendations for their respective indication. The first data from the STAR*D program is expected in...

The Type 1type 2 Hypothesis

Crow3,4 produced a formulation of the pathophysiology of schizophrenia which has had a seminal influence on subsequent attempts to link the phenomena of the illness to the diverse abnormalities of brain structure and function that are associated with schizophrenia. The foundation of this formulation was the observation that the positive symptoms of schizophrenia tend to be transient, while the negative symptoms tend to persist. Positive symptoms are clinical features that reflect aberrant mental activity not present in healthy individuals. They include delusions, hallucinations, and formal thought disorder. Negative symptoms are clinical features that reflect a diminution of mental activity normally present in healthy individuals and include blunted affect, poverty of speech, and decreased voluntary activity. Positive symptoms usually respond to treatment with dopamine blocking medication, whereas negative symptoms are less responsive.8 Indirect evidence linked negative symptoms with...

Patterns of Cerebral Activity Associated with Syndromes

Using PET to examine the patterns of rCBF associated with each of the three syndromes in a group of patients with persistent, stable illness, Liddle et al.32 confirmed that each syndrome was associated with a particular pattern of aberrant cerebral activity. In accord with this prediction, they found that psychomotor poverty was associated with underactivity in left lateral frontal cortex. Furthermore, the region of underactivity coincided with the region that is engaged during word generation in healthy subjects. In addition, psychomotor poverty was correlated with decreased rCBF in the left inferior parietal lobule, a region of association cortex that has strong reciprocal connections with the lateral frontal cortex, and bilaterally with increased rCBF in the basal ganglia and thalamus. Subsequently, Ebmeier et al.33 confirmed the finding of an association between psychomotor poverty and left frontal underactivity in an group of acutely ill schizophrenic patients, half of whom had...

Muscarinic M2 Receptors

In the caudate putamen, muscarinic M2 receptors act as inhibitory hetero-receptors on dopaminergic terminals. Consequently, selective muscarinic M2 receptor blockade may provide a therapeutic approach to schizophrenia, a disease associated with excessive dopamine transmission. BuTAC is a partial agonist at muscarinic M2 and M4 receptors, and an antagonist at muscarinic M1, M3 and M5 receptors (Rasmussen et al. 2001). In rodents, the partial agonist BuTAC exhibits antipsychotic behavior, resembling clozapine and olanzapine, and induces a reduction in dopamine cell firing in the limbic ventral tegmental area, possibly by an M2 antagonist action (Rasmussen et al. 2001). However, mutated mice lacking the muscarinic M4 receptor also display supersensivity of dopamine D1 receptors, indicating that the muscarinic M4, as opposed to the M2 receptor is also important in this respect.

From genomics to proteomics

Although these techniques are easier to apply for diseases with clear-cut lesions, such as ischemia following focal stroke (Wang et al. 2000), their potential interest and application in many psychiatric disorders is important now that large collections of brains from patients who have died are being made in different countries. These will provide samples for applying these techniques. Other developments in proteomics may be of considerable value in the development of new pharmaceutical targets through pharmacogenomics. Gene expression arrays are used to define the mechanism of action for new compounds, or to screen for direct influence of an agent on a specific pathway. Some new techniques may be specifically relevant for psychopharmacogenomics. For example, voxelation, using high-throughput analyses of spatially registered voxels harvested from the brain followed by three dimensions reconstruction, is performed before a Gene Expression Tomography (GET) which employs analyses of sets...

Reversibility of Aberrant Cerebral Activity Associated with the Three Syndromes

The available evidence from functional imaging studies that have examined the relationship between changes in regional cerebral metabolism and the reductions in symptom severity after antipsychotic treatment provides support for the hypothesis that antipsychotic medication acts by decreasing overactivity at the cerebral sites implicated in the reality distortion and disorganization syndromes. In a study of the effects of the novel antipsychotic risperidone on cerebral metabolism in previously unmedicated first episode schizophrenic patients, Liddle et al.43 found that the degree of reduction in metabolism in the left hippocampus observed 90 min after the first dose of risperidone was a significant predictor of the degree of alleviation of reality distortion during subsequent treatment. Furthermore, after 6 weeks of treatment, there was a more extensive region of reduced metabolism in the left temporal lobe. These findings indicate not only that temporal lobe metabolism decreases as...

Historical Overview Introduction to the Dopamine Receptors

Abstract A long-term search for the mechanism of action of antipsychotic drugs was motivated by a search for the cause of schizophrenia. The research between 1963 and 1975 led to the discovery of the antipsychotic receptor, now known as the dopamine D2 receptor, the target for all antipsychotic medications. There are now five known dopamine receptors, all cloned. Although no appropriate animal model or brain biomarker exists for schizophrenia, it is known that the many factors and genes associated with schizophrenia invariably elevate the high-affinity state of the D2 receptor or D2High by 100-900 in animals, resulting in dopamine supersensitivity. These factors include brain lesions sensitization by amphetamine, phencyclidine, cocaine, or corticosterone birth injury social isolation and more than 15 gene deletions in the pathways for the neurotransmission mediated by receptors for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. The elevation of D2High receptors...

