Coping With Schizophrenia and Psychosis

The Schizophrenia-free Package

What are you going to find in the Schizophrenia-FreeYour New Life Begins Today e-book: Relationships and Friends: In this chapter, I share with you my way of thinking about friends and relationships. I provide my point of view about how I see this interesting issue. I also give you some tips about how to get friends, deal with friends, and treat relationships. About Schizophrenia and Getting Well: In this chapter, I describe my way of thinking about schizophrenia and other similar mental illnesses. Living on Your Own and Being Independent: In this chapter, I share my perspective about our independence as sufferers and how to live on our own and be independent. Other Sufferers' Recovery Examples: I decided to share other sufferers' stories so you won't feel alone in your illness. Finding Your Mate and Getting Married: Having a mate is one of the most important pillars in your life as a sufferer. In this chapter, you learn some of the most important basics in this matter. Preventing Future Seizures and Getting Help: This chapter shows how to reduce the chance of having future psychotic disorder seizures and, even if you experience one, how to make it as minimal as possible. Dieting and Exercising: This chapter demonstrates how to acquire easy life habits in order to survive your years to come in the healthiest manner possible. Living by Yourself and Earning Your Own Money: This chapter shows how to earn your own money and live by yourself as a result. Ways of Getting Support: There is nothing like a good support system in order to rehabilitate in the best matter possible. This chapter discusses the most basic and powerful ways of getting support. Quitting Smoking: In this chapter, you learn the basic principles of why and how to quit smoking. Learning a Profession and Finding a Job: In this chapter, you learn the most important factors for learning a profession and finding a job.

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Potential in using drosophila zebrafish and primates as models for schizophrenia

Two major goals in building model organisms animals for schizophrenia are to address molecular mechanisms and to utilize them for transla-tional means, such as drug screening. In order to address neuronal connectivity, deficits in which may underlie the pathology of the disease, drosophila and zebrafish are frequently used in basic neuroscience. Therefore, efforts in modulating schizophrenia-associated genes in these organisms have been started in several laboratories (Drerup et al., 2009 Sawamura et al., 2008 Wood et al., 2009). In addition, these organisms are potentially useful in high throughput screening, as far as straightforward readouts relevant to the disease are available. Schizophrenia may be able to be modeled in lower organisms and rodents when we focus mainly on translatable (particularly neuropatho-logical, molecular, and physiological) markers. Nonetheless, the question of how to model high brain functions, probably more specific to primates, still remains unanswered....

General Treatment of Psychosis

The management of the psychotic PD patient begins by searching for correctable causes, including infection, metabolic derangements, social stress, and drug toxicity. Infections may not always cause fevers in the geriatric population, so a search for urinary tract infections or pneumonias is warranted. Some PD patients who did not manifest psychotic symptoms at home may decompensate upon moving into the hospital environment. In many of these cases, moving the patient into a secure familiar environment or treating the underlying medical illness may ameliorate psychotic symptoms (19). Finally, medications with CNS effects may cause or exacerbate psychosis in PD and are often overlooked. These medications include pain or sleeping medications such as narcotics, anxiolytics, hypnotics, and antidepressants. If psychotic symptoms persist despite identification and correction of the above factors, antiparkinsonian medications are slowly reduced and if possible discontinued. Antiparkinsonian...

Long Term Outcome of Treatment for Psychosis

Goetz and Stebbins (5) described 11 PD patients in a nursing home with hallucinations, all of whom were never discharged from the nursing home and died within two years. In an open-label extension of the U.S. double-blind clozapine trial, only 25 of completers died over a 26-month observational period. Forty-two percent were in nursing homes, 68 were demented, and 69 were still psychotic (4). A separate study of 39 parkinsonian patients, treated with clozapine for psychosis, found that only 15 had died over a span of five years and 33 had been admitted to nursing homes (115). There are few studies looking at whether or not patients can be weaned off their antipsychotic medications. Fernandez et al. tried to wean off clozapine or que-tiapine in psychiatrically stable PD patients with a history of drug-induced psychosis. The study had to be aborted after enrolling only six patients, who had all been on their antipsychotics for an average of 20 months (116). Five experienced worsened...

The dopamine hypothesis of schizophrenia

The dopamine hypothesis of schizophrenia has so far been the most influential hypothesis about schizophrenia (Howes and Kapur, 2009). In 1966 Jacques Van Rossum proposed that overstimulation of dopamine receptors could be part of the etiology of schizophrenia (for a historical review (Baumeister and Francis, 2002)). The hypothesis was originally based on the observation that known psycho-stimulants, such as amphetamine, induce stereotypic motor behaviors. These behaviors could be blocked by antipsychotic medication, such as chlorpromazine, which by interfering with dopamine function was known to lead to parkinsonian-like movement disorders. Arguably, the strongest support for the dopamine hypothesis was provided in the 1970th by Solomon Snyder and Philip Seeman who found that the efficacy of antipsychotic medication correlated directly with its occupancy of dopamine receptors. The identification of an effective drug target for psychosis does however not necessarily imply that this...

Interval Timing Sensitivity in Persons at Risk for Schizophrenia

Given the findings of different sensitivities to modality effects in young and aged populations, it is worthwhile to consider whether the existence of modality effects may prove a useful tool for examining the cognitive and neurophysiological bases of timing via studies of patient populations. For example, a number of studies have reported temporal processing deficits in patients diagnosed with schizophrenia (Sz). Overestimation of duration in the seconds range has been reported for verbal One difficulty with studying cognitive processing in a psychiatric population, however, is that performance deficits may be a consequence of a lack of motivation or task comprehension rather than a specific cognitive deficit. In addition, psychiatric patients are often medicated, and most psychoactive drugs have varied effects on cognitive processing. These difficulties may be circumvented through studying unmedicated individuals at genetic risk for the psychiatric disorder in question. The risk to...

Dysbindin1 in schizophrenia

Et al., 2001), variation in DTNBP1 was reported to be associated with schizophrenia (Straub et al., 2002). Such an association of this disorder with single nucleotide polymorphisms (SNPs) or combinations of them (haplotypes) in DTNBP1 has now been reported in 17 other studies across the globe (see Talbot et al., 2009). It is not surprising, then, that DTNBP1 is among the top candidate genes for schizophrenia (Allen et al., 2008 Sun et al., 2008). dysfunctional in schizophrenia, namely the dorsolateral prefrontal cortex, the superior temporal gyrus, and the hippocampal formation (Talbot et al., 2004, 2009 Tang et al., 2009). As a result, there has been increasing interest in determining the functions of dysbindin-1 to understand how its reduction may contribute to clinical features of schizophrenia. Our ability to discover those functions in living animals is limited by the absence of known pharmacologic agents affecting the levels of dysbindin-1 or its protein-protein interactions and...

Does the sdy mouse model aspects of schizophrenia

While the Dtnbp1sdy mutation has not been found in schizophrenia cases, homozygous sdy mice share multiple biological, behavioral, and cognitive features of schizophrenia. Like homozygous sdy mice as described above, schizophrenia cases display reduced synaptic dysbindin-1 (Talbot et al., 2004, 2009 Tang et al., 2009), evidence of hyperactive mesolimbic dopamine pathways (Laruelle, 2003), and disrupted glutamatergic-GABAergic interactions in prefrontal cortex (Lewis and Moghaddam, 2006). Schizophrenia cases also display the reduced PPI, decreased social interactions, and multiple cognitive deficits of homozygous sdy mice described above that are shared with other proposed mouse models of schizophrenia (Powell and Miyakawa, 2006 Maz-zoncini et al., 2009). Indeed, the spatial memory deficits displayed by homozygous mice in the Morris water maze (Cox et al., 2009) and the T-maze (Takao et al., 2008) resemble those displayed by schizophrenia cases in a virtual Morris water maze task...

Schizophrenia as an affliction of the association cortices

Schizophrenia is characterized by fundamental cognitive deficits that significantly impede daily life and social relationships (Barch, 2005). Neu-ropathological and imaging studies have shown deficits in the structural integrity and functional activity of the frontal and temporal association cortices in patients with schizophrenia, particularly in the dorsolateral prefrontal cortex (PFC) (Lewis and Gonzalez-Burgos, 2006 Ragland et al., 2007). Neuropathological studies have revealed loss of dendritic spines (Selemon et al., 1995 Glantz and Lewis, 2000) from the layer III pyramidal cells in dorsolateral PFC that form the recurrent excitatory networks which subserve representational knowledge, our mental sketchpad (Goldman-Rakic, 1995). Recent studies suggest that many of the so-called positive symptoms of schizophrenia such as hallucinations and delusions likely involve disruption of association cortical processing as well. For example, auditory hallucinations may arise from impaired...

Schizophrenia bipolar disorder and major depressive disorder

All three major psychiatric disorders, schizophrenia, bipolar disorder (BP) and major depressive disorder (MDD) affect brain cytoarchitecture. Along with numerous histopathological signals of neuronal malfunction (e.g. reduction in neuronal size, dendritic length and dendritic spines density), these diseases also affect glial cells. There are some indications for loss of astrocytes and GFAP expression in schizophrenia, BP and MDD. In BP and MDD, significant decreases in the numbers and volume of astroglial cells were detected in prefrontal and orbital cortex. It is important to note that none of these psychiatric disorders were considered previously to be associated with reactive gliosis and glial proliferation. Schizophrenia also results in a decrease in the number of oligodendrocytes and reduction in myelin in cortical areas. The consequences of astroglial loss may be multifactorial, as they can include diminished synaptic support, altered clearance of neurotransmitters and impaired...

