Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study.

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.

The MCP-1 gene (SCYA2) and mood disorders: preliminary results of a case-control association study.

The aim of this case-control study was to investigate the potential role of the A-2518G polymorphism of the gene of monocyte chemoattractant protein 1 (MCP-1, a cytokine playing an important role in innate immunity) in conferring susceptibility to mood disorders. The sample studied included 96 outpatients with DSM-IV-TR diagnosis of major depressive disorder, bipolar disorder I (BD I) or BD II and 161 matched healthy controls. All subjects were genotyped for the A-2518G polymorphism of the MCP-1 gene. Genotypic and allelic associations were explored between patients and controls and across the different diagnostic groups (chi(2) tests). No genotypic (chi(2) = 8.215, d.f. = 6, p = 0.223) or allelic (chi(2) = 5.058, d.f. = 3, p = 0.168) association for the A-2518G polymorphism of SCYA2 was found considering cases and controls. Nevertheless, important correlations were observed when patients were divided into diagnostic subgroups. A significantly higher frequency of the AA genotype (chi(2) = 7.233, d.f. = 2, p = 0.027) and of the A allele (chi(2) = 4.730, d.f. = 1, p = 0.030) was observed in subjects with BD. In addition, independently from diagnosis, a higher number of lifetime suicide attempts was found in subjects with the AA genotype of the A-2518G polymorphism of the MCP-1 gene (F = 3.802, p = 0.026). The present preliminary results, though limited by the relatively small sample, suggest a possible role of the SCYA2 in conferring susceptibility to BD and, if confirmed, may represent a biological discriminative influence between mood disorder subtypes.

Duration of untreated illness and suicide in bipolar disorder: a naturalistic study.

The aim of this naturalistic study was to evaluate the potential influence of the duration of untreated illness (DUI)--defined as the time elapsed between the occurrence of the first mood episode and the first adequate pharmacological treatment with mood stabilizers--on the clinical course of bipolar disorder (BD). Three hundred and twenty outpatients (n = 320) with a DSM-IV diagnosis of BD--either Type I or Type II--were interviewed; their clinical features were collected and they were naturalistically followed-up for 5 years. At the end of the follow-up observation, the sample was subdivided into two groups: one group with a DUI < or =2 years (n = 65) and another group with a DUI >2 years (n = 255). The main demographic and clinical variables were analyzed and compared between the two subgroups of patients using chi-square tests for dichotomous variables or Mann-Whitney U tests for continuous variables. Patients with a longer DUI showed a higher frequency of suicide attempts (Z = -2.11, P = 0.035), a higher number of suicide attempters (chi(2) = 4.13, df = 1, P = 0.04), and a longer duration of illness (Z = -6.79, P < 0.0001) when compared to patients with a shorter DUI. Moreover, patients with a longer DUI had a depressive first episode more frequently than patients with a shorter DUI (chi(2) = 11.28, df = 2, P = 0.004). A further analysis performed dividing the total sample into two subgroups on the basis of a DUI of 6 years (corresponding to the median value of the DUI in the study sample) confirmed prior findings. Results indicate a potential association between a longer DUI and a worse outcome in BD, particularly in terms of suicidality, and confirm the clinical relevance of early diagnosis and pharmacological intervention with mood stabilizers in BD.

[Kennedy V Axis assessment in an Italian outpatient and inpatient population]. / L'applicazione dell'Asse V di Kennedy a un campione clinico italiano.

INTRODUCTION: Kennedy Axis V or K Axis acts is an alternative tool to the DSM-IVTR Global Assessment of Functioning (GAF) Scale, that many researchers describe as a scale with poor inter-rater reliability and clinical utility. Unlike the GAF scale, K Axis provides a multidimensional and multiaxial approach to measure personal, social and interpersonal functioning in psychiatric outpatients and inpatients. In this study, we examined K Axis's inter-raters reliability by using it with an Italian clinical population. METHODS: Clinicians used Kennedy Axis V to assess global functioning among 180 inpatients, in 9 psychiatric services in Lombardia and Piemonte. Patients were divided into 4 different diagnostic groups, according to the DSM-IV-TR criteria. RESULTS: Intraclass correlations between two independent raters's scores reveal high level of interrater reliability for all K Axis scales (0,633 < ICC < 0,813). Highly significant results in the Kruskal-Wallis test demonstrate that the patient diagnosis influence all the scales scores. Significant differences in patients functioning profiles in all K Axis scales, apart from Violence one, were noted between different diagnosis groups. CONCLUSIONS: In this study high level of raters agreement was noted, even if K Axis scales were used in different mental health services from different clinicians. K Axis scales provide a useful profile of patient global functioning, in line with the specific pathology.

Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression.

OBJECTIVES: The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in bipolar depression. The present study aimed to assess the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) combined with brain navigation in a sample of bipolar depressed subjects. METHODS: Eleven subjects with bipolar I or bipolar II disorder and major depressive episode who did not respond to previous pharmacological treatment were treated with three weeks of open-label rTMS at 1 Hz, 110% of motor threshold, 300 stimuli/day. RESULTS: All subjects completed the trial showing a statistically significant improvement on the 21-item Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impression severity of illness scale (ANOVAs with repeated measures: F = 22.36, p < 0.0001; F = 12.66, p < 0.0001; and F = 10.41, p < 0.0001, respectively). In addition, stimulation response, defined as an endpoint HAM-D score reduction of > or =50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score < or = 8). Partial response (endpoint HAM-D score reduction between 25% and 50%) was achieved by 3/11 patients. No manic/hypomanic activation was detected during the treatment according to Young Mania Rating Scale scores (ANOVAs with repeated measures: F = 0.62, p = 0.61). Side effects were slight and were limited to the first days of treatment. CONCLUSIONS: Augmentative low-frequency rTMS of the right DLPFC combined with brain navigation was effective and well tolerated in a small sample of drug-resistant bipolar depressive patients, even though the lack of a sham controlled group limits confidence in the results.

Cytokine polymorphisms in the pathophysiology of mood disorders.

INTRODUCTION: An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder. METHODS: Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique. RESULTS: We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048). CONCLUSION: These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study.

The aim of the present study was to evaluate the efficacy of short-term low-dose intravenous augmentative citalopram (10 mg/d) versus clomipramine (25 mg/d) versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Fifty-four patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MDE and partial or no response to SSRIs per os (21-item Hamilton Depression Rating Scale [HAM-D21] score reduction, <50% or < or =25%, respectively, compared with pretreatment scores) were selected and randomized to citalopram (n = 18), clomipramine (n = 18), or placebo (n = 18) intravenous augmentation. The augmentation regimen lasted 5 days during which patients were maintained on their previous treatment with oral SSRIs. Analyses of variance with repeated measures on HAM-D(21), collected daily in blind-raters design, were performed to detect any change of depressive symptoms between the 3 groups. In addition, the number of responders and remitters was computed in the 3 groups of treatment. At end point, a significant treatment effect (F= 4.57; P = 0.015) and time-by-treatment effect (F = 11.22; P < 0.0001) were found on HAM-D21 total scores in favor of citalopram and clomipramine versus placebo, with a superiority of citalopram over clomipramine on overall symptoms (P = 0.05) as well as on anxiety-somatization symptoms (P = 0.027). The number of responders was significantly superior in the active treatment groups versus the placebo group ([chi](2)(2) = 16.36; P < 0.0001). The same result was found, considering the number of remitters ([chi](2)(2) = 13.50; P < 0.0001). Present findings suggest that both clomipramine and citalopram intravenous augmentation at low doses and for a short period are well tolerated and superior to placebo in major depressives with partial or no response to oral SSRIs with a possible superiority of citalopram over clomipramine with regard to anxiety-somatization symptoms. The lack of double-blind conditions and the limited sample size may limit the confidence in the reported results, and larger randomized controlled trials are warranted to confirm the present findings.

Switching from serotonin reuptake inhibitors to duloxetine in patients with resistant obsessive compulsive disorder: a case series.

Obsessive compulsive disorder (OCD) is a chronic disorder, currently recognized as one of the most common psychiatric disorder as well as one of the most disabling of all medical disorders. OCD is characterized by high rates of partial and/or absent response to standard, recommended treatments (serotonin reuptake inhibitors and psychotherapy). Recent investigation showed that Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor (SNRI), may be a valid alternative for some treatment-refractory patients. We present the cases of four OCD patients with comorbid mood or anxiety disorders, who were treated with serotonin reuptake inhibitors (SRIs) at adequate doses for at least 12 weeks, showing partial/no response. Patients were then switched to Duloxetine up to 120 mg/day and followed up for 12 weeks. Three out of four patients showed a Yale-Brown Obsessive Compulsive Scale(Y-BOCS) score reduction >or=35%. Duloxetine may be helpful in patients with treatment-resistant OCD, although larger and controlled studies are warranted to confirm this preliminary observation.

Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study.

Approximately 30-45% of patients with major depressive episode (MDE) do not fully respond to standard recommended treatments and further strategies of intervention, including pharmacological augmentation, have been proposed for these patients. This study was aimed to evaluate the efficacy of short-term, low-dose (10 mg/day) intravenous (i.v.) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders, 4th edition, text revision criteria MDE and partial or no response to oral SSRIs were selected and randomly assigned to citalopram (n=18) or to placebo (n=18) i.v. augmentation. The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs. Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale total scores, administered daily with blind-raters conditions, were done. With regard to the Hamilton Depression Rating Scale total scores, a significant time effect (F=42.02, P<0.0001) and timextreatment effect (F=21.17, P<0.0001) were found in favor of citalopram. Similar results were obtained from the analysis on Montgomery-Asberg Depression Rating Scale total scores: time effect (F=50.07, P<0.0001), timextreatment effect (F=19.91, P<0.0001), and treatment effect (F=4.07, P=0.05). Even though referred to a small sample, the present findings seem to suggest that short-term, low-dose, i.v. citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs. Further controlled studies performed with double-blind conditions are warranted to confirm the present results.

Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder.

INTRODUCTION: The aim of the present study was to investigate the impact of the duration of untreated illness (DUI)-defined as the time elapsing between the onset of generalized anxiety disorder (GAD) and the first adequate pharmacologic treatment-on treatment response and clinical course in a sample of subjects with GAD. METHODS: One hundred patients with GAD, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria, were enrolled and their main demographic and clinical features collected. Patients were then treated with selective serotonin reuptake inhibitors or venlafaxine for 8 weeks in open-label conditions. Treatment response and other clinical variables were analyzed after dividing the sample into two groups according to DUI (DUI 12 months). RESULTS: When the DUI was computed with respect to the first antidepressant treatment (DUI-AD), a higher improvement (Clinical Global Impressions-Severity of Illness scale) after the pharmacologic treatment was found in the group with a shorter DUI (analysis of variance with repeated measures: time effect F=654.975, P<.001; group effect: F=4.369, P=.039). When computed with respect to the first treatment with benzodiazepines (DUI-BDZ), the two groups did not show any significant difference in treatment response (time effect: F=652.183, P<.001; group effect: F=0.009, P=.924). In addition, patients with a longer DUI (DUI-BDZ or DUI-AD) showed an earlier age at onset, a longer duration of illness and a higher rate of comorbid psychiatric disorders with onset later than GAD. CONCLUSION: Results from this preliminary study seem to suggest that a shorter DUI-AD may determine a better response to pharmacologic treatment in patients with GAD, and that a longer DUI (DUI-BDZ and DUI-AD) may be associated to a worse clinical course. Further investigation on the relationship between DUI and GAD is needed.

May duration of untreated illness influence the long-term course of major depressive disorder?

The aim of this naturalistic study was to investigate the possible influence of the duration of untreated illness (DUI) on the long-term course of Major Depressive Disorder (MDD). One hundred and thirteen patients with recurrent MDD, according to DSM-IV-TR criteria, followed up for 5 years, were selected, interviewed and their clinical charts were reviewed. The DUI was defined as the interval between the onset of the first depressive episode and the first adequate antidepressant treatment. The sample was divided into two groups according to the DUI: one group with a DUI12 months (n=38). The main demographic and clinical course variables were compared between the two groups using Student's t-tests or chi-square tests. Patients with a longer DUI showed an earlier age at onset (t=2.82, p=0.006) and a longer duration of illness (t=3.20, p=0.002) compared to patients with a shorter DUI. In addition, the total number of depressive episodes occurring before the first antidepressant treatment was higher in the group with a longer DUI (t=-2.223, p<0.03). Even though limited by the retrospective nature of the study, these preliminary findings would suggest that a longer DUI may negatively influence the course of MDD. Larger prospective studies are warranted to further investigate the role of the DUI within MDD.

The use of escitalopram beyond major depression: pharmacological aspects, efficacy and tolerability in anxiety disorders.

