Pooling pharmacogenetic studies on the serotonin transporter: a mega-analysis.

Pharmacogenetic studies on antidepressants have reported an association between the promoter of the serotonin transporter gene (SERTPR) and response to antidepressant treatment. In the present study, individual subject data from three pharmacogenetic studies on SERTPR were pooled ('mega-analysis') to investigate the role of this gene in the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs). A group of 548 patients who were treated with different SSRIs in a double blind design were included; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. SERPR allelic variants were determined in each subject using a PCR-based technique. In the whole sample, subjects with SERPR() l/l variants showed a significantly better response to treatment, and this effect was independent from analyzed demographic and clinical variables but was not uniform across samples. This result supports the involvement of the SERTPR gene in response to antidepressant treatments.

Temperature regulation in depression: functional 5HT1A receptor adaptation differentiates antidepressant response.

Observations in humans and animals have indicated that chronic, but not acute, antidepressant treatment (ADT) can desensitize 5-HT1A receptor-mediated responses, such as hypothermia. We hypothesized that 5-HT1A desensitization would be necessary for an antidepressant response (ADR) to occur. To test this hypothesis, we examined 5HT1A-agonist ipsapirone (IPS)-induced hypothermia in 28 depressed patients being treated with fixed doses of nortriptyline (75 mg) at 3-day and 3-week treatment points. Decreases in 24-item Hamilton scores (>12) were used to dichotomize the response data into ADR groups of 13 responders (ADR+) and 15 nonresponders (ADR-). A two-way repeated measures analysis of variance indicated significant temperature differences in the area under the curve between response groups across time from 3-day to 3-week intervals (df=1, 26, F=6.6, p<0.02). In comparison to 3 days treatment, at 3 weeks, the ADR+ patients showed blunted hypothermic responses to IPS. ADR- did not show this effect, implicating ADR+ patients to be less responsive to 5HT1A-receptor stimulation after 3 weeks treatment. Similar effects were not found for 5HT1A postsynaptically mediated ACTH and cortisol responses. These results indicate that to achieve ADR, serotonergic neurotransmission needs to be altered as reflected by the change in 5-HT1a receptor responsiveness documented herein.

Initial conditions of psychotropic drug response: studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome.

The Hypothesis of Initial Conditions posits that differences in psychotropic drug response result from individual differences in receptor site kinetics, and differences in the sensitivity of downstream receptor-linked responses. This work examines data consistent with the hypothesis, specific to genetic and kinetic differences of the serotonin (5-HT) transporter (SERT), as they may be linked to divergent antidepressant response (ADR). The mechanisms for divergent ADR in association with different initial SERT function are considered within the context of SERT trafficking as sensitive to various different kinase and cytokine signals, some of which are dependent on the 5-HTTLPR polymorphism of the SERT gene. Pilot data suggest that human lymphocytes show kinase changes similar to those found in rat brain with ADT. These studies additionally suggest that ADT prompts a shift in cytokine gene expression toward a greater anti-inflammatory/inflammatory ratio. These latter findings are discussed within the context of a literature suggesting increased inflammatory cytokine levels in depression, and recent observations of increased temperature associated with depression. In sum, the data suggest the opportunity to identify response dependent protein (RDP) expression patterns that may differ with dichotomous ADR, and suggest new insights into understanding the mechanisms of psychotropic drug response through an understanding of initial differences in potential for psychotropic drug target regulation during therapy.

Serotonin transport kinetics correlated between human platelets and brain synaptosomes.

RATIONALE: Blood platelets have been used extensively as a model system for investigating the role of the serotonin transporter (SERT) in various psychiatric disorders, especially depression. However, to date, it is not known whether platelet serotonin (5-HT) transport would be related to that in brain. OBJECTIVES: We examined 5-HT transport kinetics simultaneously in human blood platelets and human cortical brain synaptosomes to determine whether they were correlated. METHODS: Blood platelets and synaptosomes were obtained from 25 patients undergoing epileptic surgery. Synaptosomes were obtained from normal margins of surgical neuropathology specimens of anterotemporal cortex. RESULTS: Platelet SERT V(max) was significantly correlated with brain SERT V(max) on linear regression (r=0.58, p<0.005), after controlling for the confounding effects of gender (t=-2.4, p=0.025) and time of day (t=2.1, p<0.05). Consistent with previous observations, there was a negative correlation between the maximum velocity (V(max)) of platelet 5-HT transport and pO2 (r=-0.52, p<0.01). Females had a significantly higher pO2 than males (F=4.9, p<0.05). After accounting for gender differences, addition of pO2 did not add further strength to the regression, given the aforementioned gender differences in pO2. The correlation between unadjusted values for platelet vs brain SERT V(max) was r=0.3, p=0.06. CONCLUSIONS: These results suggest that a relationship may exist between 5-HT transport in platelets and cortical synaptosomes, when appropriate controls for confounding factors are employed.

Open-label risperidone for Asperger's disorder: negative symptom spectrum response.