The utility of AAV vectors in modeling schizophrenia susceptibility

Understanding the pathophysiology of genetic polymorphisms that effect risk for psychiatric disease is challenging. Although simple model systems play an important role (Reinke and White, 2002 Davis, 2004), psychiatric disorders such as schizophrenia appear to involve complex changes in higher brain circuits (Lewis and Sweet, 2009), necessitating the study of higher mammalian species and NHPs in particular. Unfortunately, NHPs are not easily subject to genetic investigation due to a long generation time and difficulties with the manipulation of NHP embryos.

Pathophysiology of Psychosis and Risk Factors

The pathophysiology of psychosis in PD is poorly understood, but dopaminergic and serotonergic mechanisms have been proposed. One theory is that chronic excessive stimulation of dopamine receptors, particularly in the mesolimbic mesocorti-cal pathways, causes hypersensitization, resulting in psychosis when patients are treated with dopaminergic agents (36). However, exogenous dopamine supplementation by itself is not the only factor in the development of psychosis since all PD medications (anticholinergics, dopaminergics, and amantadine) can induce similar hallucinations despite their different mechanisms of action (25), and PD psychosis was described prior to the use of levodopa (37). Serotonin has been implicated because the atypical antipsychotic drugs are purported to work through their high affinity for 5-HT2 compared to D2 receptors. However, PD patients with psychosis have decreased serotonin content in the brainstem at autopsy (38). Potential explanations for this finding...

Psychosis

Psychosis is a disorder characterized by hallucinations, delusions, or disorganized thinking (13), and is estimated to occur in 20 to 40 of PD patients (14,15). The most common manifestations of psychosis in PD are visual hallucinations (14,16-18). Although visual hallucinations are a common feature of patients with dementia with Lewy bodies (DLB), and may occasionally occur in demented PD patients who are not taking medications, the vast majority of PD patients who develop psychotic symptoms do so on antiparkinsonian therapy, and may return to their nonpsychotic baseline if the PD medications are discontinued (19-21). All antiparkinsonian drugs, not just dopaminergic agents, have been demonstrated to cause psychosis (22-25). Visual hallucinations in PD may occur at any time, and may be vivid and realistic, or out of focus. Patients may experience presence hallucinations (the sensation that someone or something is in the room) or passage hallucinations (brief visions seen in the...

Schizophrenia

Persons who have received a diagnosis of schizophrenia will often experience some or all of the following Clearly, an active phase of this disorder will probably render an individual incapable of effective collaboration and communication (Bloom, Williams and Bigelow, 1992 Kaliski, 1995). In those cases where psychotic symptoms are currently inactive, and thus at least temporarily in 'remission', there may be a working basis for participation in mediation. From a classic reference designed for the families of persons with schizophrenia

So Should it be Psychiatry Psychology and

The distinctions, and divisions, between psychiatry and psychology may be exaggerated. Organisational differences, based upon education routes, may be more important than is necessary for the functional duties. It has been suggested that psychologists are as (or more) competent to treat neuroses, the more behavioural mental disorders. Psychiatrists could specialise on the psychoses. Psychologists are increasingly being recognised as the lead discipline with regard to treating, or responding to, personality disorders (Blackburn, 1993). They have certainly been prominent in the analysis and prediction of dangerousness (Monahan et al., 2001). An official inquiry into abuses at a secure mental health hospital in England, chaired by a judge, readily meted out criticism of individuals (Fallon et al., 1999). It received a recommendation that the

Evidence And Psychotherapies

The current book will provide an important update on issues such as whether or not all therapies really are equal and whether it really does not matter what the content of therapy is because outcomes are very much the same. We hope to show that, although this conclusion has some truth, in particular in its focus on the need for a positive therapeutic relationship, at the level of specific psychological disorders that range from simple phobias to severe psychoses there is evidence of differential effectiveness of therapies - that some things help and that some things do not.

Advantage of genetic animal models

Many epidemiological studies have suggested that initial brain insults associated with schizophrenia occur mainly during early neurodevelopment. Nonetheless, the real onset of the disease is in young adulthood. These observations indicate that postnatal brain maturation may play an important role in the pathology of schizophrenia (Jaaro-Peled et al., 2009). Administration of compounds that can induce psychosis in humans, such as phencyclidine, into adult animals has been widely used for modeling schizophrenia (Mouri et al., 2007). Although these models are useful in recapitulating the pathophy-siology of schizophrenia in part, it is very difficult to mimic the long-term pathological changes leading from disease-associated insults (triggers, risk factors) during pre- and peri-natal stages to the onset of the disease in young adulthood. To overcome this limitation, introduction of brain lesions by toxins during early development has been considered as an alternative strategy for...

Connections Between Interval Timing Neuropharmacology And Drug Abuse

Gene-dosage effects of the DAT can be observed. Wild-type mice (+ +) have a normal (100 ) level of the DAT. There is 50 expression of the DAT in heterozygous mice (+ -) and a total lack of the DAT in homozygous mice (- -). Dopamine stays in the synapse 100 times longer in - - mice than in + + mice. Mice without the DAT are five to six times more active than wild-type mice and have been used as an animal model of cocaine and amphetamine addiction, attention deficit hyper-activity disorders, and schizophrenia (see Cevik, this volume Gainetdinov and Other molecular mechanisms underlying the role of dopamine in interval timing may be studied using catechol-o-methyltransferase (COMT) deficient mice. Although there are many proteins involved in the biological actions of dopamine, COMT, because it metabolizes released dopamine primarily in the prefrontal cortex may be a critical marker for schizophrenia and cognitive functions such as interval timing (Egan et al., 2001).

Possible limitations of genetic animal models

As described above, schizophrenia is not caused by any single factor instead, a combination of several genetic and environmental factors results in the disease. A major limitation in most technologies for genetic manipulation in animals is that only one gene can be modified per generation, except by utilizing laborious cross-breeding experiments, whereas modulation of more than one gene may be expected to more faithfully mimic the etio-pathological condition of schizophrenia. How can we overcome this dilemma Mouse models generated by in utero gene transfer or by stereotaxic injection of virus-mediated expression or RNAi constructs, through which we can manipulate expression of more than one gene simultaneously, may open a new window toward overcoming this limitation (Kamiya et al., 2008). Although these mice are not genetic models in a strict sense (because the manipulation is not heritable), these strategies are very important to model schizophrenia by utilizing information about...

Cognitive and Emotional Factors

Accompany mental illness, at least while there is evidence of psychotic symptoms. Over the last 10 years, however, it has become increasingly apparent that, even when a well-established, global, measure of overall intellectual ability is used (for example, the Wechsler Adult Intelligence Scale (3rd edition) Wechsler, 1999), it is an inadequate predictor of the ability to make a particular decision. Indeed, even the verbal parts of such assessments, though they normally correlate positively with judgements of capacity, do not accurately predict decision-making ability (Grisso et al., 1995 Wong et al., 2000). This is, perhaps, not surprising since each subtest normally reflects a variety of skills, including abstract ability, attention, motivation, and educational background (Kaufman and Lichtenberger, 1999). As a result, similar scores, even on a single subtest and in people with the same diagnosis, may reflect different underlying patterns of skills and difficulties. Nevertheless,...

Neurological Disorders

Sometimes, especially in Japan and the Philippines, ephedrine is taken specifically as a psychostimulant. In Japan, BRON, the OTC cough medication containing methylephedrine, dihydrocodeine, caffeine, and chlorpheniramine, is very widely abused, and transient psychosis commonly results (76-78). Reports of ephedrine-related psychosis following prolonged, heavy use are fairly common (101-105). In general, psychosis is only seen in ephedrine users ingesting more than 1000 mg day, and it resolves rapidly once the drug is withdrawn (106). Ephedrine psychosis closely resembles psychosis induced by amphetamines paranoia with delusions of persecution and auditory and visual hallucinations, even though consciousness remains unclouded. Typically, patients with ephedrine psychosis will have ingested more than 1000 mg day. Recovery is rapid after the drug is withdrawn (103). The ephedrine content per serving of most food supplements is on the order of 10-20 mg, making it extremely unlikely that,...

Regionspecific targeting by in utero gene transfer

The proper development of prefrontal cortex, together with the subcortical regions of the limbic system, including the hippocampus and amygdala, is important for mediating higher brain functioning, such as cognition, memory, and emotion. Each of these regions is implicated in the pathophysiology of schizophrenia (Harrison and Weinberger, 2005). Although many types of genetically engineered animal models including inducible and conditional systems have been established, region-specific gene targeting has not

Celltypespecific targeting by in utero gene transfer

Many types of cells are reportedly impaired at functional and morphological levels in the brains of patients with schizophrenia. Smaller size and or disarray of pyramidal neurons in hippocampus and prefrontal cortex have been repeatedly reported (Benes et al., 1991 Pierri et al., 2001). Impaired dendritic arborization and orientation as

Genetic Factors In Personality Disorders

Thus, the heritability coefficient for personality disorders as a whole was .60 (.37 for Cluster A, .60 for Cluster B, and .62 for Cluster C). The lower heritability for Cluster A may seem paradoxical, given the relationship of these disorders to schizophrenia, but it could have been an artifact of a sample in which the base rates of these traits were relatively high, reducing the heritability coefficient.