Challenges for Animal Models of Autism

Tasks that could examine these behavioral symptoms in rodents have been already developed and are summarized in Table 1. However, an animal model of autism based solely on behavioral assays would be incomplete. Animal model should also address a combination of the neuro-pathological, biochemical and genetic factors implicated in autism. Another challenge lies in the fact that many clinical hallmarks of autism are difficult or almost impossible to replicate in rodents, e.g., theory of mind (ability to intuit the feelings and intentions of others) or speech deficits. It is also important to realize that assumed core psychopathological phenomena observed in autism are present as common clinical features in schizophrenia, depression, obsessive-compulsive disorder and other medical and psychiatric illnesses. What is specific for autism is a pattern of socio-behavioral aberrations and their appearance before the age of three, and animal models should try to address this fact.

Muscarinic M4 Receptors

In the central nervous system, muscarinic M4 receptors are distributed in the corpus striatum being co-localized with dopamine receptors on striatal projecting neurons. In the periphery, the subtype is present on various prejunctional nerve endings, where they act to inhibit parasympathetic and sympathetic transmission (Trendelenburg et al. 2003). The muscarinic M4 receptor may play a role in psychosis, with the mixed M1 M4 agonist xanomeline having antipsychotic effects (see above). This compound, even after acute administration, selectively inhibits mesolimbic firing of dopamine cells, suggesting that muscarinic agonists could have a faster onset of action than current antipsychotics, with fewer side effects (Mirza et al. 2003). Mice lacking the muscarinic M4 receptor also display an increased sensitivity to the disruptive effect of phencyclidine on prepulse inhibition. This preclinical effect is a model of psychosis and the data support the contention that M4 receptors are a...

Approaches To Determining And Manipulating Gene Expression

Changes in gene expression within the central nervous system (CNS) have profound effects on all other aspects of the organism. Changes in gene expression are causally associated not only with the development of the CNS but also with the complex phenomena of brain function, such as memory formation, learning, cognition, and affective state. Changes in gene expression likely underlie the pathogenesis of many sporadic or inherited CNS-related disorders, such as Alzheimer's disease, Huntington's disease, depression, and schizophrenia. Thus, insight into and characterization of gene expression profiles are necessary steps for understanding how the brain functions at the molecular level and how malfunction will result in disease. Molecular biological and genomic technologies such as gene mapping and cloning, DNA libraries, gene transfection and expression, and gene knockout and gene targeting have provided numerous benefits to neuropsychopharmacology. Genomic methods applied to pedigree and...

Overview and Pathogenesis of Alzheimers Disease

Alzheimer's disease is a devastating illness. It occurs mainly in the elderly population. Once afflicted, Alzheimer's disease produces progressive and unrelenting damage to the human brain. The average lifespan after being diagnosed with this illness is about 8-10 years 1 . Patients steadily lose cognitive functions including memory, executive functioning, and the ability to care for themselves. In addition, behavioral symptoms of agitation, depression, and psychosis are often co-morbid with Alzheimer's disease. This devastating illness affects not only the patients but also the families and anyone that provides care for them. In the United States, the staggering financial cost of the disease accounts for nearly 100 billion per year in medical and custodial expenses, with the average patient requiring about 27000 per year for medical and nursing care. Furthermore, 80 of caregivers of patients with Alzheimer's disease report stress, and about 50 report depression 2 .

Specific Metabolic Features of Women with Bipolar Disorder

Baseline data from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) demonstrated higher rates of MetS in women with schizophrenia (51.6 ), when compared with women in the general population and with men with schizophrenia (36.0 ) 18 . However, gender differences in MetS prevalence in BD patients have not emerged as clearly. The majority of studies of prevalence rates of MetS in BD have not noted significant gender differences, but have involved smaller numbers than those in the CATIE study 12, 13 . One study demonstrated a higher prevalence of MetS in bipolar women in comparison with bipolar men 14 . and a propensity towards higher waist circumferences 10 . Obese patients with either BD or schizophrenia are more likely to be women 30 , and weight gain has been shown to be associated with female sex 31 . An evaluation of data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) demonstrated greater rates of obesity in bipolar women (31...

RNA Editing of the 5HT2C Receptor

The 5-HT2C receptor is the only G-protein-coupled receptor known to be edited, and even mRNAs encoding closely related 5-HT2A and 5-HT2B receptors have not been shown to undergo RNA editing (Niswender et al. 1998). RNA editing of the 5-HT2C receptor is prominent in the central nervous system indeed, most of the receptors in the brain exist as edited isoforms (Burns et al. 1997 Fitzgerald et al. 1999 Niswender et al. 2001). Because the 5-HT2C receptor is involved in the pathogenesis of various psychological disorders, RNA editing of the 5-HT2C receptor has been proposed to play role in the etiology of schizophrenia (Sodhi et al. 2001), depression (Tohda et al. 2006), and affective disorders (Niswender et al. 2001 Gurevich et al. 2002).

