Psychopharmacology (Berl) 2006 May 20; (Read article online)

Pocivavsek A, Icenogle L, Levin ED

RATIONALE: Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer's disease. METHODS: We modeled in rats the cognitive effects of chronic decrease in hippocampal alpha7 or alpha4beta2 receptors with 4-week continuous bilateral local infusions of the alpha7 nicotinic antagonist methyllycaconitine (MLA) or the alpha4beta2 antagonist dihydro-beta-erythroidine (DHbetaE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine. RESULTS: Chronic ventral hippocampal DHbetaE infusion caused a significant (p<0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p<0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p<0.025) attenuated the memory deficit caused by chronic hippocampal DHbetaE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p<0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects. CONCLUSIONS: The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.

Pharmacotherapy 2006 Jun; 26(6): 748-58 (Read article online)

Szarfman A, Tonning JM, Levine JG, Doraiswamy PM

Study Objective. To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs. Design. Retrospective pharmacovigilance study. Data Source. United States Food and Drug Administration's Adverse Event Reporting System (AERS) database. Intervention. We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D(2)-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D(2) receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol. Measurements and Main Results. To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event. Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (> 10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D(2) receptors. Conclusion. Treatment with potent D(2)-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies.

Mol Cell Biochem 2006 May 23; (Read article online)

Raeder MB, Fernø J, Vik-Mo AO, Steen VM

Drug-induced weight gain is a major problem in the treatment of psychiatric disorders, especially with some antipsychotic- and antidepressant drugs. We have recently demonstrated that antipsychotic- and antidepressant drugs activate the SREBP (sterol regulatory element-binding proteins) transcription factors in human- and rat glial cells, with subsequent up-regulation of downstream genes involved in cholesterol- and fatty acid biosynthesis. Since stimulation of cellular lipogenesis in the liver could be of relevance for the metabolic side effects of these drugs, we have now investigated the effects of antidepressants, antipsychotic- and mood-stabilizing drugs on cell cultures of human liver cells. For several of the drugs being strongly associated with weight gain (clozapine, imipramine, and amitriptyline), we observed a very pronounced activation of SREBP. Ziprasidone and buproprion, however, which are not associated with weight gain, did hardly stimulate the SREBP system. For haloperidol, olanzapine and mirtazapine, the correspondence between metabolic side effects and SREBP stimulation in liver cells was less obvious. The mood-stabilizers did not increase SREBP activation. The results indicate a relationship between drug-induced activation of SREBP in cultured human liver cells and weight gain side-effects of antidepressant and antipsychotic drugs.

Synapse 2006 May 19; 60(2): 102-108 (Read article online)

Konradsson A, Marcus MM, Hertel P, Svensson TH, Jardemark KE

Clinical studies suggest that the efficacy of the atypical antipsychotic drug (APD) risperidone (but not clozapine) can be augmented by adjunctive treatment with agonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. By using intracellular recording, we have investigated the effect of the glycine transporter-1 (GlyT-1) inhibitor N [3-(4'-fluorophenyl)-3-(4'phenylphenylphenoxy) propyl] sarcosine (NFPS) on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex (mPFC), both when given alone and in combination with either risperidone or clozapine. Both risperidone and clozapine enhanced the NMDA-induced currents. The concentration-response curves were biphasic, and the maximal effect of clozapine on the NMDA-induced currents was significantly larger than the maximal effect of risperidone. NFPS also significantly potentiated the NMDA-induced currents, when given alone. Moreover, NFPS (1 muM) augmented the effect of both the maximal (20 nM), and a submaximal (10 nM), concentration of risperidone. In contrast, NFPS did not potentiate either the effect of the maximal (100 nM) or a submaximal (80 nM) concentration of clozapine on the NMDA-induced currents. These data may explain the beneficial clinical results of using glycine reuptake antagonists as adjuvant treatment to risperidone. Our findings also suggest that risperidone and clozapine may affect NMDA receptor-mediated neurotransmission differently in the mPFC. Synapse 60:102-108, 2006. (c) 2006 Wiley-Liss, Inc.

