Traditional Antipsychotics Research Articles

Atypicality of Atypical Antipsychotics Revisited

Background: All antipsychotic agents marketed since clozapine have been categorized as “atypical”, without regard for the true definition of “atypicality”. The standard practice of designating every new agent as “atypical” not only ignores the definition, but conveys a false sense of safety for the majority of these medications when considering the risks of movement disorders, both acute and latent. Though receptor profiles are unique to each medication, the antipsychotic effect of all agents is attributed to reducing dopamine activity in the mesolimbic area, usually through the blockade of dopamine type 2 (D2) receptors, whether the agent is “tightly” or “transiently bound”. Yet, antagonism of D2 receptors in the striatum is associated with the potential for extrapyramidal symptoms (EPS), as well as the development of tardive dyskinesia (TD). Clozapine is categorized as “atypical” because its use is not associated with EPS or TD at a rate greater than placebo, as it provides antipsychotic efficacy at a lower saturation of D2 receptors than traditional antipsychotics. As newer second-generation agents came to market, the definition of “atypical” has been modified to include a variety of characteristics unrelated to movement side effects. Nevertheless, many clinicians still assume that “atypicality” indicates a risk of EPS and TD at no-greater-than-placebo rates. Objective: This paper examines each of the 10 second-generation agents approved in the United States for treatment of schizophrenia (and cariprazine, for which approval is pending), and examines which ones meet the strict definition of “atypical” (ie, risk of EPS and TD no greater than placebo). Data source: A literature search using PubMed and Google Scholar, involving various combinations of the keywords “antipsychotic,” “atypical,” “typical,” “first generation,” “second generation,” “schizophrenia,” “tardive dyskinesia,” “movement disorders,” and “extrapyramidal symptoms,” in addition to the 11 agents by chemical name, yielded a vast set of clinical trials, systematic reviews, case reports, and receptor-profile studies. These articles and reports were narrowed to the appended reference list, based on the report’s/trial’s contribution to the discussion of “atypicality.” Results/Conclusions: Of the 10 second-generation agents currently in use, and the one awaiting approval, only clozapine, quetiapine, and iloperidone meet the criteria necessary for the designation of “atypical” (ie, rates of EPS and TD no greater than placebo).

Use of antipsychotics in the treatment of depressive disorders.

SummaryThere is a long history of using antipsychotic medications in the treatment of depressive disorders. Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical antipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid (GABA), cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration (USFDA) has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment-resistant depression. When using atypical antipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms (EPS), weight gain, and hyperglycemia.

Accidental clozapine intoxication in a toddler: clinical and pharmacokinetic lessons learnt

Clozapine, a second generation antipsychotic which is relatively safe in overdose, has been used as an effective treatment alternative to traditional antipsychotics. The therapeutic use in children remains controversial. However, in accordance with the increasing prescription in adults, the accidental ingestion in childhood becomes more frequent. We report the youngest case of accidental clozapine ingestion. A 13-month-old girl presented with acute respiratory insufficiency and coma of unknown origin. The medical history, laboratory and radiological assessment did not link to aetiology until an almost spontaneous arousal after 22 h pointed towards intoxication. The initial standard drug screening using immunoassay had been negative. Hence, liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) was performed, and clozapine was detected with a serum concentration of 736 ng/mL. This case illustrates the diagnostic and forensic pitfalls in a coma of unknown origin due to the limits of toxicological screening immunoassays. LC-MS/MS analysis by an established method showed clozapine metabolites (norclozapine and clozapine-N-oxide) are detectable for longer period, especially in urine, when compared with clozapine. The clinical course is presented in unique correlation with plasma and urine concentrations of clozapine and its metabolites. The elimination pattern of clozapine in toddlers is similar to adults, and the toxic dose was found to be lower when compared with school-age children and adults.

Psychotic exacerbation and emotional dampening in the daily life of patients with schizophrenia switched to aripiprazole therapy: a collection of standardized case reports

Blockade of the dopamine D2 receptor is a key mechanism in the antipsychotic treatment of patients with a psychotic disorder, but may also induce emotional deficits. The partial D2 agonistic profile of aripiprazole has, therefore, been suggested to favor emotional wellbeing compared with the pure dopamine antagonistic properties of traditional antipsychotics. The current study used the experience sampling method (a structured diary technique) to assess the effects of switching from treatment with traditional dopamine antagonist antipsychotics to treatment with the partial dopamine agonist aripiprazole on emotional wellbeing in the daily life of 13 patients with a diagnosis of schizophrenia. More than half of all patients experienced exacerbation of psychotic symptoms after they had switched to the aripiprazole medication regime, consequently resulting in dropout of the study. Furthermore, switching to aripiprazole treatment, when effective in terms of symptom reduction, was accompanied by decreased feelings of both positive and negative affect in daily life, suggestive of a general state of emotional dampening. Although the scale of the current study and the 54% dropout rate call for careful interpretation of the data, implementation of ecological monitoring in psychopharmacological research may open up new avenues for untangling the working mechanisms of compounds with regard to their impact on mental states.