Cognitive Therapy Areas Of Application

The last few decades have seen cognitive therapy adapted for mood, anxiety, personality, eating and substance misuse disorders. As well as these formal psychiatric disorders, cognitive therapy has been adapted for relationship problems and the psychological aspects of a range of medical disorders. Most recently cognitive therapy has been applied to the problem of anger generally and its manifestations in conflict specifically, while colleagues, mainly in England, have applied cognitive therapy to people with psychosis. A thorough review of these applications is beyond the scope of this chapter, but a brief overview is provided for the main areas of application. Interested readers may wish to follow up the references describing these adaptations and the following excellent reviews of evidence-based psy-chotherapies (Compas et al, 1998 De Rubeis & Crits-Cristoph, 1998 Fonagy et al., 2002 Kazdin & Weisz, 1998 Rector & Beck, 2001).

Multiplegene targeting feasibility for studying disease pathways

Schizophrenia is likely a polygenetic disorder with multiple genetic risk factors likely acting synergis-tically or epistatically (Harrison and Weinberger, 2005 Jaaro-Peled et al., 2009). Since in utero gene transfer technique can modulate the expression of more than one gene simultaneously, this technology is particularly useful for studying molecular disease pathways in which several risk factors may converge. In fact, we have previously reported a possible convergent molecular pathway at the centrosome in the developing cerebral cortex where DISC1, PCM1 (another risk factor for schizophrenia), and BBS4, a causative gene for Bardet-Biedl syndrome (BBS) that frequently accompanies cognitive deficits and psychosis, seem to functionally interact with one another (Kamiya et al., 2008). We found that suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4, and are exacerbated by the concomitant suppression of both DISC1...

Conditional targeting system

Discussed above, many genetic factors for schizophrenia have roles at different timings during neurodevelopment (Harrison and Weinberger, 2005 Jaaro-Peled et al., 2009), such that DISC1 has roles in cell proliferation, neuronal migration, and dendritic development spine formation in the developing cerebral cortex as well as synapse function in cerebral cortex and positioning of newborn neurons in the dentate gyrus at the adult stage (Duan et al., 2007 Jaaro-Peled et al., 2009 Kamiya et al., 2005 Mao et al., 2009). Therefore, it is critical to segregate each molecule's functions in the developmental stages as well as the adult stage in order to address these mechanisms precisely. To overcome this limitation, an inducible gene expression system has been recently applied to in utero gene transfer (Matsuda and Cepko, 2007). In this system, a plasmid construct in which Cre recombinase is expressed in response to intraperitoneally injected 4-hydroxytamoxifen (4-OHT) and a target gene or...

Nature And Nurture In Treatment

A nature-based perspective would tend to support providing biological treatment for patients with personality disorders. But the efficacy of drugs has to be proved in clinical trials. Currently, severe personality disorders are often seen by psychiatrists who prescribe pharmacotherapy. In the borderline category, patients are often prescribed as many as four to five drugs (Zanarini, Frankenburg, Khera, & Bleichmar, 2001). Yet the value of pharmacotherapy in this group is not well substantiated. While a number of drugs have been used (Soloff, 2000), the best that can be said for them is that they take the edge off symptoms such as impulsivity (Paris, 2003). Notably, all agents were originally developed for other conditions neuroleptics for schizophrenia, antidepressants for depression, and mood stabilizers for bipolar disorder. When we understand the unique pathophysiology associated with personality traits and disorders, we may be in a better position to develop more specific and more...

Cognitive Therapy for Different Populations and in Different Settings

Twenty-five years of increasingly sophisticated research suggests that cognitive therapy is effective to a clinically significant degree for a majority of patients with a variety of presenting problems in a range of populations and settings. An evidence-based conclusion is that cognitive therapy is a treatment of choice for people diagnosed with depression, generalized anxiety, panic, bulimia nervosa, psychosis and a range of somatoform disorders. More recently, preliminary outcome studies suggest cognitive therapy is a promising intervention for people diagnosed with personality disorders and substance misuse, but further research is indicated.

Anupamaa J Seshadri and Akiko Hayashi Takagi

Abstract Schizophrenia (SZ) is a highly polygenic disease with strong genetic predisposition. Although genetic susceptibility factors for SZ are likely to have an influence in some brain regions and related neural circuits during neurodevelopment, direct proof for spatiotemporal causality in the development of SZ, and the alteration of what gene function at what brain region during what developmental stage, remains to be elucidated. Gene manipulation by viral vector stereotaxically injected into a specific brain region is now becoming available for psychiatric research. This technique has several advantages, e.g., the exceptional spatiotemporal control, simultaneous manipulation of multiple genes, and its simple protocol. These properties can make this technique one of the most valuable approaches for research in SZ, which is a complex brain disorder with multifactorial, genetic, and developmental features. This review summarizes the benefits and actual use of this technique together...

Dsm Hierarchical Organization Of Mental Disorders

Notice that these categories are organized essentially along a severity continuum from psychosis (most severe) to transient situational disorders (least severe). Each of these secondary categories was further subdivided. For instance, part of the classification of personality disorders in the DSM-I had the following hierarchical structure

Crystal Structures Of Gsk30 Inhibitor Complexes

GSK-3 has been considered a target for adult onset diabetes 34-36 , stroke 37,38 , Alzheimer's disease 39,40 , bipolar disorder 41 , and schizophrenia 42,43 . The ATP binding site has been the preferred site for kinase drug design and the crystallization of inhibitors with GSK-3 P is relatively straightforward. Unphosphorylated protein and ligand readily form diffracting crystals when combined with a mixture of PEG and salt (e.g., 5 ). The PEGION screens from Hampton Research or Nextal Biotechnologies yield crystals under multiple conditions. The crystals typically have the same space group as the native unliganded protein, although exceptions have been observed (e.g., the GSK-3P complex with 6-bromoidurubin, PDB 1UV5 44 ). The space group is P212121 with unit cell dimensions 83, 86, and 127 A, and 90 angles, and there are two GSK-3P inhibitor complexes in the asymmetric unit. The Protein Data Bank contains seven crystal structures of GSK-3P in complex with non-ATP inhibitors, all of...

Examples of model mice from the library

The ENU mutant mouse library at RIKEN has been open to research community since 2002. Researchers who are interested in having mutant strains carrying allelic series of ENU-induced point mutations in their target gene may request the screening of the RIKEN library through http With respect to schizophrenia, the disrupted in schizophrenia 1 (Disc1) and serine racemase (Srr) genes were screened as candidates based upon researchers' requests and two and one mutant DISC1 is one of the risk factors for schizophrenia. It was initially identified at translocation (1 11) (q42.1 q14.3) that was linked to major mental sickness, including schizophrenia, depression, and bipolar disorder in a large Scottish family. Toronto's group designed three pairs of PCR primers, which cover entire exon 2 of the mouse Disc1 gene. We identified four point mutations (Table 2) and Toronto's group decided to analyze two missense mutations, Q31L and L100P. Extensive behavioral, pharmacological, anatomical, and...

Atypical Antipsychotics

Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or infectious causes, it is unclear how the atypical antipsychotics cause increased mortality. Since psychosis can be difficult to treat in PD, it is likely that these agents will continue to be utilized until a direct cause and effect relationship is uncovered. Number of psychosis improved

Cholinesterase Inhibitors

In multiple AD trials, cholinesterase inhibitors had mild-to-moderate benefits in both cognition and psychosis (101,102). Cholinesterase inhibitors are also effective for psychosis in DLB patients and are a potential alternative to the atypical antipsy-chotics for PD psychosis. An early open-label study with tacrine showed that five of seven demented PD patients had complete resolution of psychotic symptoms (103) however, the use of this drug has been limited because of hepatic toxicity. Fabbrini et al. (104) administered donepezil (5 mg qhs) to eight nondemented PD patients with visual hallucinations, with or without delusions. At the end of two months, subjects had decreased PPRS scores with hallucinations and paranoid ideation, being the most responsive. However, two patients experienced clinically significant motor decline. Another small open-label study enrolled six patients with PD, dementia, and psychotic symptoms and treated them with 10 mg d of donepezil (105). Five patients...

The Explanatory Pseudo Unification Generated by Freuds Compromise Model of Neuroses Dreams and Slips

As I have argued, the same moral applies to Freud By invoking the alleged causal cogency of the method of free association as a warrant for his compromise model, he generated a pseudo-unif ication of neurotic behavior with dreaming and the bungling of actions. This dubious unification was effected by conceiving of the normal activities of dreaming and occasionally bungling actions as mini-neurotic symptoms, of a piece with abnormal mentation in neuroses and even psychoses. To emphasize this monistic psychopathologiz-ing of normalcy, Freud pointedly entitled his magnum opus on slips The Psychopathology of Everyday Life (1901). To this I can only say in metaphorical theological language Let no man put together what God has kept asunder, a gibe that was used by Wolfgang Pauli, I believe, against Einstein's unified field theory.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is an effective treatment for primary psychiatric disorders, especially treatment-resistant depression. Experience with ECT for PD psychosis, however, is limited to case studies. ECT has been demonstrated to be beneficial in PD patients with psychosis (112-114), and can transiently improve parkinsonian motor symptoms, but may require a period of hospitalization, and result in significant confusion. ECT should only be considered when patients are resistant to pharmacological therapies.