Responses BY da occurs via D2 receptors

D4 receptors are abundant in the prefrontal cortex66 and may play an important role in schizophrenia and other psychiatric disorders.67 Mice lacking D4 receptors show signs of hyperexcitability.68 Application of a D4 receptor agonist produces a decrease of NMDA currents via inhibition of PKA, activation of PP1 and the consequent inhibition of Ca2+ calmodulin-dependent kinase II.69 In CA1 pyramidal neurons, quinpirole depresses excitatory transmission mediated by NMDARs by increasing release of intracellular Ca2+. This depression is dependent on transactiva-tion of platelet-derived growth factor p by D4 receptors.70 Similar effects were found in prefrontal cortical neurons but they were mediated by D2 3 receptors.71 Physical coupling between D2 receptors and NR2B subunits can also reduce NMDA currents.72 The mechanism underlying this effect involves disruption of the association between NR2B and CaMKII, thereby reducing subunit phosphorylation. It is believed that the D2-NR2B...

Membrane Stabilization by Antipsychotics

With the introduction of chlorpromazine to psychotic patients in state and provincial hospitals in North America in the late 1950s and early 1960s, the number of patients hospitalized with schizophrenia became markedly reduced. The basic science premise gradually emerged - if the target sites for antipsychotics could be found, then perhaps these sites were overactive in psychosis or schizophrenia. In the 1960s, however, no one agreed on what schizophrenia was. Inclusion criteria varied so much that it was impossible to decide which patients to study, let alone what to study. But everyone agreed that chlorpromazine and the many other new antipsychotic drugs, most of which were phenothiazines, alleviated the symptoms of schizophrenia, however defined. These surface-active potencies showed an excellent correlation with clinical antipsychotic potencies. However, I later realized that the antipsychotic concentrations were all in the micromolar range, a concentration subsequently found to...

Functional Relevance Of Danmda Receptor Interactions

In the cerebral cortex, D1 receptors and D1-NMDAR interactions play a very important role in working memory and cognitive function. In particular, accumulating evidence indicates that induction and maintenance of persistent activity in prefrontal cortex and related networks is dependent on D1-NMDAR interactions.23 Alterations of these receptors and their interactions occur in schizophrenia. One important aspect of these interactions is the existence of an optimal level of D1 receptor activation below or above which DA's effects on working memory are deleterious.93 Synchronous activity (gamma oscillations) may occur in awake animals and this activity may play an important role in cognition.95 Alterations in gamma oscillations, particularly in the frontal cortex, have been observed in schizophrenia.96-99 In humans DA D4 receptor and DA transporter-1 polymorphisms have been shown to modulate gamma activity.100

Overview of Cholinesterase Inhibitors in the Treatment of Alzheimers Disease

The use of cholinesterase inhibitors may preserve activities of daily living, slow progression of memory loss and improve behavioral and cognitive symptoms associated with Alzheimer's and related dementias. Treating Alzheimer's disease often takes great patience on the part of physicians as well as patients and caregivers. Response to drug may take weeks, sometimes months before caregivers may notice a difference in symptoms, if at all. The efficacy produced by cholinesterase inhibitors is not always clear-cut. For example, there is some evidence that donepezil may benefit moderate to severe Alzheimer's dementia in outpatients, however, the results have been conflicting in the nursing home population 17 . In addition, both donepezil and galantamine have not yet shown consistent results in improving behavioral and psychotic symptoms in patients with Alzheimer's disease. Improvement in psychosis is seen with rivastigmine which has shown improvements in behavioral symptoms in mild to...

Naa As A Marker For Neuronal Health

Are decreased include Alzheimer's disease, epilepsy, schizophrenia, multiple sclerosis and AIDS dementia complex (Table 1). Earlier, the decreases in NAA were interpreted to represent irreversible loss of neurons. However, more recent evidence indicates that these decreases also could represent reversible neuronal mitochondrial dysfunction. 53 Schizophrenia 46'47

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In turn, L-DOPA is converted to dopamine by dopa decarboxylase either in the capillary endothelium or in dopaminergic neurons. Thus, administration of L-DOPA increases the substrate for dopamine and results in increased dopamine synthesis and release. Although L-DOPA passes the blood-brain barrier, L-DOPA is rapidly converted into dopamine in the blood when administered orally. This renders approximately 95 of it unable to enter the CNS, while the remaining 5 penetrates and is then converted to dopamine. Although this was enough to alleviate parkinsonian symptoms, the large amounts of circulating dopamine created the side effect of nausea. The next step of progress came with the drug carbidopa, which inhibits peripheral DOPA decarboxylase. Thus, conversion of L-DOPA to dopamine is supressed in circulation, but continues unhindered centrally because carbidopa does not cross the blood-brain barrier. This effectively reduces the necessary dose of L-DOPA by 75 . L-DOPA and...