Escitalopram, the active (S)-enantiomer of citalopram, has been approved in many countries throughout the world for the treatment of depression and anxiety disorders. It is more potent and selective than citalopram in inhibiting serotonin re-uptake in the CNS, and less potent than various other selective serotonin re-uptake inhibitors in relation to other transporter proteins and receptors: in particular, it is six times less potent than citalopram in binding to the histamine H1 and muscarinic receptors. Escitalopram has favourable pharmacokinetics: it is rapidly absorbed, has a bioavailability of 80% and is not affected by food intake. It has little potential for drug interactions: it has low protein binding and, as it is metabolised by three CYP isozymes, any impairment in the activity of one is unlikely to have a significant effect on metabolic clearance. Caution is necessary only when it is coadministered with drugs metabolised by CYP2D6, such as metoprolol, or administered to the elderly or patients with severe hepatic or renal impairment. The multiple-dose pharmacokinetics of oral escitalopram are proportional at a range of doses including its therapeutic doses. Escitalopram is approved for the treatment of a number of anxiety disorders. It seems to be well tolerated and induces few or no discontinuation symptoms, and may be considered a first-line agent for the pharmacotherapy of obsessive-compulsive disorder, generalised anxiety disorder, panic disorder and social phobia. Further studies are needed to define its activity in impulse control disorders.

Clinical variables related to antidepressant-induced mania in bipolar disorder.

BACKGROUND: The development of mania or hypomania during antidepressant treatment is a serious complication of the clinical management of bipolar disorder (BP). The primary aim of this study was to evaluate the clinical variables related to antidepressant-induced mania or hypomania (AIM) in patients with BP. METHODS: DSM-IV BP-I or BP-II patients who had had at least one depressive episode treated with antidepressants were considered. Patients were subdivided into two groups according to the presence (n = 30) or absence (n = 106) of manic or hypomanic episodes occurring during antidepressant treatment. Possible predictive clinical variables of AIM were considered: gender, diagnostic subtype, age at onset, duration of illness, duration of untreated illness, type of antidepressant administered, number of previous spontaneous hypomanic or manic episodes, number of previous depressive episodes, presence of lifetime suicide attempts, presence of mood stabilizer treatments, presence of psychotic symptoms during spontaneous episodes, family history for psychiatric disorders in first degree relatives. Data were compared between the two groups, with (AIM+) and without (AIM-) antidepressant-induced mania, using Student's t tests and chi-square tests. RESULTS: The lack of mood stabilizer treatments during antidepressant therapy (chi-square = 37.602, df = 1, p < 0.001) and the exposure to tricyclic antidepressants (chi-square = 4.901, df = 1, p < 0.05) resulted significantly associated to the development of AIM. LIMITATIONS: This study was not done under controlled conditions and the relatively small sample studied warrants further replications. CONCLUSIONS: These results point out the risk of mania induction associated to the use of tricyclic antidepressants in BP patients, mainly in absence of adequate mood stabilizers.

Quetiapine augmentation of selective serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a six-month follow-up case series.

Obsessive-compulsive disorder (OCD) is a relatively common, often chronic and disabling disorder with high rates of partial and/or absent response to standard, recommended treatments, such as selective serotonin reuptake inhibitors (SSRIs) and psychotherapy. This article presents the cases of four patients suffering from OCD and comorbid mood or anxiety disorders, who were treated with SSRIs at adequate doses for at least 12 weeks, showing a partial response. Quetiapine treatment was added to SSRIs at a dose of 25 mg/day and titrated up to 200 mg/day. Patients were followed up for 6 months. After 12 weeks, all the patients were classified as "much improved" on the Clinical Global Impression-Improvement scale and showed a Yale-Brown Obsessive-Compulsive Scale score reduction > or =35%. After 6 months of follow-up, all the patients maintained the same level of improvement. Although quetiapine augmentation to SSRIs has shown mixed results in published controlled trials in the acute treatment (12 weeks) of patients with treatment-resistant OCD, this case series indicates that patients who benefit from this pharmacologic regimen in the acute phase tend to maintain such an improvement. Larger follow-up studies are warranted to confirm our findings.

Neurobiology of dynamic psychotherapy: an integration possible?