Synapse 2006 May 19; 60(2): 141-151 (Read article online)

Ko F, Tallerico T, Seeman P

To develop a new strategy for identifying possible psychotic- or antipsychotic-related pathway genes, rats were treated with clinical doses of haloperidol and clozapine for 4 days, and the altered expression of genes was compared with the genes altered in expression after amphetamine sensitization. The objective was to identify genes with expression altered in the same direction by haloperidol and clozapine but in the opposite direction in the amphetamine-sensitized rat striatum. These criteria were met by 21 genes, consisting of 15 genes upregulated by amphetamine, and 6 genes downregulated by amphetamine. Of the 21 genes, 15 are not presently identified, and only 3 genes (cathepsin K, GRK6, and a gene with accession number AI177589) are located in chromosome regions known to be associated with schizophrenia. Synapse 60:141-151, 2006. (c) 2006 Wiley-Liss, Inc.

J Neurol Neurosurg Psychiatry 2006 Jun; 77(6): 796-8 (Read article online)

Potvin S, Pampoulova T, Mancini-Marië A, Lipp O, Bouchard RH, Stip E

Few data have been gathered about the impact of psychoactive substances on extrapyramidal symptoms (EPS) in schizophrenia, and so far, inconsistent results have been reported. We studied 41 outpatients with schizophrenia (based on DSM-IV criteria), who were divided into two groups: with (n = 17) and without (n = 24) a substance use disorder (alcohol, cannabis, and/or cocaine). Both groups were matched for sociodemographic data and psychiatric symptoms (Positive and Negative Syndrome Scale). EPS were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale, and all patients were stable on either quetiapine or clozapine. Patients receiving anticholinergic drugs were excluded. Analyses of variance were conducted on both groups and showed that schizophrenia patients with a comorbid substance use disorder (especially cocaine) displayed more EPS compared with non-abusing patients.

Int J Neuropsychopharmacol 2006 May 17; 1-12 (Read article online)

Wadenberg ML, Wiker C, Svensson TH

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.

Neuropsychopharmacology 2006 May 17; (Read article online)

McCreary AC, Glennon JC, Ashby CR, Meltzer HY, Li Z, Reinders JH, Hesselink MB, Long SK, Herremans AH, van Stuivenberg H, Feenstra RW, Kruse CG

Combined dopamine D(2) receptor antagonism and serotonin (5-HT)(1A) receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D(2/3) antagonist and 5-HT(1A) agonist. SLV313 possessed high affinity at human recombinant D(2), D(3), D(4), 5-HT(2B), and 5-HT(1A) receptors, moderate affinity at 5-HT(7) and weak affinity at 5-HT(2A) receptors, with little-no affinity at 5-HT(4), 5-HT(6), alpha(1), and alpha(2) (rat), H(1) (guinea pig), M(1), M(4), 5-HT(3) receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT(1A) receptors (pEC(50)=9.0) and full antagonist activity at hD(2) (pA(2)=9.3) and hD(3) (pA(2)=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT(1A) syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT(1A) antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT(1A)-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT(1A) receptor agonist and full D(2/3) receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.Neuropsychopharmacology advance online publication, 17 May 2006; doi:10.1038/sj.npp.1301098.

Health Technol Assess 2006 May; 10(17): 1-182 (Read article online)

Lewis SW, Davies L, Jones PB, Barnes TR, Murray RM, Kerwin R, Taylor D, Hayhurst KP, Markwick A, Lloyd H, Dunn G