Current Concepts and State of Knowledge

Cognitive enhancing drugs, also known as smart drugs, are needed to treat cognitive disabilities and improve the functional outcome, wellbeing, and quality of life for patients with neuropsychiatric disorders and brain injury (Sahakian and Morein-Zamir 2007). Cognitive enhancing drugs are used in treating cognitive impairment in disorders such as AD, schizophrenia, and ADHD. In neurodegenerative diseases, such as AD, cognitive enhancing drugs are used to slow down or compensate for the decline in cognitive and behavioral functioning that characterizes such disorders. There are currently 700,000 people with dementia in the United Kingdom, most of whom have AD. Each year, 39,400 new cases are diagnosed in England and Wales, translating to a new case every 14 min. Current costs of long-term care for dementia in the United Kingdom are estimated at 4.6 billion, and with an increasing aging population, this estimate is expected to rise to 10.9 billion by the year 2031. Likewise, the number...

Discovery of the Antipsychotic Dopamine Receptor

At the CINP (Collegium Internationale Neuro-Psychopharmacologicum) meeting held in Paris in July 1975, during the evening courtyard reception at the City Hall of Paris, I rushed up to Dr. Paul Janssen and showed him the chart correlating the average clinical antipsychotic doses with the in vitro antipsychotic potencies. He laughed and said that averaging the clinical doses for each antipsychotic was like averaging all the religions of the world. Nevertheless, the correlation remains a cornerstone of the dopamine hypothesis of schizophrenia, still the major contender for an explanatory theory of schizophrenia causation.

The Placebo as a Therapeutic Intervention

In 2001, Hrobjartsson et al. attempted to answer the question of whether placebo treatment conferred therapeutic benefit by systematically reviewing 130 clinical trials in which patients were assigned to either placebo or no treatment. They looked at the difference in outcome between the placebo and the no-treatment groups, rather than looking at the effect of the intervention arm of each trial. The underlying disease processes in each trial were diverse and involved 40 clinical conditions, such as asthma, schizophrenia, and chronic pain syndromes. In their analysis, they found no significant placebo effect in trials with binary outcomes, either subjective or objectively measured, nor in trials with continuous, objective outcomes. However, they did find a significant difference in trials with continuous subjective outcomes and in trials where pain was investigated (Hr bjartsson and G0tzsche 2001). The authors acknowledged several limitations to their study, including the inability to...

Neurological disorders

NR-mediated glutamate toxicity is considered a common pathological pathway of many acute and chronic neurological disorders such as brain trauma, brain ischemia, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS dementia, and Lou Gehrig's disease.6-810136 Since NR function and activity are determined by a specific set of NR genes expressed in a given cell and by the level of that expression, abnormal transcription of the NR genes may contribute to NR pathological effects. 5.7.2 promoter polymorphism and Schizophrenia and the severity of chronic schizophrenia.50 This initial survey was confirmed in an extended study with twice as many schizophrenics and controls.147 This observation was confirmed in an independent study of 122 Han Chinese sibling pair families.149 The authors believed that the (GT)n polymorphism in the NR2A promoter played a significant role in the etiology of schizophrenia. However, whether a trans factor interacts with these repeats...

The DrugH Antiporter1 DHA1 12 Spanner Family

Experimental studies have indicated that amphetamine-type agents interact with the VMAT2 and deplete vesicular neurotransmitters via a carrier-mediated exchange mechanism 151 . The cytoplasmic levels of transmitter are increased due to disruption of the vesicular transmitter storage of transmitter, such that more neurotransmitter is available for release by transporter-mediated exchange 151 . It has been proposed, based on its functions as a critical regulator of neurotransmitter disposition within the brain, that the VMAT2 transporter might be a possible target for drugs used in addictive disorders, Parkinson's disease and schizophrenia 152,153 .

Insomnia Accompanying Major Psychiatric Illnesses

Adequate control of anxiety in patients with anxiety disorders often produces adequate resolution of the accompanying insomnia. Sedative use in the anxiety disorders is decreasing because of a growing appreciation of the effectiveness of other agents, such as adrenergic receptor antagonists (see Chapter 10) for performance anxiety and serotonin reuptake inhibitors for obsessive-compulsive disorder and perhaps generalized anxiety disorder. The profound insomnia of patients with acute psychosis owing to schizophrenia or mania usually responds to dopamine-receptor antagonists (see Chapter 18) benzodiazepines, often used adjunctively in this situation to reduce agitation, will result in improved sleep.

