Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study.

OBJECTIVE: Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD. METHODS: The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using chi(2) test, transmission disequilibrium test, and pedigree-based association. SNP rs1556314 was also genotyped in our case-control sample set comprised of 184 BD and 195 healthy Caucasian subjects. RESULTS: The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, p(permutation) = 0.015) in the case-control dataset and in the family design (p = 0.018, p(permutation) = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families. CONCLUSION: Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

BACKGROUND: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Chronic lithium treatment attenuates intracellular calcium mobilization.

Elevated basal intracellular calcium (Ca(2+)) levels ([Ca(2+)](B)) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca(2+) homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca(2+) signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca(2+) homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca(2+)](B), lysophosphatidic acid (LPA)-stimulated Ca(2+) mobilization ([Ca(2+)](S)), and thapsigargin-induced store-operated Ca(2+) entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca(2+)](B) (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca(2+)](S) and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca(2+)](B) in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca(2+) mobilization in BLCLs suggests that modulation of intracellular Ca(2+) homeostasis may be important to the therapeutic action of lithium.

Relevance of the catatonic syndrome to the mixed manic episode.

BACKGROUND: Catatonic symptoms have been associated with mixed mania in the older psychiatric literature, however, to date no systematic studies have been performed to assess their frequency in these patients. METHOD: Ninety-nine patients with bipolar disorder manic or mixed episode were assessed for the presence of catatonia. RESULTS: Thirty-nine patients fulfilled criteria for mixed mania of whom 24 were catatonic. Among the patients with pure mania, only three were catatonic. Eighteen catatonic patients with mixed mania required admission to the acute care unit (ACU). LIMITATIONS: Our findings only apply to severely ill patients with mixed mania who require ACU admission. Nevertheless, it is important to know, that the likelihood of overlooking catatonia in less severely ill patients with mixed mania is low and that it does not need to be routinely assessed on a general ward. CONCLUSIONS: Catatonia is frequent in mania and linked to the mixed episode. Catatonia in mixed mania is likely to be found among the severely ill group of patients with mixed mania, who require emergency treatment.

Mental health program monitoring: towards simplifying a complex task.

Finding measures that can assess areas of expected program impact, provide valid results, and be easily integrated into routine program practices is a significant challenge. This paper is intended to assist program staff by providing an accessible inventory of measures appropriate for routine monitoring of the status and outcome of individuals using mental health outpatient and community programs. The inventory is not exhaustive, but rather includes examples of solid measures for assessing outcomes in four key domains--symptoms, functioning, quality of life, and satisfaction. These can provide a core of information, to which measurement of more in-depth issues can be added to address specific concerns.

Elevated monoamine oxidase a binding during major depressive episodes is associated with greater severity and reversed neurovegetative symptoms.

Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDEs), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE; however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDEs secondary to major depressive disorder and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC was analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F(2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F(2,38)=5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. As MAO-A creates oxidative stress, facilitates apoptosis, and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.

Continuing education to go: capacity building in psychotherapies for front-line mental health workers in underserviced communities.

OBJECTIVE: To address the gaps between need and access, and between treatment guidelines and their implementation for mental illness, through capacity building of front-line health workers. METHODS: Following a learning needs assessment, work-based continuing education courses in evidence-supported psychotherapies were developed for front-line workers in underserviced community settings. The 5-hour courses on the fundamentals of cognitive-behavioural therapy, interpersonal psychotherapy, motivational interviewing, and dialectical behaviour therapy each included videotaped captioned simulations, interactive lesson plans, and clinical practice behaviour reminders. Two courses, sequentially offered in 7 underserviced settings, were subjected to a mixed methods evaluation. Ninety-three nonmedical front-line workers enrolled in the program. Repeated measures analysis of variance was used to assess pre- and postintervention changes in knowledge and self-efficacy. Qualitative data from 5 semistructured focus groups with 25 participants were also analyzed. RESULTS: Significant pre- and postintervention changes in knowledge (P < 0.001) were found in course completers. Counselling self-efficacy improved in participants who took the first course offered (P = 0.001). Dropouts were much less frequent in peer-led, small-group learning than in a self-directed format. Qualitative analysis revealed improved confidence, morale, self-reported practice behaviour changes, and increased comfort in working with difficult clients. CONCLUSION: This work-based, multimodal, interactive, interprofessional curriculum for knowledge translation of psychotherapeutic techniques is feasible and helpful. A peer-led group format is preferred over self-directed learning. Its application can build capacity of front-line health workers in helping patients who suffer from common mental disorders.