OBJECTIVES: To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to, or having unacceptable side-effects from, their current medication. DESIGN: Two pragmatic, randomised controlled trials (RCTs) were undertaken. The first RCT (band 1) compared the class of older, inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders, whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects. The second RCT (band 2) compared the new (non-clozapine) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs. Both RCTs were four-centre trials with concealed randomisation and three follow-up assessments over 1 year, blind to treatment. SETTING: Adult mental health settings in England. PARTICIPANTS: In total, 227 participants aged 18--65 years (40% of the planned sample) were randomised to band 1 and 136 (98% of the planned sample) to band 2. INTERVENTIONS: Participants were randomised to a class of drug. The managing clinician selected the individual drug within that class, except for the clozapine arm in band 2. The new atypical drugs included risperidone, olanzapine, quetiapine and amisulpride. The conventional drugs included older drugs, including depot preparations. As in routine practice, clinicians and participants were aware of the identity of the prescribed drug, but clinicians were asked to keep their participating patient on the randomised medication for at least the first 12 weeks. If the medication needed to be changed, the clinician was asked to prescribe another drug within the same class, if possible. MAIN OUTCOME MEASURES: The primary outcome was the Quality of Life Scale (QLS). Secondary clinical outcomes included symptoms [Positive and Negative Syndrome Scale (PANSS)], side-effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure. RESULTS: Recruitment to band 1 was less than anticipated (40%) and diminished over the trial. This appeared largely due to loss of perceived clinical equipoise (clinicians progressively becoming more convinced of the superiority of new atypicals). Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75% power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks. The recruitment to band 2 was approximately as planned. Follow-up assessments were completed at week 52 in 81% of band 1 and 87% of band 2 participants. Band 1 data showed that, on the QLS and symptom measures, those participants in the conventional arm tended towards greater improvements. This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample. Participants reported no clear preference for either class of drug. There were no statistically significant differential outcomes for participants entering band 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance. Net costs over the year varied widely, with a mean of pound18,850 in the conventional drug group and pound20,123 in the new atypical group, not a statistically significant difference. Of these costs, 2.1% and 3.8% were due to antipsychotic drug costs in the conventional and atypical group, respectively. There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year. The results for band 2 showed an advantage for commencing clozapine in quality of life (QLS) at trend level (p = 0.08) and in symptoms (PANSS), which was statistically significant (p = 0.01), at 1 year. Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects. Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p < 0.05). Net costs of care varied widely, but were higher than in band 1, with a mean of pound33,800 in the clozapine group and pound28,400 in the new atypical group. Of these costs, 4.0% and 3.3%, respectively, were due to antipsychotic drug costs. The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient admission for commencing the drug. There was a trend towards higher mean participant utility scores in the clozapine group. CONCLUSIONS: For band 1, there is no disadvantage in terms of quality of life and symptoms, or associated costs of care, over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs. Conventional drugs were associated with non-significantly better outcomes and lower costs. Drug costs represented a small proportion of the overall costs of care (<5%). For band 2, there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs, but with increased associated costs of care. The results suggest that conventional antipsychotic drugs, which are substantially cheaper, still have a place in the treatment of patients unresponsive to, or intolerant of, current medication. Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance, valid measures of utility in serious mental illness, low-dose 'conventional' treatment in first episode schizophrenia, QLS validity and determinants of QLS score in schizophrenia, and into the possible financial and other mechanisms of rewarding clinician participation in trials.

Adm Policy Ment Health 2006 May 11; (Read article online)

Luchins DJ

The wide scale use of expensive atypical antipsychotic medications has led to a dramatic increase in the proportion of direct costs schizophrenia being allocated for medications. Although there is evidence that the atypical antipsychotic, clozapine, may lead to cost savings in patients with refractory schizophrenia the cost-effectiveness of the other atypical antipsychotics remains in question. We therefore reviewed the published, long-term randomized, prospective cost-effectiveness treatment studies that compared an atypical to a typical antipsychotic. There were serious methodological problems with all. In general, those that were based on efficacy trials showed an advantage for atypicals while those based on effectiveness studies found the opposite. It appears that to the extent that studies mimic "real world" conditions they fail to support the cost-effectiveness of the atypical antipsychotics.

Neuropharmacology 2006 May 10; (Read article online)

Brea J, Castro M, Loza MI, Masaguer CF, Raviña E, Dezi C, Pastor M, Sanz F, Cabrero-Castel A, Galán-Rodríguez B, Fernández-Espejo E, Maldonado R, Robledo P

The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT(2A), 5-HT(1A), and 5-HT(2C)), dopamine (D(1), D(2), D(3) and D(4)), alpha-adrenergic (alpha(1), alpha(2)), muscarinic (M(1), M(2)) and histamine H(1) receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED(50)=1.19mg/kg), apomorphine-induced stereotypies (ED(50)=0.75mg/kg), catalepsy (ED(50)=2.13mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.

Amino Acids 2006 May 15; (Read article online)

Marchesi C, Dall'asta V, Rotoli BM, Bianchi MG, Maggini C, Gazzola GC, Bussolati O

We report here that chlorpromazine, a first generation antipsychotic drug, inhibits anionic amino acid transport mediated by system X(-) (AG) (EAAT transporters) in cultured human fibroblasts. With 30 microM chlorpromazine, transport inhibition is detectable after 3 h of treatment, maximal after 48 h (>60%), and referable to a decrease in V(max). Chlorpromazine effect is not dependent upon changes of membrane potential and is selective for system X(-) (AG) since transport systems A and y(+) are not affected. Among antipsychotic drugs, the inhibitory effect of chlorpromazine is shared by two dibenzodiazepines, clozapine and olanzapine, while other compounds, such as risperidon, zuclopentixol, sertindol and haloperidol, are not effective. Transport inhibition by clozapine and olanzapine, but not by chlorpromazine, is reversible, suggesting that the mechanisms involved are distinct. These results indicate that a subset of antipsychotic drugs inhibits EAAT transporters in non-nervous tissues and prompt further investigation on possible alterations of glutamate transport in peripheral tissues of schizophrenic patients.