Practical guidelines for the acute emergency sedation of the severely agitated older patient

The vulnerability of older people to serious underlying medical illness and adverse effects of psychotropics means that the safe and effective treatment of severe agitation can be lifesaving, the primary management goals being to create a safe environment for the patient and others, and to facilitate assessment and treatment. We review the literature on acute sedation and provide practical guidelines for the management of this problem addressing a range of issues, including aetiology, assessment, pharmacological and non-pharmacological strategies, restraint and consent. The assessment of the agitated older patient must include concurrent assessment of the likely aetiology of, the risks posed by, and the risks/benefits of management options for, the agitation. A range of environmental modifications and non-pharmacological strategies might be implemented to maximize the safety of the patient and others. Physical restraints should only be considered after appropriate assessment and trial of alternative management and if the risk of restraint is less than the risk of the behaviour. Limited evidence supports a range of pharmacological options from traditional antipsychotics to atypical antipsychotics and benzodiazepines. It is advised to start low and go slow, using small increments of dose increase. Medical staff are frequently called to sedate agitated older patients in hospital settings, often after hours, with limited access to relevant medical information and history. Safe and effective management necessitates adequate assessment of the aetiology of the agitation, exhausting all non-pharmacological strategies, and resorting to pharmacological and/or physical restraint only when necessary, judiciously and for a short-term period, with frequent review and the obtaining of consent as soon as possible.

PKC-β Activation and Pharmacologically Induced Weight gain During Antipsychotic Treatment

Atypical antipsychotics (APDs) are now the most widely used drugs in the treatment of several mental disorders such as schizophrenia, bipolar disorder and other severe behavioral disturbances [1]. Thanks to great patient benefits such as the reduction of serious side effects, for example extrapyramidal symptoms, including tardive dyskinesia and heart arrhythmias [2], APDs are replacing the traditional antipsychotics, butyrophenones and phenothiazines. In recent years, however, APDs have been found to exert a very strong impact on body metabolism, leading to the development of severe obesity, dys lipidemia and changes in insulin sensitivity, which are major risk factors associated with the development of cardiovascular complications [3]. The WHO considers this as a problem of global importance, not only because metabolic syndrome is a major cause of death in the general population, but also because it affects patients treated with APDs; up to 60% of deaths in this group are caused by this disease (with a mortality ratio of 1:57, compared with the general population) [4,5]. There is still uncertainty regarding the mechanism by which APDs can lead to severe weight gain and all of its effects, most notably the development of diabetes. In this article, we present evidence highlighting the involvement of the b isoform of the protein kinase C family (PKC-b) in this unfortunate side effect of APDs related to weight gain [6]. First, we have to keep in mind that high glucose levels resultant of PKC-b activation, drive mesenchymal stem cells from both adipose tissue (adipose derived stem cells [ADSc]) and muscle (muscle derived stem cells [MDSCs]) towards an adipogenic potential in a reactive oxygen species (ROS)-dependent mechanism [7].

All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2High Receptors

The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low). The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia. All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine. These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.

The Need for a Proper Definition of a “Treatment Refractoriness” in Tourette Syndrome

OPINION article Front. Integr. Neurosci., 06 June 2011 https://doi.org/10.3389/fnint.2011.00022

Dopamine D2 Receptors as Treatment Targets in Schizophrenia

The antipsychotic effectiveness of chlorpromazine and haloperidol started a search for their therapeutic targets. The antipsychotic receptor target turned out to be a dopamine receptor, now cloned as the dopamine D2 receptor. The D2 receptor is the common target for antipsychotics. Antipsychotic clinical doses correlate with their affinities for this receptor. Therapeutic doses of antipsychotics occupy 60 to 80% of brain D2 receptors in patients, but aripiprazole occupies up to 90%. While antipsychotics may take up to six hours to occupy D2 receptors, much clinical improvement occurs within a few days. The receptor has high- and low-affinity states. The D2High state is functional for dopamine-like agonists such as aripiprazole. Most individuals with schizophrenia are supersensitive to dopamine. Animal models of psychosis show that a variety of risk factors, genetic and nongenetic, are associated with behavioral supersensitivity to dopamine, reflected in elevated levels of dopamine D2High receptors. Although antipsychotics such as haloperidol alleviate psychosis and reverse the elevation of D2High receptors, long-term use of traditional antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic such as aripiprazole can result in the emergence of psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism and rarely result in tardive dyskinesia because they are released from D2 within 12 to 24 hours. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2High receptors and desensitizing them in early-stage psychosis.