Characterization Of Depressive And Anxiety Disorders

The primary clinical manifestations of major depression are significant depression of mood and impairment of function. Some features of depressive disorders overlap those of the anxiety disorders, including panic-agoraphobia syndrome, severe phobias, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Extremes of mood also may be associated with psychosis, as manifested by disordered or delusional thinking and perceptions that often are congruent with the predominant mood. Conversely, secondary changes in mood may be associated with psychotic disorders. This overlap of disorders can lead to errors in diagnosis and suboptimal treatment. Mood and anxiety disorders are the most common mental illnesses, each affecting up to 10 of the general population at some time in their lives.

The Burden of Reductionistic Thinking

Another factor that has significantly influenced research patterns has been the quest to identify, with increasing specificity, cures for mental disorders. This search represents something of a conundrum, which can be outlined in broad strokes as follows Psychological distress is a heterogeneous and nonspecific concept, and its experience is unique to each sufferer. One can define, albeit in rather nebulous terms, some of the features that separate one form of psychological distress from another, but it remains true that most people with schizophrenia, or most depressed patients, share in common only the most obvious features of their diagnoses. Nevertheless, the aim of much of mental health research in the past 50 years has been to search for increasingly specific remedies. We are therefore placed in the awkward position of positing molecular cures for molar concepts that are heterogeneous, nonspecific, and experienced in an absolutely unique...

Effects On Cognitive Function

Several cognitive functions, including auditory processing and attention, spatial organization, verbal learning, semantic and verbal memory, and executive functions, are impaired in schizophrenia patients. Potent D antagonist neuroleptics have very limited beneficial effects on such functions. Some atypical antipsychotic agents with mixed DJ5-HT2A activity (including clozapine, quetiapine, olanzapine, and risperidone), as well as the D2 partial agonist aripiprazole, seem to improve cognitive functioning in psychotic patients. Nevertheless, significant long-term gains in social and occupational function during long-term treatment of chronically psychotic patients with these drugs are not well documented.

Miscellaneous Pharmacological Effects

Elimination half-lives with respect to total concentrations in plasma are typically 20-40 hours. However, complex patterns of delayed elimination may occur with some drugs, particularly the butyrophenones and their congeners. Biological effects of single doses of most antipsychotics usually persist for at least 24 hours, permitting once-daily dosing once the patient has adjusted to initial side effects. Elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably in the CNS metabolites of some agents have been detected in the urine several months after drug administration was discontinued. Slow removal of drug may contribute to the typically delayed exacerbation of psychosis after stopping drug treatment. Repository (depot) preparations of esters of neuroleptic drugs, as well as risperidone incorporated into carbohydrate microspheres, are absorbed and eliminated much more slowly than are oral preparations. For example, half of an oral dose...

Clinical Aspects Of Bacterial Meningitis

Bacterial meningitis is clinically characterized by stiff neck, headache, fever, photophobia, malaise, vomiting, alteration of consciousness, seizures, confusion, irritability, and, rarely, acute psychosis. Cerebrospinal fluid (CSF) usually reveals an elevated white blood cell count of more than 1000 white blood cells l, consisting of more than 60 polymorphonuclear leukocytes, an elevated total protein content and a decreased CSF serum glucose ratio. A CSF white blood cell count of less than 1000 cells l may be found early in the disease, in partially treated bacterial meningitis, in overwhelming bacterial meningeal infection ('apurulent bacterial meningitis') and in immunosuppressed and leukopenic patients.

Burden And Outcome Of Bipolar Disorder

BPAD are chronic disorders with a high rate of recurrence and relapses. More than 90 of individuals who have a single manic episode will have future episodes (Hopkins and Gelenberg, 1994). Ten to 15 of patients will have more than 10 episodes in their life. Bipolar disorder is therefore one of the leading causes of disability which contributes to the important economic burden of bipolar disorder to society. Patients with BD suffer great losses in productivity, with more bed rest and absenteeism days (see Pini et al., 2005 for review). The economic burden was estimated in a cost-to-illness study around US 45 billion in 1991 in the USA, representing 70 of the annual cost of schizophrenia (Wyatt and Henter, 1995). Worldwide, bipolar disorder is listed as the sixth leading cause of disability (Murray and Lopez, 1996).

An Hypothesis For Atypical Antipsychotic Drug Action

As discussed earlier, atypical antipsychotic drugs appear to preferentially increase cortical dopamine efflux. This effect may be related to the superlative effects of these compounds on negative and cognitive symptoms of schizophrenia and their beneficial behavioral effects in animal models of the idiopathic disorder. We have integrated these findings into an hypothesis of atypical antipsychotic drug action that has, at its core, indirect activation of dopamine D1 receptors in the frontal cortex. This hypothesis predicts that activation of cortical dopamine transmission should alleviate cognitive dysfunction in schizophrenia, and results to date support this notion.68-72 However, all the treatments utilized to date have nonspecific actions on multiple neurotransmitter systems. Indeed, at doses of clozapine that produce cognitive improvement in PCP-treated monkeys, the drug has considerable antimuscarinic actions (that likely limit the cognitive improvement produced by the drug).6...

