Kegg Pathway: Antipsychotics

Actas Esp Psiquiatr. 2009 Jul; 37(4): 205-212
Roncero C, Rodríguez-Urrutia A, Grau-López L, Casas M

The disorders classified as control of the impulses; explosive intermittent disorder, pathological gambling, kleptomania, pyromania, pathological gambling, hair pullers, compulsive purchases, skin picking and onychophagia are a heterogeneous set of clinical entities, most of them with little prevalence. Nevertheless, they cause important personal and social dysfunctions and present great comorbidity with other psychiatric disorders. Antipsychotics, antidepressive agents, serotoninergic agonists, naltrexone, beta blockers antiandrogen, lithium and anticonvulsants have been used in their pharmacological treatment. Currently, interest is growing on the use of the antiepileptics because their possible usefulness has been described in these disorders. However, the neurobiological effects are only partially known in some cases. We have reviewed the literature regarding the treatment of these disorders with mood stabilizers, (lithium, carbamazepine, valproate, phenitoin, oxcarbacepin, topiramate, lamotrigin, leviteracetam) and have described those studies on which the current knowledge and evidence are based. The results must be considered as provisional and must be updated in the future, since they are mostly based on case reports, case series or opened clinical trials, their being little knowledge based on double blind clinical trials. Key words:Impulse control disorders. Antiepileptic drug. Explosive intermittent disorder. Pathological gambling. Kleptomania. Pyromania. Hair pullers. Actas Esp Psiquiatr 2009;37(4):205-212.

Psychiatry Res. 2009 Nov 17;
Suvisaari J, Perälä J, Saarni SI, Kattainen A, Lönnqvist J, Reunanen A

We investigated the prevalence of coronary heart disease (CHD) and myocardial infarction (MI) in persons with DSM-IV psychotic disorders. We also examined cardiac conduction abnormalities, and the role of antipsychotic medication in them. The study was based on a nationally representative survey of 8028 persons aged 30 years or over from Finland. Diagnoses of CHD and MI were based on electrocardiographic findings, health examination, and register information. QTc was calculated using the Bazett formula, and Minnesota classification was used for conduction abnormalities. We found that large Q-waves suggesting past MI were significantly more frequent in persons with schizophrenia, while the prevalence of CHD in persons with psychotic disorders did not differ significantly from the remaining study sample. Prevalence of prolonged QTc interval was significantly increased in persons with schizophrenia and in users of typical Antipsychotics. However, low-potency antipsychotic use but not diagnosis of schizophrenia remained an independent predictor of prolonged QTc interval in a logistic regression. Low-potency antipsychotic use was associated with ventricular conduction defects, and high-potency antipsychotic use with premature beats. Symptoms and signs of CHD should be actively monitored patients with schizophrenia, and the electrocardiogram should be monitored for all types of changes in persons receiving antipsychotic medication.

Pharmacopsychiatry. 2009 Nov; 42(6): 277-283
Lambert M, Schimmelmann BG, Naber D, Eich FX, Schulz H, Huber CG, Karow A

INTRODUCTION: 'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various Antipsychotics. METHODS: Response and remission rates were assessed in 528 severely ill patients with schizophrenia at baseline, week 2, 4 and 12 using PANSS, SWN-K, CGI-S, and SOFAS. The clinical measures were combined to one outcome criterion (CombOut). Predicitive validity was analyzed for CombOut using linear regression models. RESULTS: Rate and time to response differed markedly between outcome measures. 32% reached positive symptom response at week 2, 58% at week 4 and 85% at week 12. Non-response at week 4, but not at week 2 was predictive for later non-response. The combined outcome criterion was best predicted by early response in subjective wellbeing (T=-7.88, p<0.001) and social functioning (T=-7.43, p<0.001). DISCUSSION: Rate and time to response might depend on sample characteristics and outcome measure. In severely ill patients early antipsychotic response is possibly delayed from the first 2 to the first 4 weeks. Early response in subjective wellbeing and social functioning are strong predictors for overall outcome, which make them a useful supplementation to the assessment of symptomatic response.

Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;
Deng C, Weston-Green K, Huang XF

Atypical Antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical Antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.

Bipolar Disord. 2009 Dec; 11(8): 827-839
Macfadden W, Alphs L, Haskins JT, Turner N, Turkoz I, Bossie C, Kujawa M, Mahmoud R

Objective: No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable Antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. Methods: This study included patients with bipolar disorder type I with >/= four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25-50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. Results: Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). Conclusions: Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.