CNS Drugs 2006; 20(5): 389-409 (Read article online)

Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Höschl C

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors. Balancing presynaptic and postsynaptic D(2) receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors.Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (e.g. by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors.In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.

Prog Neuropsychopharmacol Biol Psychiatry 2006 Apr 26; (Read article online)

Rocha FL, Hara C

OBJECTIVE: A substantial number of patients treated with clozapine shows insufficient response. The author presents the results of adding aripiprazole in patients resistant to clozapine. METHOD: Three cases of individuals with psychotic symptoms despite clozapine use and with significant side effects that were treated via this combination are presented. Response was evaluated by clinical assessment. RESULTS: Good clinical results were obtained in all three patients, with improvement of psychotic symptoms and of some of the side effects of clozapine. CONCLUSION: The findings from this case series suggest that adjunctive therapy with aripiprazole can be of benefit for treating clozapine resistant schizophrenic patients.

Psychiatry Res 2006 Apr 29; (Read article online)

Jahn T, Hubmann W, Karr M, Mohr F, Schlenker R, Heidenreich T, Cohen R, Schröder J

Motoric neurological soft signs (NSS) were investigated by means of the Brief Motor Scale (BMS) in 82 inpatients with DSM-III-R schizophrenic psychoses. To address potential fluctuations of psychopathological symptoms and extrapyramidal side effects, patients were examined in the subacute state, twice at an interval of 14 days on the average. NSS were significantly correlated with severity of illness, lower social functioning, and negative symptoms. Modest, but significant correlations were found between NSS and extrapyramidal side effects as assessed on the Simpson-Angus Scale. Neither the neuroleptic dose prescribed to the patient, nor scores for tardive dyskinesia and akathisia were significantly correlated with NSS. Moreover, NSS scores did not significantly differ between patients receiving clozapine and conventional neuroleptics. Patients in whom psychopathological symptoms remained stable or improved over the clinical course showed a significant reduction of NSS scores. This finding did not apply to those patients in whom psychopathological symptoms deteriorated. Our findings demonstrate that NSS in schizophrenic psychoses are relatively independent of neuroleptic side effects, but they are associated with the severity and persistence of psychopathological symptoms and with poor social functioning.

Int J Offender Ther Comp Criminol 2006 Jun; 50(3): 245-54 (Read article online)

Reisner AD

A case of Munchausen syndrome by proxy (factitious disorder by proxy) wherein the patient presented with symptoms of severe borderline personality disorder and questionable psychotic symptoms is discussed. This patient was also adjudicated for harassing and stalking a child protective services worker assigned to her case. Issues pertaining to possible feigning of psychotic symptoms were addressed in her inpatient treatment. Despite doubts concerning the veracity of some of her psychotic symptoms, the patient responded well to clozapine, and she was subsequently able to stay out of the psychiatric hospital for longer periods and make a reasonably good adjustment to living in a group home. After refusing to continue with clozapine therapy because of weight gain concerns, her adjustment declined.

J Clin Psychiatry 2006 Mar; 67(3): 461-7 (Read article online)

Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y

OBJECTIVE: We investigated the effect long-term clozapine add-on therapy has on rehospitalization rate and mood polarity patterns in patients with bipolar disorders. METHOD: Clinical data from medical records of 51 patients with bipolar disorder (DSM-IV) treated with clozapine add-on for more than 6 months at the Refractory Bipolar Disorders Clinic of Seoul National University Hospital were retrospectively analyzed. Patients had been registered from 1995 to 2004. Rehospitalization rates were compared before and after clozapine add-on. The clinical polarity of episodes resulting in hospitalizations was also compared. Twenty-seven bipolar patients treated with clozapine add-on for more than 3 years were further analyzed for long-term stability. RESULTS: The number of hospital days per year was reduced in 90.2% of patients after clozapine add-on. Total number and duration of hospitalizations per year decreased, and the effect size of clozapine add-on was substantially large (Wilcoxon z = -5.48, p < .01 for number of hospitalizations/year; Wilcoxon z = -5.32, p < .01 for hospital days/year; r = -0.54 and -0.53, respectively). Significant reductions were found in the number and duration of hospitalizations associated with manic, depressive, and hypomanic episodes. Number and duration of hospitalizations associated with mixed episodes did not show significant changes. The long-term efficacy of clozapine add-on was supported by continuous reduction in hospital days per year in the 27 selected patients. CONCLUSION: Long-term clozapine add-on therapy was effective in reducing the number and duration of rehospitalizations of bipolar patients resistant to conventional treatment. A significant reduction was found in rehospitalizations associated with manic, depressive, and hypomanic episodes, whereas mixed episode-associated rehospitalizations did not show significant changes.