B CB1 receptors and preterm birth Corticosterone and prenatal stress

The study by Dey and colleagues (Wang et al., 2008) also reported a shift in peak levels of corticosterone (CCS) to an earlier gestational age in CB1 receptor knockout mice (from day 17-18 in wild type to day 15-16 CB1 in knockouts). Strikingly, a similar shift of the maternal CCS peak values was observed in prenatally stressed rats (day 17 compared to day 18 of gestation in controls) (Fride and Weinstock, 1985 Weinstock et al., 1988). These observations support our earlier contention that the sequelae of prenatal manipulation of the ECS, such as seen after marijuana consumption during pregnancy, overlap with the consequences of prenatal stress (Fride and Mechoulam, 1996). Therefore, we speculate that the impairments in emotional regulation and cognitive performance induced by prenatal exposure to stress (Fride and Weinstock, 1988 Fride et al, 1985, 1986, 2004), which have also been observed as a consequence of pre- and perinatal cannabinoid exposure (Campolongo et al., 2007 Mereu et...

Pharmacological Interventions

Sibutramine affects the reuptake of norepinephrine, serotonin and dopamine, and was originally thought to be a potential antidepressant compound, but was ultimately commercialized as a weight loss agent. Sibutramine was tested in a 12-week doubleblind, randomized, placebo-controlled study in 37 overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder 70 . For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. Although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg, and presented with a higher rate of anticholinergic side effects and sleep disturbances, greater weight loss was observed at week 12 versus placebo (-3.8 vs. -0.8 kg). A similarly designed study with clozapine conducted among 21 patients by the same research group failed to demonstrate a therapeutic advantage for adjunctive sibutramine 71 . Because sibutramine affects serotonin...

Do The Clinical Potencies Of Antipsychotics Correlate With The Dissociation Constants At D2

The clinical potencies of antipsychotic drugs correlate with their ability to block dopamine D2 receptors.1-4 This is shown in Figure 1 (left), where the average doses for controlling acute schizophrenia are graphed vs. the dissociation constants at the dopamine D2 receptor for antipsychotic drugs. The dissociation constants in Figure 1 were obtained using 3H raclopride and human cloned dopamine D2 receptors,5-9 as listed in Table 1.

Methods In Studying The Regulation And Trafficking Of Transmembrane Transporters

Normal behavior and general health depend on the proper functioning of neurotrans-mitter transporters (Jaber et al., 1997 Beckman and Quick, 2000). Studies show that neurotransmitter transporters play a role in regulating the time course of neurotransmitter levels in the synaptic cleft (Isaacson et al., 1993 Giros et al., 1996 Diamond and Jahr, 1997). Distinct behavioral effects caused by altered transporter function are demonstrated by the actions of cocaine, amphetamine, and alcohol (Amara and Sonders, 1998) by diseases such as depression, obsessive-compulsive disorder, schizophrenia, and epilepsy (Beckman and Quick, 2000) and by the binding of therapeutic drugs to transporters for the treatment of drug abuse and psychiatric disease (Iverson, 2000). These behavioral effects are probably caused by the ineffective regulation of transporters in vivo.

Pharmacokinetic Properties

In general, these classes of drugs are rapidly absorbed from the GI tract (Table 13.1), but there is considerable individual patient variation in peak plasma concentrations.83 Chlorpromazine has been the most widely studied phenothi-azine, and it is believed that thioxanthenes and phenothi-azines are metabolized following a very similar pathway. Compared with the phenothiazines, the thioxanthenes are less likely to form phenolic metabolites.84 Chlorpromazine undergoes extensive first-pass metabolism yielding numerous metabolites. Numerous sites of attack by microsomal CYP450 system (especially CYP2D6) are possible, and most of these reactions happen to various degrees.85,86 Several metabolites have been isolated and characterized. Phase I reactions include oxidative N-demethylation to give primary and secondary amines, aromatic hydroxylation that yields phenols, side chain tertiary amine oxidation that affords Noxide metabolites, S-oxidation to give sulfoxide and sulfones, oxidative...

Key Advances Related to Dopamine Receptors

Many of the significant advances in dopamine receptors and the dopamine hypothesis of psychosis or schizophrenia are listed in Table 1.1. Between 1976 and 1979, it became clear that there were two main groups of dopamine receptors, D1 and D2 23, 35, 36, 37 . The D1-like group of receptors were associated with dopamine-stimulated adenylate cyclase 38, 39 , but were not selectively labeled by 3H haloperidol. The antipsychotic potencies at these D1 receptors did not correlate with clinical antipsychotic potency 26 . The D1-like receptors now consist of the cloned Di and D5 receptors 40,41 . Although the density of D2 receptors in postmortem human schizophrenia tissues is elevated 26, 59, 60-62 , some of this elevation may have resulted from the antipsychotic administered during the lifetime of the patient. An example of this elevation is shown in Fig. 1.3, where it may be seen that the postmortem tissues from half of the patients who died with schizophrenia revealed elevated densities of...