Int J Neurosci. 2009; 119(10): 1509-1522
Kirschbaum KM, Hiemke C, Schmitt U

Extrapyramidal motoric symptoms are casual side effects under antipsychotic medication. New generation Antipsychotics are expected to have a reduced risk due to different receptor affinities. Here, haloperidol and the new generation Antipsychotics, risperidone, amisulpride, and aripiprazole, were examined with both catalepsy test and rotarod performance test to screen for their usability in mice. Mice treated with haloperidol, risperidone, and aripiprazole showed dose and time-dependent impairment. Amisulpride-treated mice showed no signs of catalepsy. Catalepsy test and rotarod performance test were useful methods to detect side effects of both generation Antipsychotics. Catalepsy test provided more specificity whereas the rotarod test provided higher degree of sensitivity to motor impairment including catalepsy.

Eur J Pharmacol. 2009 Nov 14;
Dyhring T, Nielsen EO, Sonesson C, Pettersson F, Karlsson J, Svensson P, Christophersen P, Waters N

A new pharmacological class of CNS ligands with the unique ability to stimulate or suppress motor and behavioral symptoms depending on the prevailing dopaminergic tone has been suggested as "dopaminergic stabilizers". The molecular mode-of-action of dopaminergic stabilizers is not yet fully understood, but they are assumed to act via normalization of dopaminergic signaling, through interactions with the dopamine D(2) receptor. Here we have evaluated the dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162, as well as the new compound N-{[(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (NS30678) in a series of cellular in vitro dopamine D(2) receptor functional and binding assays. Neither ACR16, (-)-OSU6162, nor NS30678 displayed detectable dopamine D(2) receptor mediated intrinsic activity, whereas they concentration-dependently antagonized dopamine-induced responses with IC(50) values of 12.9muM, 5.8muM, and 7.0nM, respectively. In contrast to the high affinity typical Antipsychotics haloperidol and raclopride, the dopaminergic stabilizers ACR16 and (-)-OSU6162 both displayed fast dopamine D(2) receptor dissociation properties, a feature that has previously been suggested as a contributing factor to antipsychotic atypicality and attributed mainly to low receptor affinity. However, the finding that NS30678, which is equipotent to haloperidol and raclopride, also displays fast receptor dissociation, suggests that the agonist-like structural motif of the dopaminergic stabilizers tested is a critical dissociation rate determinant. The results demonstrate that dopaminergic stabilizers exhibit fast competitive dopamine D(2) receptor antagonism, possibly allowing for temporally variable and activity-dependent dopamine D(2) receptor occupancy that may partly account for their unique stabilization of dopamine dependent behaviors in vivo.

BMC Psychiatry. 2009 Nov 17; 9(1): 72
Acquaviva E, Legleye S, Auleley GR, Deligne J, Carel D, Falissard B B

ABSTRACT: BACKGROUND: The aim of this work is to estimate the French frequencies of dispensed psychotropic prescriptions in children and adolescents. Prevalence estimations of dispensed prescriptions are compared to the frequencies of use of psychotropic reported by 17year-old adolescents. METHODS: Prescription data is derived from national health insurance databases. Frequencies of dispensed prescriptions are extrapolated to estimate a range for the 2004 national rates. Self-report data is derived from the 2003 and 2005 ESCAPAD study, an epidemiological study based on a questionnaire focused on health and drug consumption. RESULTS: The prevalence estimation shows that the prevalence of prescription of a psychotropic medication to young persons between 3 and 18 years is about 2.2 %. In 2005, the self-report study (ESCAPAD) shows that 14.9% of 17year-old adolescents took medication for "nerves" or "to sleep" during the previous 12 months. The same study in 2003 also shows that 62.3% of adolescents aged 17 and 18 reporting psychotropic use, took the medication for anxiety and 56.8% to sleep. Only 49.7% of these medications are suggested by a doctor. CONCLUSIONS: This study underlines a similar range of prevalence of psychotropic prescriptions in France to that observed in other European countries. Nevertheless, the proportion of Antipsychotics and benzodiazepins seems to be higher, whereas the proportion of methylphenidate is lower. Secondly, a disparity between the prevalence of dispensed prescriptions and the self-report of actual use of psychotropics has been highlighted by the ESCAPAD study which shows that these treatments are widely used as "self-medication".

