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ABSTRACT: The 5HTTLPR genetic variant of the serotonin transporter gene (SERT or 5-HTT), which is comprised of a short (SERT-s) and a long (SERT-l) allele, is associated with major depressive disorder and post-traumatic brain disorder.
The present study sought to determine whether the total thalamus and major subregions are altered in size in major depressive disorder and in relation to the 5HTTLPR genotype.
We investigated the influence of 5HTTLPR genotype, psychiatric diagnosis, suicide and other clinical factors on the volume of the entire post-mortem thalamus.
Major depressive disorder, SERT-ss genotype and suicide emerged as independent factors contributing to an enlargement of the total thalamus. The majority of the volume enlargement associated with the SERT-ss genotype occurred in the pulvinar, whereas enlargement associated with major depressive disorder occurred in the limbic nuclei and in other regions of the thalamus. A history of antidepressant treatment was associated with reduced thalamic volume.
The 5HTTLPR genetic variation may affect behaviour and psychiatric conditions, in part, by altering the anatomy of the thalamus.
The British Journal of Psychiatry 05/2008; 192(4):285-9. · 6.62 Impact Factor
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ABSTRACT: The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT.
Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance.
Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects.
The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.
Biological Psychiatry 04/2007; 61(6):813-8. · 8.28 Impact Factor
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ABSTRACT: Cognition in schizophrenia is impaired in a variety of cognitive domains. Galantamine, a cholinesterase inhibitor with putative nicotinic agonist-like effects, improves cognition in Alzheimer's patients.
Sixteen schizophrenic or schizoaffective patients stabilized on risperidone were administered galantamine (n=8) or placebo (n=8) in a randomized, double-blind trial. The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) assessed changes in cognitive performance over an eight-week treatment interval.
Clinical symptoms improved in both groups during the trial with no evidence that galantamine exacerbated extrapyramidal symptoms. Patients treated with galantamine experienced an overall improvement in cognitive performance (RBANS Total scale score; galantamine = 12.1 +/- 12.8 SD, placebo = .5 +/- 13.5, t = 2.32, p < .04). Confidence intervals suggest that RBANS Attention and Delayed Memory subscale performance was robustly improved in galantamine patients by approximately one standard deviation, effectively normalizing cognitive performance in these domains.
Adjunctive treatment with galantamine improves memory and attention in patients with schizophrenia who are stabilized on risperidone, providing the opportunity to improve functional outcome in these patients.
Biological Psychiatry 09/2006; 60(6):530-3. · 8.28 Impact Factor
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ABSTRACT: Mitogen-activated protein kinase (MAPK) signaling pathways respond to dopaminergic and serotonergic agents and mediate short- and long-term effects of intracellular signaling in neurons. Here we show that the antipsychotic agent, clozapine, selectively activates the MEK/ERK MAPK pathway, and inhibition of this pathway reverses clozapine's actions in the conditioned avoidance response (CAR) paradigm, a rodent behavioral assay of antipsychotic activity.
Phosphorylation patterns of MAPK pathway enzymes were determined by quantitative immunoblot analysis and immunohistochemistry of rat prefrontal cortex. Kinase inhibitors were used to assess the role of MAPK signaling pathways in mediating clozapine-induced suppression of CAR.
Clozapine administration selectively increased phosphorylation of MEK1/2 but had no effect on p38 or JNK phosphorylation. Pretreatment with the 5-HT2A agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride blocked the clozapine-induced increase in MEK1/2 phosphorylation. Immunohistochemistry revealed that clozapine treatment elevated the number of cells in the prefrontal cortex positive for phosphoERK, the downstream substrate of MEK1/2. Prior administration of MEK1/2 inhibitors U0126 or Sl327, or ERK inhibitor 5-iodotubercidin, reversed suppression of CAR induced by clozapine, whereas administration of vehicle, JNK or p38 inhibitors (L-JNK-1 and SB203580, respectively) had no effect. Inhibition of kinases upstream to MEK1/2 (PI-3K, PKC, and CaMKII) by administration of LY294002, bisindolylmaleimide, or KN-62, respectively, also reversed clozapine-induced suppression of CAR.
These data support the hypothesis that the MEK/ERK signal transduction cascade participates in clozapine's antipsychotic actions.
Biological Psychiatry 04/2005; 57(6):617-23. · 8.28 Impact Factor
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ABSTRACT: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders.
Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain.
There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects.
The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.
American Journal of Psychiatry 08/2004; 161(7):1270-7. · 12.54 Impact Factor
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ABSTRACT: High affinity for serotonin-2A (5-HT2A) over dopamine (DA) D2 receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT2A/low D2 receptor blockade. Thus, addition of a 5-HT2A receptor antagonist to an ineffective dose of a D2 receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT2A receptor antagonists can confer an atypical (clozapine-like) profile on a D2 receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT2A receptor antagonist treatment to a traditional D2 receptor blocking regimen has been suggested. However, the ability of 5-HT2A receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT2A receptor antagonist MDL 100,907 in combination with the DA D2 receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, −30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc; −60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, −60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, −30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT2A receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT2A receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window.
Pharmacology Biochemistry and Behavior.