Objectif : Aborder l'écart entre les besoins et l'accès, et entre les lignes directrices de traitement et leur mise en œuvre pour la maladie mentale, par la création de capacité des travailleurs de première ligne de la santé. Méthodes : À la suite d'une évaluation des besoins d'apprentissage, des cours de formation continue en milieu de travail sur les psychothérapies fondées sur des données probantes ont été mis au point à l'intention des travailleurs de première ligne dans des milieux communautaires sous-desservis. Les cours de 5 heures sur les fondements de la thérapie cognitivo-comportementale, la psychothérapie interpersonnelle, la technique d'entrevue motivationnelle, et la thérapie comportementale dialectique comportaient tous des simulations enregistrées sur vidéo, des plans de leçon interactifs, et des rappels de comportement en pratique clinique. Deux cours, offerts en ordre séquentiel dans 7 milieux sous-desservis, ont été soumis à une évaluation de méthodes mixtes. Quatre-vingt-treize travailleurs de première ligne non médicaux se sont inscrits au programme. Une analyse de variance des mesures répétées a servi à évaluer les changements des connaissances et de l'auto-efficacité avant et après l'intervention. Les données qualitatives de 5 groupes de discussion semi-structurés de 25 participants ont également été analysées. Résultats : Des changements significatifs des connaissances (P < 0,001) avant et après l'intervention ont été observés chez ceux qui ont terminé le cours. L'auto-efficacité en counseling s'est améliorée chez les participants qui ont suivi le premier cours offert (P = 0,001). Les décrocheurs étaient beaucoup moins fréquents dans les petits groupes d'apprentissage menés par les pairs que dans le format autodirigé. L'analyse qualitative a révélé une confiance améliorée, un meilleur moral, des changements du comportement dans la pratique auto-déclaré, et une plus grande assurance de travailler avec des clients difficiles. Conclusion : Ce programme d'études en milieu de travail, multimodal, interactif, interprofessionnel pour la transmission des connaissances en techniques psychothérapeutiques est faisable et utile. Le format du groupe mené par les pairs est préféré à l'apprentissage autodirigé. Son application peut renforcer la capacité des travailleurs de la santé de première ligne d'aider les patients qui souffrent de troubles mentaux communs.

Further support for association of the mitochondrial complex I subunit gene NDUFV2 with bipolar disorder.

BACKGROUND: The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients. METHODS: Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5'-nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3'UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca(2+)](B) in BLCLs were determined. RESULTS: The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni-corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca(2+)](B) associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes. CONCLUSIONS: While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca(2+) abnormalities in BD remains equivocal.

Factors predicting practice location and outreach consultation among University of Toronto psychiatry graduates.

OBJECTIVE: To identify the determinants of practice location and of outreach consultation of recently graduated psychiatrists. METHODS: We surveyed 153 psychiatrists who graduated from the University of Toronto Department of Psychiatry between January 1990 and June 2002 (response rate 51%), on the basis of a self-administered mail questionnaire. The survey assessed factors that influenced practice location and outreach consultation, such as demographics, links to practice communities, and outreach experiences, including rural or northern electives as a resident. RESULTS: Professional variables were rated as the most important factors in choosing a practice location. Variables such as age or sex were not significantly associated with location. Nine percent reported working in communities of less than 100,000, and only 1% practised in Northern Ontario. Eighteen percent practised in the same location where they were born or raised. Forty-four percent had rural or northern experience as a resident but almost exclusively in the form of short, fly-in consultation electives. Twenty-four percent indicated that they provide outreach consultation. Psychiatry residents who participated in outreach electives were 10 times as likely as those who did not participate to continue outreach as a consultant. CONCLUSION: Although early exposure to rural or northern medicine leads to significantly greater continued involvement in outreach activities after graduation, our findings suggest the need for more long-term, on-site residency training opportunities in rural and remote areas.

Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder.

Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.

Comorbidity and pathophysiology of obsessive-compulsive disorder in schizophrenia: is there evidence for a schizo-obsessive subtype of schizophrenia?

Epidemiologic and neurobiologic evidence suggests that patients with comorbid obsessive-compulsive disorder (OCD) and schizophrenia may represent a special category among patients with schizophrenia. Efforts to examine the neurobiology of this group have focused on neuroimaging studies and neuropsychologic testing. Convergent evidence suggests that there may be a specific pattern of neurobiologic dysfunction in this subgroup of patients accounting for symptom co-expression. This review indicates that future studies should distinguish among (1) apparent obsessive-compulsive symptoms (OCS) that occur only in the context of psychosis and that may overlap with psychotic phenomenology, representing a forme fruste of psychosis; (2) OCS occurring only in the prodromal phase of schizophrenia; (3) neuroleptic-induced OCS or OCD; and (4) OCS or frank OCD occurring concurrently with schizophrenia. We examine the evidence for a putative schizo-obsessive disorder and outline suggestions for identifying OCS in the presence of psychosis.