Inducible gene expression models

Precise control of gene expression is an invaluable tool in studying complex physiological processes. The usefulness of tissue- or cell-specific promoters to express target genes in the selected tissues or cells has been widely used with success (Zhu et al., 2002). However, if the activity of a promoter is constitutive, there is no control over the timing of the expression. In the beginning, a major reason to have a temporal control over-expression of a transgene was to avoid its possible adverse or even lethal developmental effects. This has been, for example, critical for animal models of neurodegen-erative diseases as the effects of the mutation are thought to take place mostly in adulthood. Thus, attempts have been made to generate inducible mouse models to avoid potential toxic effects of transgenes during early development (e.g., Yama-moto et al., 2000). In the field of genetic animal models of schizophrenia and related developmental disorders, the issue of temporal regulation...

General Treatment of Dementia

Similar to the guidelines governing the general treatment of psychosis, any sudden change in cognition or behavior is most likely due to a medical cause. Therefore, infections, metabolic and endocrine derangements, and hypoperfusion states should be considered and treated if present. A switch to an unfamiliar environment may also precipitate an acute deterioration in cognitive status, and can be helped to a small degree with reassurance and frequent orientation. Substance abuse, including reliance on over-the-counter preparations containing antihistamines, is another factor that may be commonly overlooked. A review of the medication list is necessary

Inducible expression of mutant DISC1

We generated a mouse model of conditional and inducible expression of human mutant DISC1 using the Tet-off system (Pletnikov et al., 2008). Mutant DISC1 is a hypothetical protein product of the balanced t(1 11) chromosomal translocation identified in a Scottish pedigree with high load of major mental disorders, including schizophrenia and major depression (Millar et al., 2001 Ishizuka et al., 2006 Chubb et al., 2008). Fine mapping and cloning have identified a disrupted gene on associated with increased spontaneous locomotor activity in male but not female mice, decreased social interaction and increased aggressive behavior in male mice when measured in open field test, and decreased spatial recognition memory in Morris water maze in female mice only despite comparable rates of learning between mutant and control mice. These alterations are reminiscent of positive and negative symptoms, and cognitive impairments seen in schizophrenia (Ross et al.,

Inducible expression of the fragment of human DISC1

Taken together, this study was the first to convincingly demonstrate that disruption of DISC1 functions during early postnatal period but not adulthood can produce a set of behavioral, neuroanatomical, and neurophysiolo-gical alterations that are consistent with aspects of schizophrenia and mood disorders. The weak Another successful example of using inducible genetic mouse model to explore the developmental etiology of schizophrenia-like neurobehavioral abnormalities has been reported by Kelly and associates (Kelly et al., 2009). Their study sought to evaluate a role of the G-protein subunit Gas in the pathophysiology of neurobehavioral schizophrenia-like abnormalities in mice. Recently, a polymorphism that increases mRNA levels of Gas was associated with schizophrenia (Kelly et al., 2009). The authors analyzed the relative contributions of developmental vs. postnatal expression of the transgene to schizophrenia-related behavioral alterations. Gas mice exhibited unaltered startle...

Project Title Developing Cellular Cardiomyoplasty For Injured Heart

Conditions and because of the limitations of definitive therapeutic interventions. R02MH49428 There is abundant evidence to suggest that neuropsychiatric disorders such as schizophrenia and autism are caused in many cases by genetic abnormalities that affect development and function of forebrain neural systems involved in cognition and emotion. The largest structures of the forebrain are the cerebral cortex and the striatum both have been implicated as having a role in neuropsychiatry disorders. The goal of my research is to understand how genes regulate development of the striatum. To this end, my laboratory has identifies the D1x genes, which encoded a family of homeodomain transcription factors that are candidates for having a central role in striatal development. There are four known D1x genes that are expressed in the embryonic forebrain. The aims of the experiments proposed in this grant application are focused on (1) elucidating the sequence of these genes and their encoded...

Familial Parkinsonism

Less common than ARJP are autosomal dominant forms of early onset PD. The best characterized is the Contursi kindred, a familial PD due to a mutation in the a-synuclein gene (62). The pathology of the Contursi kindred is typical Lewy body PD however, given the young age of onset, by the time the individual dies, Lewy body pathology is typically widespread in the brain. Lewy neurites are also prominent in many cortical areas. Some young onset autosomal dominant PD kindreds, such as the Iowa kindred, have atypical clinical presentations and include family members with dementia and psychosis. The Iowa kindred has a multiplication of the a-synuclein gene (63). Families with duplications have a milder phenotype than those with a triplication of the a-synuclein gene, suggesting a role for overexpression of a-synuclein in the pathogenesis of even sporadic PD (64). The pathology in cases with gene triplication is associated with severe Lewy body-related pathology in the cortex, hippocampus,...

Neurophysiology of NR1KD mice sensory processing and gamma oscillations

Changes in NR1-KD mice in the coherence or phase coupling of gamma and theta oscillations. The rhythmic firing of neuron ensembles is described as gamma or theta oscillations based on their frequency (for example 20-80 Hz), and the interstructural synchronization of these oscillations is enhanced during cognitive tasks (Siapas et al., 2005 Sirota et al., 2008). In the study by Dzirasa et al., multiple recording electrodes were placed in different structures of the brain, including prefrontal cortex, hippocampus, and pre-limbic cortex, and oscillations are simultaneously detected at different frequencies and in different brain regions. Coupling of gamma oscillations to other firing rhythms, like theta oscillations, was measured by recording local field potentials while mice explored novel environments or remained in their home cage. The authors report that NR1-KD show a profound deficit in the interstructural (hippocampal-cortical) phase coupling between theta and gamma oscillations....

Iimonoamine Oxidase Fadcontaining

And dopamine, and the synthetic tertiary amine 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) has been found to be oxidized by both forms of MAO, which suggests that MAO may oxidize MPTP analogs and generate toxic effects on the central nervous system. These features make MAO an extremely important enzyme related to neuronal dysfunction in schizophrenia, Parkinson's disease, Down's syndrome, and some other neurodegenerative diseases and psychological disorders in human, and vast numbers of its inhibitor have been developed as medicines.

Dopaminergic hyperfunction in the striatum

A dopaminergic hyperfunction in schizophrenia, as originally postulated, has been found in the striatum of patients using a variety of techniques. Some, though not all, postmortem studies have detected, an increase in subcortical dopamine and homo-vanillic acid (HVA a metabolite of dopamine) even in unmedicated patients (Davis et al., 1991). This is consistent with the repeated findings of increased Fluoro-Dopa (F-Dopa) uptake in the striatum of patients with schizophrenia, which measures dopamine synthesis by the dopamine synthesizing enzyme L-amino-acid decarboxylase (Frankle, 2007). An increase in F-Dopa uptake has recently been found also in prodromal patients (Howes et al., 2009). Because prodromal patients have not yet fully developed the disease, this is an indication of increased striatal dopamine synthesis at an early stage in the disease process. Evidence for elevated dopamine release in the striatum comes from PET imaging studies showing an augmented amphetamine-induced...

Cortical dopaminergic hypofunction

Since depletion of dopamine in the prefrontal cortex impairs working memory in monkeys (Brozoski et al., 1979) and working memory deficits are central to schizophrenia, it has been thought that altered dopamine input to the prefrontal cortex could be involved in the cognitive deficits of schizophrenia. Rather than a hyperfunction of the prefrontal dopamine system, as measured in the striatum and postulated by the original hypothesis of schizophrenia, a hypofunc-tion of the prefrontal dopamine system was proposed (Davis et al., 1991 Weinberger, 1987). Direct evidence for a decrease in presynaptic dopamine synthesis was later provided by a postmortem study that showed a decrease in tyrosine hydroxylase immunoreactivity in the prefrontal cortex (Akil et al., 1999). If in schizophrenia the cortical dopaminergic projections are indeed hypoactive, D1 receptors may be upregu-lated in the cortex of patients, to compensate for decrease in dopamine release. Using 11C NNC as a D1-specific PET...

Marshall L Silverstein

During the past 30 years, the fields of personality disorders and psychoanalytic self psychology have developed important reformulations of personality. The contemporary period of conceptualizing personality disorders began by operationalizing diagnostic criteria and assigning these disturbances to their own axis of classification in the multiaxial structure that originated with the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III American Psychiatric Association, 1980). Thus, continually refining criteria and differentiating personality disorders from syndromal disorders securely established a basis for investigating the clinical psychopathology of the personality disorders. This approach continued the neo-Kraepelinian tradition that substantially influenced contemporary American concepts of schizophrenia and affective disorders. It set the pace for the empirical studies that were to follow, emphasizing matters of diagnostic overlap or comorbidity,...

Summary And Conclusions

Of course, if modality-specific switch-accumulator modules are assumed, then it should be possible to isolate these timing modules in the brain. The evidence from the study with persons at high risk for developing schizophrenia is valuable in this regard because it indicates that it is possible for modality differences to be exacerbated in some populations. Significantly, the exaggerated modality effect appeared to be mediated by the visual modality because differences in auditory response functions between the HrSz and NC groups failed to obtain. This outcome provides additional support for the idea that there are multiple modality-specific switch-accumulator modules and that these modules can be independently modulated.