In the last decades, Kandel's innovative experiments have demonstrated that brain structures and synaptic connections are dynamic. Synapses can be modified by a wide variety of environmental factors, including learning and memory processes. The hypothesis that dynamic psychotherapy process involves memory and learning processes has opened the possibility of a dialogue between neuroscience and psychoanalysis and related psychotherapy techniques. The primary aim of the present article is to critically review the more recent data on neurobiological effects of dynamic psychotherapy in psychiatric disorders. Relevant literature has been selected using the databases currently available online (i.e., PubMed). The literature search has been limited to the past 10 years and to genetic, molecular biology, and neuroimaging studies that have addressed the issue of changes induced by psychotherapy. Most of the genetic studies on mental disorders have demonstrated that psychiatric conditions result from a complex interaction of genetic susceptibility and environmental effects. For none of the many psychiatric conditions investigated has a purely genetic background been found. Molecular biology studies have indicated that gene expression is influenced by several environmental factors, including early experiences, traumas, learning, and memory processes. Neuroimaging studies (using fMRI and PET) have found that not only cognitive but also dynamic psychotherapy has measurable effects on the brain. In addition, psychotherapy may modify brain function and metabolism in specific brain areas. Most of these studies have considered patients with major depressive disorders and compared the effects of psychotherapy with the effect of standard pharmacotherapy. In conclusion, recent results from neuroscience studies have suggested that dynamic psychotherapy has a significant impact on brain function and metabolism in specific brain areas. The possible applications and developments of this new area of research toward the conceptualization of an integrative approach to treatment of psychiatric disorders are discussed.

Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar disorder.

BACKGROUND: Based on the dopamine hypothesis, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorder (BP). METHODS: In our study, three polymorphisms of the DRD1 gene, -800T/C, -48A/G, and 1403T/C, were analyzed in 286 BP trios. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data to test for the presence of linkage disequilibrium between DRD1 and bipolar disorder. With the extended transmission disequilibrium test (ETDT), we also calculated the maternal transmission and paternal transmission for each allele. RESULTS: Although no association was found for each individual polymorphism, there is a significant association between DRD1 and BP for haplotype TDT analysis (chi(2) = 16.068, df = 3, p =.0011). CONCLUSIONS: These results indicate that DRD1 may play a role in the etiology of bipolar disorder.

Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder.

OBJECTIVES: The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. METHODS: Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. RESULTS: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p = 0.0504). This trend may become more significant with a larger sample size. SIGNIFICANCE: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.

Intramuscular preparations of antipsychotics: uses and relevance in clinical practice.

Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called "depot", are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, especially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.

Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.

RATIONALE: Recent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl- d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3' untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl- d-aspartate 2B) were associated with OCD in affected families. OBJECTIVES: The objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design. METHODS: Using the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity. RESULTS. Under a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested ( P=0.014). In addition, there was a significant positive association with OCD diagnosis ( P=0.002) for the 5072G-5988T haplotype under the recessive model. CONCLUSIONS: Although preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

Early age at onset as a risk factor for poor outcome of bipolar disorder.

The primary aim of our study was to investigate the effect of the age at onset (AAO) of Bipolar Disorder (BP) on the clinical course of the illness. We studied 320 subjects with a diagnosis of BP I or BP II who had been previously recruited for a genetic research protocol. All subjects gave their informed consent to participate in the study. Each subject was interviewed using the SCID I. The main clinical variables were compared between subjects with early (/=18 years) age at onset of BP (chi square tests and t-tests for independent samples). In addition, a logistic regression analysis was applied to the variables that were significantly related to earlier onset of BP in the exploratory analyses. We found a significantly earlier AAO in subjects with anxiety disorders (t=2.44, P=0.015) and rapid cycling course (t=3.16, P=0.002). When we compared a number of clinical characteristics between early and later onset of BP, subjects with early AAO had more frequent suicidal ideation/attempts (chi(2)=12.12, P=0.002), Axis I comorbidity (chi(2)=8.12, P=0.004), substance use disorders (chi(2)=5.45, P=0.019) and rapid cycling course (chi(2)=9.87, P=0.002). The Odds Ratios associated with these variables were: 1.407 (suicide ideation), 1.646 (Axis I comorbidity), 1.468 (substance abuse), and 2.082 (rapid cycling course). Overall, these results suggest a role of early AAO as a significant predictor of poor outcome in BP and, if replicated, they may have important clinical implications.