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Genetic predispositions and prenatal insults result in aberrant brain development involving prefrontal and temporolimbic areas. The functional activity of these regions and neurotransmitter systems are altered, resulting in the symptomatology of schizophrenia. Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. A newer generation of antipsychotics have been introduced in the 1990s that have...

Potential Pathophysiological Mechanisms for Glucose Elevation

Data from a 6-month randomised trial of schizophrenia subjects with baseline BMI 28-30 randomised to olanzapine or risperidone found no worsening or differences between the groups on parameters such as insulin sensitivity and disposition index (measure of pancreatic beta-cell functioning) using intravenous glucose tolerance testing. Treatment-emergent weight gain and small increases in visceral fat were observed in both treatment groups The hypothesis suggested was that these data were consistent with a non-linear relationship between obesity and insulin resistance. There have been a number of other studies, albeit small cohorts that have evaluated a variety of antipsychotics in forms of testing such as hyperinsulinaemic euglycaemic clamps 45 , comparison of visceral fat 42, 43 , and intravenous glucose tolerance tests 46, 47 . Some studies were carried out in healthy subjects, some in schizophrenia subjects and importantly some were limited to non-obese subjects. The studies,...

Other Psychiatric Disorders and the Immune Response

Finally, although the picture is far less clear, there has been speculation that immune system activation may contribute to the pathophysiology of psychotic disorders, including schizophrenia, possibly related to an autoimmune diathesis (Pearce 2001 Rothermundt et al. 2001). Elevated levels of cytokines and their receptors, including IL-2, sIL-2, and IL-6, have been reported in the blood and CSF of patients with schizophrenia, and a high level of CSF IL-2 has been found to predict subsequent schizophrenic relapse (Rothermundt et al. 2001). In a related fashion, consideration has been given to the role of viral infection early in development (Pearce 2001), based on seasonal birth patterns that have been reliably replicated in large epidemiological studies of patients with schizophrenia. These findings are consistent with in utero infections of relevant brain structures, including the hippocampus, during critical periods of development (especially during the second trimester) (Pearce...

Dopaminemediated Learning Aging and pd

In PD, there is a decline in some forms of memory while leaving others relatively intact 98-99 . These patients suffer from impaired working memory and have problems in organizing and using new materials as well as applying strategies. Evidence indicates that these problems are probably due to dysregulation in prefrontal cortex as a result of decreased subcortical input into the frontal cortex 100-101 . In the prefrontal cortex, D1 and D5 receptors play an essential role in mediating working memory functions, whereas less is known about the importance of other dopamine receptor subtypes (D2, D3, D4) in the prefrontal cortex 94 . D1-like antagonists that inhibit D1 and D5 receptors (but not D2 receptors) suppress prefrontal cortex, disrupting working memory, whereas prefrontal infusion of low levels of D1 agonists (but not D2 agonists) improves working memory. Interestingly, D4 receptors, are also abundantly expressed in the prefrontal cortex, and seem to be involved with working...

Pharmacogeneticspharmacogenomics in the

Anti-PD drugs, such as L-DOPA, with respect to adverse effects. Some PD patients exhibit L-DOPA- induced dyskinesias, whereas, others remain free despite treatment with L-DOPA. This may be due to changes in neuroplasticity among patients depending on their age and genetics 179 . In fact, genetic variability among individuals may affect differences in the expression of drug-metabolizing enzymes, receptors, and signaling proteins involved in the signal transduction pathways, resulting variability in drug responses 180 . The role of pharmacogenetics in the treatment of PD is relatively unexplored. Well-recognized drug-related complications (dopamine dysregulation syndrome) include hallucinations and psychosis 181 . The etiology of these complications is not clearly dose related, while the management can be difficult and needs to be tailored to the individualized therapy. Cholinergic and DA-ergic drugs may both influence cognitive function. Therefore, use of pharmacogenetics may improve...

Neurobiology of Suicide and the Serotonergic System

Although knowledge regarding the neurobiology of suicide is still limited, the 5-HT system has drawn attention and been studied more extensively than other neu-rotransmitter systems. Studies have shown that traits like impulsivity and aggression, which are related to lower 5-HT activity, are more closely associated with suicide than are objective severity of depression or psychosis (Mann et al. 1999). Recent studies have examined the relationship between suicide, impulsivity and aggression, and lower levels of CSF 5-HIAA. Mann and colleagues (Mann et al. 1997) found lower levels of CSF 5-HIAA in depressed patients with a history of a high lethality or well-planned suicide attempt compared with depressed patients with a history of only low lethality suicide attempts. Lower levels of CSF 5-HIAA are also reported in suicide attempters with schizophrenia (Ninan et al. 1984) and may predict suicidal behavior in this population as well (Cooper et al. 1992). Moreover, the degree of...