Translinbinding elements

Translin binds consensus sequences in the neighbourhood of breakpoints of chromosomal translocations in haematological malignancies (Aoki et al., 1995). The presence of translin-binding sequence, together with or within Alu repeats, has been detected in the formation of the bcr-abl fusion gene in CML (Jeffs et al., 1998 Martinelli et al., 2000). Translin-binding motifs occur in liposarcoma showing t(12 l6) (ql3 pl 1) in the close vicinity of the translocation breakpoint (Hosaka et al., 2000). TRAX binding sequences have been found within about 150-250kb of the translocation breakpoint at lq42.1, which dislocates and segregates the DISCI and DISC2 candidate genes in patients with schizophrenia (Millar et al., 2000). The alveolar rhabdomyosarcoma is characterised by t(2 13)(q35 ql4) and a fusion gene PAX3-FKHR results out of this translocation. The breakpoints in the derivative chromosome 13 contain sequences that resemble those of translin (Chalk et al., 1997). We have noted earlier...

Michele P Kelly and Nicholas J Brandon

Keywords cAMP cGMP cyclic nucleotide second messenger mouse model transgenic knockout mutant psychiatry schizophrenia phosphodiesterase intracellular signaling Phosphodiesterases (PDEs) are the only enzymes known to degrade cyclic nucleotides, and there are 11 families of PDEs identified to date (c.f., Bender and Beavo, 2006 Lugnier, 2006). Most PDE families are expressed in the brain, but no two PDEs show the same regional subcellular distribution, enabling exquisitely precise regulation of cyclic nucleotide signaling (c.f., Houslay and Milligan, 1997). Great attention has been paid in recent years to the potential of PDEs as therapeutic targets for treatment of neurological dysfunction and psychiatric disorders, particularly schizophrenia (Houslay et al., 2005 Brandon et al.,

Other mouse models showing changes in PDE activity

Gas transgenic mice, which overexpress either a wild-type isoform (Gas mice) or a constitutively active isoform (Gas* mice) in the forebrain, exhibit a number of behavioral (hyperlocomotor activity, sensorimotor gating deficits, and hippocampus-dependent associative and spatial memory impairments) and anatomical endophenotypes (enlarged ventricle, reduced striatum) associated with psychiatric diseases such as schizophrenia (Kelly et al., 2007, 2008, 2009). These behavioral abnormalities appear to be related to compensatory decreases in cortical and hippocampal cAMP that are triggered by a PKA-dependent upregulation of total PDE activity. Studies in Gas* mice suggest that this upregula-tion of total PDE activity is specifically due to increased activity of PDE1 and, possibly, PDE4 (Kelly et al., 2008). Consistent with a role for upregulated PDE activity in the behavioral deficits of these mice, the pan-PDE4 inhibitor rolipram ameliorates sensorimotor gating deficits...

The Risks Posed by Prenatal and Perinatal Infection

There has also been a long-standing suspicion that prenatal infections and obstetrical complications may play a role in certain neurodevel-opmental disorders and psychiatric conditions (Mednick et al, 1998). Viral infections have been implicated as possible causative agents for both autism and attention-deficit hyperactivity disorder (ADHD), although both of these pediatric conditions are obviously very complex and can be caused by other factors as well. Even more has been written about the possible involvement of prenatal infections as the reason for the brain dysfunction underlying schizophrenia (Brown, 2006 Byrne et al, 2007 Torrey and Torrey, 1979 Yolken et al, 1997). Concerns about exposure to influenza during pregnancy have been

Dynamic Psychotherapy

Monsen et al. (1995) conducted a prospective study of 25 outpatients in a unit specialising in personality and psychosis 23 patients met DSM-III criteria for personality disorder at the outset. Treatment consisted of intensive psychodynamic psychotherapy, based on self-psychology and object relations, delivered over an average of 25.4 months. At the end of therapy 72 of patients no longer met criteria for personality disorder and showed significant change in affect consciousness, characterological defences and symptoms as measured by the clinical scales of the Minnesota Multiphasic Personality Inventory and the Welsh Anxiety and Repression scales. At follow-up (mean period of 5.2 years) these changes remained generally stable.

The Construct Of Psychopathy

He described psychopaths as individuals incapable of leading normal lives who cause great distress in their community, despite an outer mask of robust mental health. By analogy with semantic aphasia, he hypothesized that their attributes resulted from a deep disorder in semantic processing, which impaired emotional awareness of what the most important experiences of life mean to others. He proposed 16 criteria, such as absence of psychosis or nervousness, superficial charm, unreliability, insincerity, lack of remorse, egocentricity, and interpersonal unresponsiveness, although some criteria seem peripheral to the construct (e.g., suicide rarely carried out, fantastic and uninviting behavior with or without drink). A further source of conceptual drift is the absence from the PCL-R of several items considered critical by Cleckley, notably absence of psychosis and absence of nervousness. The omission of these exclusionary criteria questions whether the measurement model matches that...

Mouse Models With Reduced Gsk3 Activity

These GSK-3P heterozygous knockout mice were used by Beaulieu et al. and O'Brian et al. in two recent studies. In the first study Beaulieu et al. demonstrated in dopamine transporter knockout mice that this monoamin-ergic neurotransmitter implicated in multiple brain disorders such as Parkinson's disease, schizophrenia, or attention deficit hyperactivity disorder 42 can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt PKB and GSK-3 43 . In this study increased dopamine neurotransmission arising either from administration of amphetamine or from the lack of dopamine transporter resulted in inactivation of Akt and concomitant activation of GSK-3a and GSK-3P. These biochemical changes were effectively reversed by the administration of the GSK-3 inhibitor lithium. The GSK-3P heterozygous knockout mice reproduced the effect of lithium in behavioral tests, thus establishing this cascade as an important mediator of dopamine action in vivo.

Fertility and Aging Men An Introduction to the Male Biological Clock

Although increasing maternal age has long been known to be associated with an increased incidence of birth defects, new data show that the age of the male does matter and the genetic quality of sperm does decline with age. Several studies have demonstrated that older men are at higher risk of fathering a child with various genetic diseases such as schizophrenia and Down Syndrome, to name a few. Additionally, there has been an increased risk of miscarriage with increasing paternal age.

Advanced Paternal Age and Reproductive Capacity

A trend toward advanced parental age is simultaneously occurring in American men. The birth rate among men 25 to 44 years has been steadily increasing since the 1970s, whereas the birth rate of men less than 25 years has been decreasing (Hamilton et al., 2003). An improved understanding of the effects of increased parental age on the developing fetus and newborn is imperative for counseling older couples preparing for childbearing. Advanced paternal age has been suggested to result in increased spontaneous abortions, autosomal dominant disorders, trisomy 21, and recently, schizophrenia. In contrast to the effects of combined parental age in trisomy 21, schizophrenia is associated with spontaneous mutations arising in the paternal germ cells. Although schizophrenia is a complex disease of unclear etiology, there is substantial evidence for a genetic component (Kendler et al., 1993). Since most individuals with schizophrenia are born to unaffected parents and have reduced...

Relationship to White Matter Physiology Pathology

The applications of DTI are rapidly growing, in part because the diffusion tensor is exquisitely sensitive to subtle changes or differences in tissue at the microstructural level. DTI studies have found differences in development (e.g., Barnea-Goraly et al. 2005 Snook et al. 2005) and aging (e.g., Abe et al. 2002 Pfefferbaum et al. 2005 Salat et al. 2005), and across a broad spectrum of diseases and disorders including traumatic brain injury (diffuse ax-onal injury) (Werring et al. 1998 Salmond et al. 2006), epilepsy (Concha et al. 2005a), multiple sclerosis (Cercignani et al. 2000 Rovaris et al. 2002 Assaf et al. 2005), ALS (Ellis et al. 1999 Jacob et al. 2003 Toosy et al. 2003), schizophrenia (Buchsbaum et al. 1998 Lim et al. 1999 Agartz et al. 2001 Jones et al. 2006), bipolar disorder (Adler et al. 2004 Beyer et al. 2005), OCD

Psychological Science Barriers to Participation in Mediation

It has been specifically acknowledged that by virtue of various psychological disabilities, not all persons may be capable of participating in mediation. 'In order for the mediation process to work, the parties must be able to understand the process and the options under discussion, and to give voluntary and informed consent to any agreement reached' (ADA Mediation Guidelines Work Group, 2000, p. 7). Psychological science has identified several conditions that may impair (and even obviate) meaningful engagement (Drogin, 2000c). Most prominent among these are depression, substance dependence, schizophrenia, and mental retardation.

Clinical manifestation

Impairment of alertness, neck stiffness and focal or lateralising neurological signs (e.g. hemiparesis, aphasia) are not typical for HIVE. Psychotic symptoms without cognitive or motor disturbance do not warrant a diagnosis of HIVE. The coincidence of psychosis with HIVE is rare. Focal and generalized epileptic seizures are rare manifestations of HIVE.