Pharmacogenomics J. 2009 Nov 17;
Liu YR, Loh EW, Lan TH, Chen SF, Yu YH, Chang YH, Huang CJ, Hu TM, Lin KM, Yao YT, Chiu HJ

Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to Antipsychotics. A total of 401 schizophrenia in-patients treated with Antipsychotics for >2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency >/=0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical Antipsychotics and use of atypical Antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with Antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia.The Pharmacogenomics Journal advance online publication, 17 November 2009; doi:10.1038/tpj.2009.55.

BMJ. 2009; 339: b4818
Mashta O

Br J Clin Pharmacol. 2009 Nov; 68(5): 743-51
Jolly K, Gammage MD, Cheng KK, Bradburn P, Banting MV, Langman MJ

AIMS: To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs. METHODS: Case-control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care. RESULTS: Noncardiac drug risk was posed by Antipsychotics and antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical Antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively. CONCLUSIONS: Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.

Int J Neurosci. 2009; 119(12): 2274-9
Hall DA, Agarwal P, Griffith A, Segro V, Seeberger LC

Aripiprazole is an atypical antipsychotic that is a partial agonist at the D2 and 5HT1a receptors and an antagonist at 5HT2a receptors. Despite previous hypotheses that it would be less likely to cause movement disorders, recent reports suggest it actually may be more likely to cause movement disorders than other atypical Antipsychotics. This case series illustrates the variety of movement disorders associated with aripiprazole use at three movement disorder clinics. It also suggests that aripiprazole be used with caution in patients with a prior history of dystonia, parkinsonism, or previous tardive dyskinesia.

Issues Ment Health Nurs. 2009 Dec; 30(12): 803-5
Housel AK, Waterbury N, Argo TR

J Affect Disord. 2009 Nov 13;
Bond DJ, Kauer-Sant'anna M, Lam RW, Yatham LN

BACKGROUND: Numerous studies have demonstrated an association between bipolar disorder (BD) and obesity. However, these reports are limited by retrospective or cross-sectional designs, and the assessment of patients with lengthy illnesses. Prospective data, and data on weight gain early in the course of BD, are lacking. METHODS: We prospectively measured weight gain and laboratory metabolic indices over 12months in 47 patients with BD receiving maintenance treatment following their first manic episode, and in 24 age- and gender-matched healthy subjects. RESULTS: Although approximately two-thirds of patients had experienced previous depressive or hypomanic episodes, there was no difference between patients and healthy subjects in mean body mass index or rates of overweight or obesity at recovery from the first mania. Mean weight gain over 12months was 4.76kg in patients and 1.50kg in healthy subjects (p=0.047). Combined rates of overweight and obesity at 6months and 12months exceeded 50% in patients, and were almost double those of healthy subjects. Logistic regression demonstrated that weight gain in the first 6months was significantly associated with male gender and prescription of olanzapine or risperidone. Patients who were obese at 6months and/or 12months had significantly greater mean serum triglyceride levels and fasting glucose levels than non-obese patients. LIMITATIONS: This was a naturalistic study. CONCLUSIONS: Even in patients with previous depressions and hypomanias, clinically significant weight gain in BD begins following the first manic episode, suggesting that it is primarily related to treatment with mood stabilizers and second-generation Antipsychotics. However, the very small number of patients in our sample who were medication-free precludes a meaningful analysis of the degree to which weight gain might be an inherent feature of post-manic BD.

J Clin Psychopharmacol. 2009 Dec; 29(6): 603-4
Lee E, Leung CM

J Clin Psychopharmacol. 2009 Dec; 29(6): 529-36
Lin CC, Bai YM, Wang YC, Chen TT, Lai IC, Chen JY, Chen SY, Gau SS, Liou YJ