Side effects of antipsychotic agents: Neuroleptic malignant syndrome

Summary - Neuroleptic malignant syndrome is a rare, potentially life-threatening complication which is an unpredictable, idiosyncratic reaction to antipsychotics. In patients receiving traditional antipsychotics, neuroleptic malignant syndrome occurs with an incidence of 0.2-3.3%. However, neuroleptic malignant syndrome also appears in patients treated with atypical antipsychotics, especially Clozapine. A possible cause of neuroleptic malignant syndrome is blockade of dopamine receptors in the nigrostriatal tracts or hypothalamic nuclei. If signs and symptoms of the Neuroleptic malignant syndrome are identified in time, full recovery is possible. This is a report of a female patient with neuroleptic malignant syndrome treated by traditional antipsychotics. As soon as neuroleptic malignant syndrome symptoms were recognized, the antipsychotic drugs were discontinued, symptomatic therapy was initiated and symptoms of neuroleptic malignant syndrome disappeared. However, the patient's psychotic symptoms persisted and an atypical antipsychotic was administered. During the next few days the psychotic symptoms gradually disappeared and the patient accomplished good recovery.

Psychopharmacology of aggression in children and adolescents with primary neuropsychiatric disorders: A review of current and potentially promising treatment options.

Research examining the role of pharmacological therapy in the treatment of children and adolescents with clinical disorders is growing. Clinical disorders that present with comorbid aggression can add a challenge to treatment. Child and adolescent neuropsychiatric disorders associated with aggression include attention-deficit hyperactivity disorder, various mood disorders and in particular bipolar disorders/pediatric mania, schizophrenia, mental retardation, oppositional defiant disorder, conduct disorder, and autism spectrum disorders. This review describes the psychopharmacy to treat these disorders and the aggression that often appears comorbidly. Existing literature regarding the efficacy and safety of psychotropics for youth with neuropsychiatric disorders also is discussed. In addition, general guidelines for psychopharmacy of aggression in children and adolescents are presented. Studies reviewed in this article provide evidence for the use of psychostimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood-stabilizers, atypical antipsychotics, traditional antipsychotics, and selective serotonin reuptake inhibitors in treating pediatric aggression with the choice of medication dependent on symptomology. Despite increased support for pediatric psychotropic use, there is a need for more long-term safety and efficacy studies of existing medications and newer, safer, and more effective agents with fewer side effects for the pharmacological treatment of all childhood disorders in which aggression is prominent.

Conditioned Avoidance Response in the Development of New Antipsychotics

Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6 polymorphisms on the response to other groups of clinically used drugs. Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult to establish clear relationships of their pharmacokinetics and pharmacodynamic parameters to genetic variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be recommended at present. There is initial evidence for a gene-dose effect on commonly used selective serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature. A number of clinical studies have indicated that there are significant relationships between the CYP2D6 genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone and haloperidol. However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dyskinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size, inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice. There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-tramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic. Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient. Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response. To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships, further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.

Rhabdomyolyse et élévation des enzymes musculaires sous olanzapine

Introduction “Atypical” antipsychotics tend to replace traditional antipsychotics as first line therapy for psychotic disorders, due to their better side-effect profile with fewer extrapyramidal manifestations, allowing a better observance. Nevertheless, second-generation antipsychotics may also lead to adverse events such as metabolic disorders, agranulocytosis or muscle damage. Cases of rhabdomyolysis (aside neuroleptic malignant syndrome) have been reported in patients receiving olanzapine (Zyprexa ®). Methods We reviewed the cases of olanzapine induced rhabdomyolysis reported to the French national database of drug adverse events and retrieved additional cases published in the medical literature. Results We collected 13 cases from the French pharmacovigilance database and eight additional cases from the literature. Seventeen patients needed hospitalization. Creatine kinase (CK) rate ranged between 413 and 34,500 UI/L. Outcome was favorable in 85% of the cases (17 out of 20 cases) after discontinuation of olanzapine. Conclusion Although rhabdomyolysis is a rare side effect (< 1%) of olanzapine, this adverse event should be evoked when a patient with olanzapine presents with muscle pain, unexplained fatigue or weakness. Prompt dosage of CK should be performed. However, it remains uncertain whether a mild and asymptomatic muscle enzyme increase without any metabolic disorder requires the discontinuation of olanzapine therapy.