Synaptic transmission

Overexpression of cell surface D2 dopamine receptors (D2Rs, Iizuka et al., 2007), such mice may model the dopaminergic hypothesis of schizophrenia according to which its positive symptoms are associated with hyperactivity of the mesolimbic dopaminergic pathway and with hyperstimulation of D2Rs. by pyramidal cells evident in reduced paired-pulse facilitation in the homozygous mice. Such an impairment in the pyramidal cells was consistent with the fact that they displayed (1) less frequent miniature EPSCs (mEPSCs) in both heterozygous and homozygous mice and (2) smaller amplitude mEPSCs and eEPSCs in homozygous mice. The EPSC alterations indicate abnormally low basal levels of excitatory input on the deep pyramidal cells despite their lower spike thresholds in both the heterozygote and homozygote mice. This may be due to the reduced GABAergic input observed in the prelimbic homozygous sdy mice (Trantham-Davidson et al., 2008). Such input derives in part from fast-spiking,...

Ldopa and parkinsonian syndrome

Parkinson's disease is a common neurological disorder, affecting 1 of the people over the age of 60 years it is a disease with the signs of rigidity, resting tremor, postural instability, which is due to underproduction of the neurotransmitter dopamine (DA) (70). One of the factors leading to PD is the marked loss of melanized nigrostriatal dopamine neurons, one of the principal components responsible for the normal control of movement. Signs of PD do not appear until a large majority of the nigrostriatal DA neurons have been damaged. Another factor that may mitigate the loss of nigrostriatal DA neurons in PD is a reduced rate of DA activation (71). Also, mitochondrial swelling was noticed as a result of low concentrations of DA, causing a mitochondrial damage triggering neurodegenerative process and PD (72). DA receptors are expressed not only in the central nervous system (CNS), but also in several peripheral tissues including arteries, heart, thymus, and peripheral blood...

Considering a Patient for a Surgical Procedure

Psychiatric symptoms (hypomania, depression, suicide, or impulse control disorders) can be aggravated or induced by functional neurosurgery (33). Patients referred for surgical consideration are usually referred in the knowledge that they have an absence of dementia or active psychiatric symptoms, and yet a recent review revealed that the presence of depression (60 ), anxiety (40 ), and psychosis (35 ) with 23 of the 40 patients assessed requiring preoperative psychiatric management (34).

Cognitive Behaviour Therapy

Although the school of behaviour therapy evolved empirical treatments for the management of schizophrenia, it chiefly focused on social skills and behavioural disturbances (Meichen-baum, 1969). Moreover the behavioural work was dominated by operant reward systems through external reinforcers, both positive and negative. This was an acceptable option in the 1970s. In the postmodern era this began to be seen as mechanistic with no reference to the patient's own attitudes and inner experiences. As management of schizophrenia shifted to the community, there were serious concerns whether the reinforcement-based improvement would generalise to the community settings. Unfortunately studies were not devised to answer this issue. The cognitive behavioural approach, with its success in the management of depression and anxiety disorders (Department of Health, 2001), soon turned its focus to schizophrenia. It had the advantage of collaborative relationship and shared formulation of the patient's...

Cognitive Remediation

Cognitive remediation is much more popular in the US than the UK (Turkington, Dudley & Warman, 2004). It is a rehabilitative approach, which has traditionally been applied to cognitive deficits in stroke and traumatic head injuries, with good evidence (Cicerone et al., 2000). Therapists using this approach hope to correct the cognitive deficits of schizophrenia, which affect neuropsychological functioning in the affected individuals. Studies show improvement in the laboratory environment, but do not appear to generalise to patients' own environment (Lehman et al., 2004). Trials of cognitive remediation have focussed on attention, verbal memory, visual memory and executive functioning. Although there are few positive results, a meta-analysis of pooled data did not show clear differences between cognitive remediation and controls (Pilling et al., 2002a). Moreover, trials are small in size and not adequately controlled for medication effects. Perhaps the mechanisms of cognitive deficits...

Psychodynamic Therapy

Psychodynamic therapy has had a historical role in emphasising a psychological perspective of psychosis. Concepts of psychodynamic therapy may inform understanding of psychotic experiences. Clinicians working with psychosis will frequently sense the avoidant defensive attitude some patients have when confronted with reality. Moreover a sense of dissolution of ego boundaries is distinct in acute psychotic episodes. However, psychodynamic therapy for schizophrenia is not a viable approach (Mueser & Berenbaum, 1990) as there is little evidence to suggest that psychodynamic techniques are effective in the management of symptoms of psychosis (Malmberg, 2001).

Relationship to Behavioural and Neural Functioning

As for FA, MTR is a non-specific marker of neural damage, such as demyelina-tion. Many of the published MT studies have focused on patients with multiple sclerosis, who show decreased MT in both ROI and whole-brain histogram analyses. In other diseases, results are similar, indicating MTR is a viable marker for affected white and gray matter. MTR has been shown to increase with brain development during the first several years of life (Rademacher et al. 1999 van Buchem et al. 2001) and regional decreases with aging have been found (Armstrong et al. 2004). Differences in MTR were sufficiently large to distinguish patients with mild cognitive impairment from patients with Alzheimer's disease and controls (Kabani et al. 2002a Kabani et al. 2002b). A number of published studies have also used magnetization transfer methods to compare the brains in patients with schizophrenia against healthy control subjects (Foong et al. 2001 Bagary et al. 2003 Kiefer et al. 2004 Kubicki et al. 2005)....

Primary psychotic disorders

Psychosis that occurs independently of infection with HIV is to be seen as a comor-bid condition. Diseases such as schizophrenia, schizophreniform disorder and brief psychotic disorder can be classified into this group. Typical symptoms are delusions, hallucinations, disorganized speech (e.g. frequent derailment or incoherence) or grossly disorganized or catatonic behavior. Etiopathogenetically, a biopsychoso-cial concept, the vulnerability-stress-coping model, is assumed. It is thought that genetic and psychosocial factors determine a predisposition or an increased vulnerability for psychotic decompensation. Therefore, an infection with a neuropathological virus such as HIV could trigger a pre-existing psychosis (Einsiedel 2001).

Social and Interpersonal Processes

Social relationships are intimately tied to well-being and mental health (Sullivan, 1953). The close association between mental health and social interpersonal processes is highlighted by the pervasiveness of severely impoverished social networks and deficits in social skills of persons with schizophrenia, depression, social anxiety, and eating disorders for example. Primary assumptions embedded in social and interpersonal perspectives in behavioral medicine are that interpersonal disturbances may function as (1) causally disruptive phenomena in the development of mental illness, (2)

Cognitive and Psychiatric Disturbances

On rare occasions, other psychotic states, mimicking schizophrenia or other delusional syndromes, may occur in MS. Limited data suggest that the patient with these symptoms may have more disease in the temporal lobe periventricular area (127,128). Also, one must always consider the possibility of iatrogenic symptomatology in patients being treated with a variety of the medications used in MS.

Molecular genetic techniques in zebrafish

Multiple schizophrenia susceptibility genes have been identified including neuregulin 1 (Stefansson et al., 2002, 2003), COMT (catechol O-methyl transferase) (Egan et al., 2001 Bilder et al., 2002), dysbindin (Straub et al., 2002) and DISC1 (Disrupted In Schizophrenia 1) (Millar et al., 2000). There are established molecular genetic techniques available to readily study the function of these susceptibility genes in zebrafish. Mor-pholino oligonucleotides (MOs) are used in zebrafish to transiently decrease the expression of a particular gene reviewed in (Bill et al., 2009) . MOs are designed anti-sense to a targeted RNA and contain 25 morpholine bases with a neutrally charged phosphorodiamidate backbone. In addition to loss-of-function studies, methods have been developed to perform gain-of-function studies in zebrafish. Specifically, in vitro transcribed mRNA of a particular gene can be injected into the embryo, resulting in protein overexpression. The length of transient expression...

Zebrafish as a model to study brain development

The zebrafish model system can be used to study a multitude of neurodevelopmental processes that may be disrupted in schizophrenia pathogenesis including neurogenesis, neuronal migration and cell fate determination. Neurogen-esis occurs in both the larval and adult zebrafish (Tropepe and Sive, 2003 Grandel et al., 2006 Zupanc, 2008 Lam et al., 2009). Adult neurogen-esis in the teleost brain including regions homologous to the hippocampus and olfactory bulb in mammals has been extensively studied and I refer readers to multiple reviews describing this work in detail (Grandel et al., 2006 Zupanc, 2008 Lam et al., 2009).

Katsuo Furukubo Tokunaga

Abstract Schizophrenia is a debilitating mental illness that affects 1 of the population worldwide. Although its molecular etiology remains unclear, recent advances in human psychiatric genetics have identified a large number of candidate genetic risk factors involved in schizophrenia. Modeling the disease in genetically tractable animals is thus a challenging but increasingly important task. In this review, I discuss the potential problems and perspectives associated with modeling schizophrenia in fruit flies, and briefly review the recent studies analyzing the molecular and cellular functions of Disrupted-In-Schizophrenia-1 (DISC1) in transgenic flies. Keywords schizophrenia genetic model Drosophila sleep cAMP ATF mushroom body

Bloodinjury And Injection Phobia

People who require frequent administration of medication by injection, such as diabetics or those with chronic psychosis, are in danger if they are not able to tolerate injections. In a sample of over 1 200 people with insulin-dependent diabetes (Mollema et al., 2001) around

Cognitive Reserve May Provide Some Functional Protection

Cognitive reserve implies that people have different capacities to withstand functional decline in the context of the amount of brain injury, and there may be a number of reasons for this. Cognitive reserve presumably reflects cognitive and or brain capacity, which in turn sets the threshold for neurocognitive dysfunction after brain injury (276, 277). The fact that cognitive reserve is associated with educational and occupational attainment may either point to the benefits of environmental enrichment. Alternatively, greater educational and occupational accomplishment reflects stronger premorbid cognitive abilities and greater intrinsic functional brain capacity. This second possibility is supported by the evidence that cognitive reserve is associated with increased brain size and weight, increased dendritic arborization and length, and improved neuronal efficiency. Genetic predisposition also influences neuronal development and ultimately the amount of brain reserve that exists....