Switching to a different second-generation antipsychotic (SGA) with a lower risk of weight gain is recommended for overweight or obese psychiatric patients undergoing SGA treatment. However, there have been no complete reports regarding the long-term metabolic effects of switching to amisulpride. In this open-label 1-year study, we investigated the effects on body weight and other metabolic profiles when psychiatric patients treated with another SGA were switched to amisulpride treatment. Forty-six schizophrenia or schizoaffective inpatients with a body mass index greater than 27 kg/m were enrolled in the switch group. These patients were cross-titrated to amisulpride treatment and followed up for 1 year prospectively. Another 46 inpatients matched with the baseline body mass index of those in the switch group were enrolled as the control group retrospectively. The results showed that the switch group had greater weight loss than the control group (7.80 +/- 6.67 vs 2.60 +/- 6.23 kg, respectively; repeated-measure analysis of variance, P < 0.0005). During the treatment course, the amisulpride-treated patients showed significantly decreased fasting triglyceride, total cholesterol, glucose, and insulin resistance levels; decreased diastolic blood pressure and pulse rate; and a significant increase in high-density lipoprotein cholesterol levels after switching to amisulpride (all with a P < 0.05). The prevalence of metabolic syndrome in amisulpride-treated patients also decreased significantly from 65.2% to 30.4% (McNemar test, P < 0.0005). These findings suggest that switching to amisulpride could be an effective treatment of overweight or obese psychiatric patients treated previously with other SGAs.

J Clin Psychopharmacol. 2009 Dec; 29(6): 517-9
Mitchell AJ

Curr Psychiatry Rep. 2009 Dec; 11(6): 429-36
Rao S, Zisook S

Anxious depression has been conceptualized in at least two related but separate ways: 1) major depressive disorder with at least one comorbid Axis I anxiety disorder and 2) major depressive disorder with a high level of anxiety with or without one or more comorbid Axis I anxiety disorders. Using either definition, patients with anxious depression seem to have a more chronic course of illness, an increased incidence of suicidal thoughts and behavior, greater functional and occupational impairment, and poorer response to treatment. Multiple classes of medications are used to treat anxious depression, most commonly first- and second-generation antidepressants, atypical Antipsychotics, and benzodiazepines. Certain patients with anxious depression may require lower starting doses, more gradual dose escalations, higher end point doses, longer duration of treatment, and/or early augmentation with other agents. Nonpharmacologic treatments such as targeted psychotherapy and preventative stepped-care approaches also may be effective. Well-conceived, randomized controlled treatment trials are necessary to make further gains in the management of patients with anxious depression.

Biochem Soc Trans. 2009 Dec; 37(Pt 6): 1415-8
Chen J, Tsang SY, Zhao CY, Pun FW, Yu Z, Mei L, Lo WS, Fang S, Liu H, Stöber G, Xue H

The SCZ (schizophrenia)-associated GABA(A) receptor (gamma-aminobutyric acid type A receptor) beta(2) subunit gene GABRB2 was recently associated with BPD (bipolar disorder). Although weaker than its association with SCZ, significant association of GABRB2 with BPD was found in both German and Chinese, especially for the haplotypes rs1816071-rs187269 and rs1816072-rs187269 for which the M-M variants showed higher frequency in disease than the control. Significant genotype-dependent reduction in GABRB2 expression was shown for BPD, but to a lesser extent than that for SCZ. Temporal effects on GABRB2 expression were observed. Moreover, for the homozygous major genotypes of rs1816071, rs1816072 and rs187269, expression increased with time in CON but decreased in SCZ and BPD. The genotypes of these three SNPs (single nucleotide polymorphisms) were further correlated with Antipsychotics dosage in SCZ cohorts. The findings highlight the importance of GABRB2 in neuropsychiatric disease aetiology, with respect to haplotype association, as well as reduction of and temporal effects on gene expression in both SCZ and BPD, but to a lesser extent in the latter, supporting the suggestion that functional psychosis can be conceptualized as a continuous spectrum of clinical phenotypes rather than as distinct categories.

Curr Pharm Des. 2009 Nov 12;
McCreary AC, Jones CA

Schizophrenia is a complex psychiatric disorder characterised by positive and negative symptoms, cognitive impairments, attentional problems, anxiety and depressive symptoms. The use of atypical Antipsychotics has generally improved clinical outcome yet medical need remains in the treatment of this disease. The potential use of 5-HT(1A) receptor agonism is emerging as one potential area that could be exploited to improve clinical management of the disease. 5-HT(1A) receptor agonism will not reduce hyperprolactinaemia but does appear to enhance effects on positive, negative and cognitive symptoms and also treat attentional depressive and anxiety symptoms. However, these improvements are not at the expense extrapyramidal side effects and indeed may attenuate the effects of D(2) receptor antagonism. Agonism at the 5-HT(1A) receptor might therefore offer potential benefits to the pallet of existing strategies for the treatment of schizophrenia. We review existing data in support of this. However, further clinical data are needed to prove these hypotheses.