Risperidone: the search for a better antipsychotic.

Risperidone, the latest agent in the continuing search for a better antipsychotic drug, seems to be an important addition to our treatment armamentarium for several reasons. First, risperidone is as effective as traditional antipsychotics for treating schizophrenia and perhaps more effective for treating refractory schizophrenia. Second, and related to the first point, risperidone is effective in the treatment of the negative symptoms of schizophrenia. Third, risperidone has a superior side-effect profile causing relatively few, if any, EPSEs. Fourth, risperidone may have an antidyskinetic property that, rather than simply not causing tardive dyskinesia, may actually improve those symptoms.

Prescriptions Into Practice: Aripiprazole (Abilify): A Novel Atypical Antipsychotic Medication

In the past, treatment of psychosis was centered on conventional agents, whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen emergence of newer antipsychotic agents, first with clozapine and then with risperidone, olanzapine, quetiapine and ziprasidone. In general, while demonstrating similar efficacies to traditional agents, use of these compounds may be associated with lower risk of extrapyramidal symptoms (EPS) and possibly less cognitive impairment and better effects on negative symptoms. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain, lipid, and other metabolic abnormalities. Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug, displaying clinical efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole use is also associated with lower rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole may experience EPS at a rate similar to that seen with placebo. Within the antipsychotic medication class, the introduction of aripiprazole may provide an alternative therapeutic option to traditional antipsychotics without some use limiting side effects of other atypical medications.

Bipolar depression: trial-based insights to guide patient care

For the majority of patients with bipolar disorder, major depressive episodes represent the most debilitating and difficult-to-treat illness dimension. Patients spend significantly more time depressed than manic or hypomanic, and attempt suicide more frequently during this illness phase, yet the availability of treatments remains limited. The discovery of more effective therapeutics for managing depressive episodes is arguably the greatest unmet need in bipolar disorder. This article provides an evidence-based summary of pharmacological treatments for the acute and longitudinal management of bipolar depression. Clinical trial results are reviewed for a diverse array of compounds, inclusive of traditional mood stabilizers (eg, lithium and divalproex), atypical antipsychotics, unimodal antidepressants, and modafinil. Where applicable, differences in efficacy across compounds are examined through discussion of number needed to treat and effect size determinations. A pragmatic clinical approach is presented for management of the depressed phase of bipolar disorder.

Costs, Control or Just Good Clinical Practice?

Medications are central to the psychiatric armamentorium in U.S. jails and prisons. Psychiatric medications are used both to stabilize acute symptoms as well as maintain mental health once symptoms are reduced. Both jails and prisons rely heavily on traditional antipsychotics, but both have a full array of atypical medications in their formularies. The heavy reliance on cheaper traditional medications when alternatives are present suggests that cost remains a factor. The fact that psychiatrists prescribe off the formulary and are more influenced by demonstrated efficacy in formulary decision-making, in contrast, supports the notion that they are indeed concerned with good practice.

Inflammation-related genes up-regulated in schizophrenia brains

BackgroundMultiple studies have shown that brain gene expression is disturbed in subjects suffering from schizophrenia. However, disentangling disease effects from alterations caused by medication is a challenging task. The main goal of this study is to find transcriptional alterations in schizophrenia that are independent of neuroleptic treatment.MethodsWe compared the transcriptional profiles in brain autopsy samples from 55 control individuals with that from 55 schizophrenic subjects, subdivided according to the type of antipsychotic medication received.ResultsUsing global and high-resolution mRNA quantification techniques, we show that genes involved in immune response (GO:0006955) are up regulated in all groups of patients, including those not treated at the time of death. In particular, IFITM2, IFITM3, SERPINA3, and GBP1 showed increased mRNA levels in schizophrenia (p-values from qPCR ≤ 0.01). These four genes were co-expressed in both schizophrenic subjects and controls. In-vitro experiments suggest that these genes are expressed in both oligodendrocyte and endothelial cells, where transcription is inducible by the inflammatory cytokines TNF-α, IFN-α and IFN-γ.ConclusionAlthough the modified genes are not classical indicators of chronic or acute inflammation, our results indicate alterations of inflammation-related pathways in schizophrenia. In addition, the observation in oligodendrocyte cells suggests that alterations in inflammatory-related genes may have consequences for myelination. Our findings encourage future research to explore whether anti-inflammatory agents can be used in combination with traditional antipsychotics for a more efficient treatment of schizophrenia.

Therapeutic possibilities of cysteamine in the treatment of schizophrenia

Schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future.