Drosophila as a model for cellular and molecular studies of susceptibility genes

Although a number of animal models have been used to examine different pathophysiological aspects of schizophrenia (Arguello and Gogos, 2006), flies are most suitable for examining cellular and molecular processes, which occur upstream of the observed clinical psychopathology. The complete genome sequence of Drosophila melanoga-ster has been determined as early as in 2000 (Adams et al., 2000), and direct comparison of the genomic sequences demonstrates that a large number of genes are conserved between flies and humans (Venter et al., 2001), making Drosophila as an ideal model system for the study of molecular and cellular functions. Such an approach would help to identify the cellular and synaptic substrates underlying the developmental or functional disruptions observed in schizophrenic patients, and to identify molecular and genetic components interacting with the gene products, resulting in the elucidation of gene pathways and cellular processes involved in psychological...

Physical Psychological And Socioeconomic Sequelae

Apart from the physical injuries sustained by child soldiers, another area of concern for aid agencies and healthcare workers is the psychological health of these children. A recent Belgian study revealed the extent of this problem in a voluntary survey of former child soldiers of Uganda's notorious Lord's Resistance Army. Of the 301 children interviewed, 77 had witnessed at least one killing, 39 had been forced to kill, 39 had abducted other children, 63 had looted and burned civilian homes, and 52 had been seriously beaten. A secondary survey was conducted on a randomly selected subgroup of 75 children, of whom 71 agreed to participate. They completed a questionnaire designed to evaluate the extent of posttraumatic stress disorder (PTSD). A score of greater than 24 on the impact of event scale-revised (IES-R), which is a self-report scale akin to the DSM-IV criteria for PTSD, indicates clinically significant symptoms. The mean IES-R score was 53.5, with 97 of participants falling...

Symptom Distress in Patients with Advanced Cancer

Prior to death and that the early symptoms were often misdiagnosed as anxiety, anger, depression, or psychosis.60 In a survey of 140 patients with cancer who were referred for neurologic assessment of encephalopathy, a multifactorial cause of this problem was found for most patients. A single cause of the altered mental status was found in 33 of patients whereas 67 had multiple causes. Drugs (especially opioids), metabolic abnormalities, infection, and recent surgery were the most common etiologic fac-tors.61 In important work, Bruera and colleagues studied 66 episodes of cognitive failure in 39 patients admitted to a palliative care service and demonstrated that this condition is often reversible during the last weeks of life.62 Drugs, sepsis, and brain metastasis were found to be the most frequently detected etiologic factors, and 22 (33 ) of the 66 episodes improved, 10 spontaneously and 12 as a result of treatment. Although delirium is more commonly seen at the end of life, it can...

Documentng Effective Treatment

There are well established efficacious ESTs for anxiety, depression, bipolar disorder, schizophrenia, tobacco addiction, obesity, anorexia, cocaine abuse, and more. No treatment for personality disorder is listed as well established efficacious, but treatments for avoidant (social skills training) and borderline personality disorder (dialectical behavior therapy) have made it to the list of probably or possibly efficacious approaches (Chambless & Ollendick, 2001, Table 2).

Arthur A Simena Ralph DiLeonea and Amy FT Arnstenb

Abstract Schizophrenia is a disorder of the association cortices, with especially prominent structural and functional deficiencies in the dorsolateral prefrontal cortex (PFC). True dorsolateral PFC is found only in higher primates, and is characterized by highly elaborate pyramidal cells with extensive recurrent connections. The development of the primate PFC also involves distinct developmental and genetic pathways. Thus, primate models may be particularly important in determining the functional impact of genetic changes in patients with schizophrenia. Genes involved with pyramidal cell network connectivity may be especially important to study in primates, as their effects may be magnified in the extensively connected primate neurons. Adeno-associated virus technology appears particularly promising for studying the impact of genetic insults on the structure and function of the primate association cortex. Schizophrenia is a profound cognitive disorder with established...

Amanda Elkin Sridevi Kalidindi Kopal Tandon and Peter McGuffin

The World Health Organization (WHO) estimates that at least one in four people will experience a clinically significant episode of psychiatric illness at some point in their lives. Although most such disorders are short lived and do not result in specialist care many cases become disabling and the WHO Global Burden of Disease Study (Murray and Lopez, 1997) has estimated that in health economic terms unipolar depression (UPD) vies with cardiovascular disease as the leading cause of disability in adults world wide. Schizophrenia and bipolar affective disorder (BPD) are also major public health problems which feature in the WHO's top ten of economically burdensome diseases. Between them, the affective disorders (UPD and BPD) and schizophrenia also account for over 60 of completed suicides. Therefore we will here focus on these three conditions as the main exemplars of common complex psychiatric disorders with substantial genetic contributions.

Clinical features and epidemiology

Schizophrenia is characterized by hallucinations, delusions, disorder of the form of speech and psychomotor disturbance. These are collectively often called positive symptoms. Negative symptoms are less conspicuous but can be more disabling and include diminished motivation, social withdrawal and cognitive impairment, such that the old name for the syndrome was dementia praecox (early dementia). It typically arises in early adulthood with a lifetime risk of around 1 in both men and women, although the average age of onset is consistently earlier in men.

Positional candidate genes

Despite the fact that there remain ambiguities surrounding linkage findings in schizophrenia, several groups have been sufficiently emboldened to embark on detailed searches within putative linkage regions which has led to the publication within the past two years of a flurry of papers implicating several positional candidate genes in schizophrenia. Essentially, a positional candidate is a gene within a region of the genome identified by linkage studies that could plausibly be involved in the pathogenesis of the disorder. Having identified a candidate, its role is then examined further by testing for allelic association. This involves identifying DNA variants or polymorphisms within the gene and then testing whether a particular allele (an alternative variant) or a particular haplotype (a block of alleles carried together on the same chromosome) is more common in cases than in healthy controls. As an alternative to such case-control comparisons, a within-family design can be used. For...

The great areal expansion of the association cortices

As can be seen in Figs. 1 and 2, the PFC expands tremendously from rodents to primates, even on the medial surface (Fig. 2) where rodent PFC is concentrated. The region of PFC most afflicted in schizophrenia the granular dorso-lateral PFC- does not exist in rodents, or even in some lower primates (Preuss, 1995). Instead, the medial PFC in rodents shares greatest anatomical and functional homology with some medial PFC areas in monkey (Preuss, 1995).

Interactions Between Medical Illness and Psychiatric Symptoms Longitudinally

Of corticosteroids, which are known to produce side effects that include euphoria, and less commonly depression and psychosis (Lyons et al, 1988). Typically trials of treatments for psychiatric disorders among illnesses like MS exclude patients from enrollment while exacerbations are occurring to reduce the likelihood of spontaneous improvement in psychiatric symptoms resulting from resolution of the exacerbation (Mohr et al, 2005). This avoids problems illustrated above with arrow (c), in which changes in illness-driven psychiatric symptoms result in high rates of spontaneous remission. However, given MS patients with relapsing forms of the disease may have an exacerbation every 1-2 years, 16.7-33.3 of all patients enrolled in a trial might be expected to experience an exacerbation during the course of a 16-week intervention, resulting in MS-related increases in psychiatric symptoms. Assuming that an exacerbation may last 2 months, 8.4-16.7 of the sample could be in exacerbation at...

The Influence of Environmental Factors on Psychiatric Symptoms

Can produce symptoms of mania and psychosis (Black and Friedman, 2006 Lyons et al, 1988). Similar to how features of the medical illness can have variable effects on psychiatric symptoms, so can treatments of the illness. These treatments can exert continuous or episodic influences on psychiatric symptoms, potentially influencing RCT outcomes.

Advent of viral technology

Highly efficient gene discovery analyses are revealing gene expression changes associated with PFC function and or schizophrenia. The challenge that remains is how to most efficiently and effectively manipulate these genes to assess functional consequences in animal models. There are a number of approaches for manipulating gene expression including both transgenic and viral methods. Viral methods allow for efficient testing of gene function with spatial (e.g. specific brain region) and temporal (e.g. during development or in the adult) control. In the case of the PFC and schizophrenia, viral approaches offer the advantage of being effective across species, including NHPs that cannot be manipulated via

Relevance to DISC1 function

DISC1 has emerged as one of the most important schizophrenia susceptibility genes. DISC1 was initially implicated in risk for schizophrenia when a Scottish family was identified with a translocation between chromosome 1 and chromosome 11 leading to a truncation of the DISC1 gene, reduced DISC1 expression, and strong linkage to schizophrenia and other serious mental illness (Wilson-Annan et al., 1997 Millar et al., 2001 Porteous and Millar, 2006). Single nucleotide polymorphisms in DISC1 were later found to be associated with schizophrenia but with much lower penetrance (Porteous et al., 2006). DISC1 interacts with a great many proteins including NDEL1 and PDE4B, and cAMP regulates some of these associations (Brandon, 2007). DISC1 shows very high conservation between human and rhesus monkey relative to rodent species (Bord et al., 2006), consistent with the need to study NHPs. One important question with regard to DISC1 is whether the effects of polymorphisms depend on specific...