Genetic Studies Knockout or Other Studies

Loss of spontaneous and evoked EPSCs in immature granule cells and exhibit problems in motor coordination (248). Knockout of NR2D produces mice with lower sensitivity to stress and altered monoaminergic neuronal function (249), and overexpression of NR2D produces prominent impairment of NMDA-dependent LTP (250). The most essential subunits must be NR1 and NR2B, based on transgenic mouse studies (reviewed in refs. 6 and 251). Knockout of NR1 leads to death shortly after birth. Although neuroanatomy is generally normal, some of the sensory input connections are disturbed. Because NR1 appears to be required for all functional NMDARs, NMDARs must be essential for nervous system function after birth, although they are not required for the general pattern of neural development. Mice with only a partial KO of NR1, expressing about 5 of normal levels, survive to adulthood but display behavioral abnormalities resembling schizophrenia, supporting earlier studies showing that...

Support for the Serotonin 2C Receptor

The 5-HT2C receptor has been implicated as a potential therapeutic target in a wide variety of conditions including obesity, anxiety, depression, obsessive-compulsive disorder, schizophrenia, migraine, and erectile dysfunction. The 5-HT2 receptor family currently accommodates three receptor subtypes, 5-HT2A, 5-HT2B and 5-HT2C receptors, which are similar in terms of their molecular structure, pharmacology, and signal transduction pathways. Because the binding properties of 5-HT toward the The involvement of 5-HT2C receptors in psychiatric disorders has been hypothesized based largely on pharmacological and clinical studies. A number of atypical and typical antipsychotic agents, including clozapine, loxapine, and chlorpromazine, have a relatively high affinity for 5-HT2C binding sites as well as 5-HT2A. Some conventional and atypical antidepressants (e.g., tricyclics, doxepin, mianserin, and trazodone) also exhibit a similar binding affinity (Canton et al. 1990, 1996 Roth and...

Reversal of Disrupted and Persistent LI

The four schizophrenia-relevant aberrations of LI, i.e., those induced by amphetamine, NMDA antagonists, and low and high-dose scopolamine, have been tested with typical and atypical antipsychotics to assess the predictive validity of these models for the identification of clinical treatments for schizophrenia. In recent years, new therapeutic strategies for schizophrenia, considered hoped to improve negative symptoms and cognitive dysfunction, have emerged. These strategies include enhancement of NMDA transmission via the glycineB modulatory site on the NMDAR, either directly by agonists such as glycine transporter and d-serine, or indirectly by inhibiting the glycine transporter (GlyT1), and enhancement of cholinergic transmission using acetylcholinesterase inhibitors such as physostigmine, muscarinic agonists such as xanomeline, and alpha-7 nicotinic receptor agonists. Table 1 summarizes the distinct responses of five LI models (including haloperidol-induced persistence) to typical...

Interactions between Dopaminergic and Glutamatergic Neurotransmission

The prefrontal cortex mediates a range of neurotransmitter-mediated processes associated with planned behavior, which are controlled and directed according to shifting environmental demands. In prefrontal cortex, dopaminergic systems are modulated by glutamatergic neurotransmission, and this modulation is closely associated with the pathogenesis of schizophrenia 51 . Studies on the interaction between dopaminergic and glutamatergic neurotransmitter systems in prefrontal cortex indicate that application of the D4 receptor agonist, PD168077 produces a reversible decrease in the NMDA receptor-mediated current, and this effect can be blocked by selective D4 receptor antagonists 52 . Modulation of NMDA receptors in prefrontal cortex by dopamine D4 receptors is associated with the inhibition of protein kinase A, activation of protein phosphatase 1, and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 not only inhibits the expression of NMDA...

Affinities for 5HT2A D2 Receptors and 5HT2C Receptors

Interest in the role of 5-HT in schizophrenia was revived by the hypothesis that clozapine and other antipsychotics with minimal potential to impair motor function (so-called atypical antipsychotic drug) were more potent 5-HT2A than DA D2 antagonists (Meltzer 1989). This hypothesis, now generally accepted, led to the

Postmortem Studies of 5HT2C Function

Decreased messenger ribonucleic acid (mRNA) expression of 5-HT2C receptors has been reported in postmortem prefrontal cortex tissues in 55 patients with schizophrenia and 55 controls (Castensson et al. 2003). Castensson et al. (2005) reported that the decrease in expression of the 5-HT2C receptor was not related to drug action and might be a core feature of the illness. Decreased expression of the 5-HT2C receptor has also been reported in bipolar disorder patients (Iwamoto and Kato 2003). Diminished 5-HT2C receptor expression would be expected to facilitate limbic DA release.