Int J Neuropsychopharmacol 2006 May 4; 1-13 (Read article online)

Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA

Glycogen synthase kinase-3 (GSK3) has been recognized as an important enzyme that modulates many aspects of neuronal function. Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia, and GSK3 is a potential protein kinase target for psychotropics used in these disorders. We previously reported that serotonin, a major neurotransmitter involved in mood disorders, regulates GSK3 by acutely increasing its N-terminal serine phosphorylation. The present study was undertaken to further determine if atypical antipsychotics, which have therapeutic effects in both mood disorders and schizophrenia, can regulate phospho-Ser-GSK3 and inhibit its activity. The results showed that acute treatment of mice with risperidone rapidly increased the level of brain phospho-Ser-GSK3 in the cortex, hippocampus, striatum, and cerebellum in a dose-dependent manner. Regulation of phospho-Ser-GSK3 was a shared effect among several atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone. In addition, combination treatment of mice with risperidone and a monoamine reuptake inhibitor antidepressant imipramine or fluoxetine elicited larger increases in brain phospho-Ser-GSK3 than each agent alone. Taken together, these results provide new information suggesting that atypical antipsychotics, in addition to mood stabilizers and antidepressants, can inhibit the activity of GSK3. These findings may support the pharmacological mechanisms of atypical antipsychotics in the treatment of mood disorders.

Ann Pharmacother 2006 May 2; (Read article online)

Rami AF, Barkan D, Mevorach D, Leitersdorf E, Caraco Y

OBJECTIVE: To report a case of classic clozapine-induced systemic lupus erythematosus that also developed on rechallenge. CASE SUMMARY: A 32-year-old white woman diagnosed with schizophrenia presented in 1996 with clinical characteristics and laboratory markers consistent with drug-induced lupus (DIL). Clozapine, started 1 year prior, was withdrawn, with complete biological and clinical remission within 3 months. In 2004, 1 week after rechallenge with clozapine for uncontrolled schizophrenia, the patient developed clinical and biological signs and symptoms consistent with the diagnosis of DIL. Again, discontinuation of clozapine was followed by full remission within 2-3 months. DISCUSSION: DIL was first described more than 50 years ago, with multiple drugs implicated in the causation. Clozapine-induced lupus was reported recently, but does not meet the usual criteria for a diagnosis of DIL. We report a classic case of clozapine-induced lupus that, according to the Naranjo probability scale, demonstrates a highly probable relationship between DIL and clozapine. CONCLUSIONS: DIL demands a high index of suspicion for diagnosis. Although clozapine has an extensive safety profile, DIL must be considered as one of its serious adverse effects.

FEBS J 2006 May; 273(10): 2232-43 (Read article online)

Isaac G, Fredriksson A, Danielsson R, Eriksson P, Bergquist J

Several studies have shown that deficient uptake or excessive break down of membrane phospholipids may be associated with neurodegenerative and psychiatric disorders. The purpose of the present study was to examine the effects of postnatal iron administration in lipid composition and behavior and whether or not the established effects may be altered by subchronic administration of the neuroleptic compounds, clozapine and haloperidol. In addition to motor activities such as locomotion, rearing and activity, a targeted lipidomics approach has been used to investigated the brains of eight groups of mice (four vehicle groups and four iron groups) containing six individuals in each group treated with vehicle, low dose clozapine, high dose clozapine and haloperidol. Lipids were extracted by the Folch method and analyzed using reversed-phase capillary liquid chromatography coupled on-line to electrospray ionization mass spectrometry (LC/ESI/MS). Identification of phosphatidylcholine (PC) and sphingomyelin (SM) molecular species was based on their retention time, m/z ratio, head group specific up-front fragmentation and analysis of the product ions produced upon fragmentation. A comparison between the Ve-groups and Fe-groups showed that levels of PC and SM molecular species and motor activities were significantly lower in Fe-Ve compared to Ve-Ve. The effects of neuroleptic treatment with and without iron supplementation were studied. In conclusion our results support the hypothesis that an association between psychiatric disorders and lipid and behavior abnormalities in the brain exists.