The greatly increased complexity of primate PFC neurons

Pyramidal cell network connections as a key site of vulnerability in schizophrenia between PFC pyramidal neurons whose activity is sculpted by GABAergic interneurons (Goldman-Rakic, 1995). The interconnection of precise microcircuits is a fragile process, and many of the genetic alterations associated with schizophrenia appear to impact these network connections. These include genes key to the development of dendritic architecture (Lewis and Levitt, 2002), but also gene products needed for appropriate activity of the established circuit. For example, physiological studies in monkeys indicate that recurrent excitation between PFC pyramidal cells depends on N-methyl-D aspartate (NMDA) receptors (M. Wang and A. Arnsten, unpublished), and several genes associated with NMDA transmission have been linked to schizophrenia (Coyle et al., 2003). Disrupted In Schizophrenia (DISC1) and nicotinic a7 receptors have also been localized in PFC spines, and both have strong links to schizophrenia...

Self Psychologically Influenced Framework For Personality Disorders

A related form is the schizotypal personality disorder, representing generally a more compromised adaptation having much in common clinically with schizoid personality. Because it is also linked with the genetic familial influences of the soft schizophrenia spectrum, schizotypal disorder is likely associated with an inborn deficit of responsivity to maternal care coupled with chronic exposure to the impaired empathic capacities of genetically vulnerable mothers. Such mothers are undoubtedly compromised in anticipating or ministering to the needs of young infants. Perhaps this inborn deficit in such vulnerable children and infants represents an aspect of temperament related to the compromised neurodevelopmental disturbance of schizophrenia and schizophrenia spectrum conditions (Murray, O'Callaghan, Castle, & Lewis, 1992). Difficulties may become apparent when a child early on shows subtle manifestations of a genetic vulnerability to a schizophrenia spectrum condition. Thus, in one type...

Psychological Functioning In People With Intellectual Disabilities Mental Illness And Dementia

With a diagnosis of schizophrenia (or one of its variants) or an affective disorder (such as severe depression), or bipolar disorder (manic depression). (For details of the clinical features of these conditions, see sections 4 and 5, of Gelder et al. (2000). For personal accounts of the experience of mental illness, see British Psychological Society (2000) and Solomon (2002)). About 40 of people who experience a single episode of mental illness recover fully. Most of the remainder make at least a partial recovery, although they may continue to need treatment and support at times only a small minority require assistance for almost all their lives (Kuipers and Bebbington, 1987).

Zebrafish as a model to study behavior

Schizophrenia is characterized by a multitude of positive and negative symptoms including hallucinations, delusions and social withdrawal as well as cognitive deficits (Lewis and Lieber-man, 2000 Harvey et al., 2002). In the field of schizophrenia research, the mouse is typically used as a model to study the behavioral abnormalities seen in schizophrenia including deficits in working memory, impaired sensory motor gating and increased activity hyperloco-motion (Lipska and Weinberger, 2000 Arguello and Gogos, 2006 Powell et al., 2009). It is difficult to generate an animal model that can recapitulate all of clinical symptoms of a complex behavioral disease like schizophrenia. However, zebrafish provide the unique opportunity to perform large forward genetic screens to identify new genes involved in a particular behavior in addition to studying behavior in a genetically characterized mutant line. Of particular interest to the field of schizophrenia are behavioral assays relating to...

Cns Disorders And Gsk3 Inhibitor Lithium

Lymphocytes of patients with schizophrenia have impaired GSK-3 protein levels and activity 52 , and GSK-3 is reduced in the frontal cortex of postmortem schizophrenic brains 53 . Since the Wnt family of genes plays a central role in normal brain development, it is possible that during development impairment in GSK-3 may lead to abnormal neuronal development.

Behavioral pharmacology of NR1KD mice

This behavioral readout is most easily amenable to evaluating drugs with antipsychotic action, and also has construct validity because exploratory ambulation is regulated by neurotransmitters and neurocircuits that have been implicated in schizophrenia. NR1-KD hyperactivity is attenuated by first- and second-generation antipsychotics haloperidol, clozapine, olanzapine, and by the D2 dopamine receptor agonist quinpirole (Mohn et al., 1999 Duncan et al., 2006 Ramsey et al., 2008). The same antipsychotic doses that attenuate MK-801-induced hyperactivity are also effective in NR1-KD mice. It is likely that, in the behavioral paradigm of locomotor activity in a novel environment, the majority of drugs that reverse MK-801-induced hyperactivity will also attenuate NR1-KD hyperactivity. It is of interest to determine whether non-dopaminergic drugs will be effective in normalizing the exploratory behavior of these mice. Because their hyperactivity is a result of...

Natural History And Longterm Outcome In Personality Disorder

There are fewer data on natural history and long-term outcome in other personality disorders. Existing findings suggest that the prognosis for schizotypal personality disorder may be limited (Aarkrog, 1981,1993 McGlashan, 1986a Stone, 1993). McGlashan found that these patients fared only slightly better than those with schizophrenia and a Scandinavian study providing a 20-year follow-up of 50 schizotypal individuals showed poor social and occupational functioning (Aarkrog, 1993). Schizoid personality disorder, infrequently seen in psychiatric settings in the absence of comorbidity, also appears stable over time (Wolff &

DISC1 analyses in flies

Disrupted-In-Schizophrenia-1 (DISC1) is a promising genetic factor for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression, and autism spectrum conditions (Harrison and Weinberger, 2005 Ishizuka et al., 2006 Chubb et al., 2008 Kilpinen et al., 2008 Jaaro-Peled et al., 2009). DISC1 was originally identified as the gene located on chromosome 1 and interrupted by a balanced translocation t(1q42.1 11q14.3) that is linked to psychopathology including schizophrenia, depression, and bipolar disorder in a large Scottish family (St Clair et al., 1990 Millar et al., 2000). Cellular and molecular studies have revealed that the DISC1 protein has multiple functions and is located in several distinct domains in cells, including the centrosome, the postsynaptic density, the mitochondria, and the nucleus (Millar et al., 2005 Kirkpatrick et al., 2006). DISC1 has specific protein interactors, which correspond to each subcellular domain, including NudE-like...

Humanistic Therapies Theoretical Basis

These givens can live an authentic existence (Heidegger, 1962), true to their experience of the world. However, attempts to avoid the angst, or existential anxiety, which accompanies the awareness of one's essential nothingness (Kierkegaard, 1954) can lead a person into a life of inauthenticity or bad faith (Sartre, 1951), in which, for example, their actions are determined by conformity with values other than their own. Another path to psychological disturbance, but in this case to a likely diagnostic label of psychosis, is an authenticity untrammelled by any acknowledgement of external reality. Although an early meta-analysis suggested less favourable outcomes for humanistic therapies (Smith, Glass & Miller, 1980), more recent meta-analyses have indicated large effect sizes for pre- to post-treatment change in these therapies, particularly with relationship problems, anxiety and depressive disorders and trauma, with treatment gains generally being maintained at follow-up (Elliott,...

NR1KD as a representative model of NMDA receptor hypofunction

Means exhaustive, a short list of models for these regulatory genes includes those that have been implicated in schizophrenia by genetic or postmortem studies. Mutants for serine racemase (Basu et al., 2009 Labrie et al., 2009), glutamate carboxypeptidase II (Han et al., 2009), calcineurin (Miyakawa et al., 2003), and neuregulin 1 (Stefansson et al., 2002, and see accompanying chapter of this issue) all have indications of impaired NMDA receptor function, and display altered phenotypes relevant to schizophrenia. In this sense the NR1-KD mouse is merely a representative in the much larger effort to understand the physiological consequences of sustained NMDA receptor hypofunction that can be achieved with genetic models.

Clinical features of FRAXE disease

Patients with the expanded FRAXE repeats show mild to borderline mental retardation, with delays in language development a common problem. Some FRAXE patients also exhibit behavioral abnormalities, such as attention deficit, hyperactivity, autistic-like behavior, even schizophrenia and obsessive-compulsive disorder (OCD) (Gecz 2000b Wang et al. 2003). Most patients with FRAXE are not easily distinguished from the general population as there are no consistent physical features in these patients, and FRAXE is considered to be a non-syndromic form of mental retardation. However, among FRAXE patients, reports of a long, narrow face, mild facial hypoplasia, a high-arched palate, irregular teeth, hair abnormalities, angiomata, clin-odactyly, thick lips and nasal abnormalities can be found (Barnicoat et al. 1997 Biancalana et al. 1996 Carbonell et al. 1996 Hamel et al. 1994 Knight et al. 1996 Mulley et al. 1995 Russo et al. 1998). In addition, in some families, the FRAXE fragile site does...

Origin of STn Overactivity in PD

The DBS technique was useful in suggesting the neural pathway through the STn mediate temporal memory retrieval. But the way this occurs in finer detail remains elusive. Future research revolving around the attempt to identify the respective neural mechanisms underlying the time-specific distortions of learning and retrieval may bring new insights for the underlying neurobiological mechanisms associated with cognitive sequelae of mental disorders (i.e., PD, schizophrenia).