OBJECTIVE: Asperger's disorder consists of negative symptoms similar to those seen in schizophrenia, autism, schizoid personality disorder, and schizotypal personality disorder. We investigated whether risperidone, which is effective in treating the negative symptoms of schizophrenia, would improve such symptoms observed in Asperger's disorder in a prospective, open-label trial. METHOD: Thirteen male patients aged 6 to 18 years who were diagnosed with Asperger's disorder by DSM-IV criteria were enrolled in a 12-week, prospective, open-label pilot study from March 13, 2002 to August 11, 2003. All subjects were started on risperidone 0.25 mg twice per day. Doses were increased based on clinical indication and tolerability. The primary efficacy variable was the Scale for the Assessment of Negative Symptoms (SANS). Each subject's baseline score served as his control. Secondary efficacy measures included the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Montgomery-Asberg Depression Rating Scale, Global Assessment Scale, and a modified Asperger Syndrome Diagnostic Scale. RESULTS: We found a statistically significant improvement from baseline for last-observation-carried-forward (LOCF) analyses as well as for analyses of 12-week completers (N = 9) in our primary outcome measure, SANS scores (F = 13.41, p < .0001 for 12-week completers; F = 9.64, p < .0001 for LOCF). We also found statistically significant improvement in all secondary efficacy measurements (F values range, 8.41 to 15.73, p values range, < .0001 to < .005 for 12-week completers; F values range, 6.53 to 7.75, all p < .0001 for LOCF). CONCLUSIONS: Subjects' symptoms significantly improved after risperidone. The open-label nature of this small pilot study suggests caution in interpreting these data, but the results suggest that placebo-controlled trials should follow.

Improved potency of escitalopram on the human serotonin transporter: demonstration of an ex vivo assay technique.

The potency of escitalopram ("Lexapro," s-citalopram, LU-26-054) was compared with that of racemic citalopram ("Celexa") using plasma samples from drug-treated normal controls applied to an assay of human serotonin [5-hydroxytryptamine (5-HT)] transport inhibition in blood platelets. Samples were available for both 4-hour and 24-day drug administration. The data indicated that 5-HT transport inhibition was fully manifest for each drug within 4 hours of administration, without significant increase in platelet transport inhibition by 24-day treatment. In addition, a dose-response relationship could be seen for escitalopram and citalopram with increasing 5-HT transport inhibition observed with increasing dose. It was evident from the data that escitalopram was significantly more potent than its racemate in inhibiting human platelet 5-HT transport. Thirty milligrams of escitalopram approximated the effect of 60 mg of racemic citalopram, and similarly, 10 mg of escitalopram approximated that of 20 mg of its racemate. This is the first demonstration of escitalopram's pharmacodynamic effect on the human 5-HT transporter. The results demonstrate its superior potency at the human 5-HT transporter site.

Initial platelet serotonin (5-HT) transport kinetics predict nortriptyline treatment outcome.

According to the hypothesis of initial conditions, drug response may be determined by different initial states of neurotransmitter protein recognition systems. Platelet serotonin (5-HT) transport kinetics were studied as initial-conditions predictors of antidepressant response in 24 depressed patients before and after 3 weeks of treatment with nortriptyline (75 mg). The initial affinity of the 5-HT transporter (5-HTT) correctly predicted 71% of the outcome. The pretreatment affinity constant ( Km) correlated (r = 0.61; p < 0.002) with that measured after 3 weeks of treatment (Kapp). Responding patients had a significantly higher initial Km before treatment and a significantly higher Kapp after treatment. Nonresponders had an initial Km significantly lower than that of 24 controls. Nortriptyline plasma levels were not statistically different between response groups. These results are consistent with two previously published observations, which indicate that the initial affinity of the 5-HTT predicted response to fluvoxamine or fluoxetine in the same way. Insofar as all three drugs increase the apparent affinity of the 5-HTT, it appears that a better response is related to those cases where the initial affinity is already higher before treatment.

Historical studies of premenstrual tension up to 30 years ago: implications for future research.

The biology and treatment of premenstrual tension syndrome has advanced significantly in the past 30 years. Newer research expands on earlier literature that has been accumulated before 1972. This review selectively considers this earlier literature, because it defines the nature and impact of what was then considered to be premenstrual tension syndrome. The authors consider a set of earlier studies that suggest a role for personality, psychodynamics, and cultural variables in the etiology, impact, and treatment of the cyclic disorders. This review also considers studies of the biology of premenstrual tension that suggest a role for sodium and water fluctuations, the renin-angiotensin-aldosterone system, ovarian hormones, monoamines, and acetylcholine. Current applications and potential research directions based on this information are also discussed.

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome.

BACKGROUND: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS: Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p <.025), and a drug dose response effect (r =.40, p <.01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. CONCLUSIONS: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.

An hypothesis of initial conditions: receptor-effector systems as determinants of psychopharmacologic drug response.

A variety of biological factors have been sought to explain why psychopharmacologic drug response varies between patients. In addition to variables such as age, race, gender, age of onset, severity, number of previous episodes, prior drug treatment, comorbidity and hormonal state, there have been investigations also into a variety of pharmacokinetic and pharmacodynamic variables such as dose, absorption, metabolism, distribution, globulin/protein binding, excretion and rate of titration, all potentially considered to explain differences in drug response. However, it is clear that, in many cases, such variables do not fully account for differences in drug response. In this work, it is hypothesized that drug response may also be significantly determined by the initial conditions of receptor site kinetics, as well as the sensitivity of downstream receptor-linked responses. This theory of initial conditions suggests that drug-action depends on receptor affinity and capacity, as well as on the conditions determining gene regulatory factors, which may influence transcription of gene products related to the emergent drug properties mediated through the receptor. Under one such scenario, dose response would be related, in the expected direction, to the initial affinity conditions of the receptor. For example, if the net effect of a drug were to decrease the apparent affinity of the receptor for its endogenous ligand, a stronger response could then be expected within a lower dose range, for those cases in which the initial affinity conditions for the receptor are already lower. The principle of initial conditions may apply not only to therapeutic psychotropic drugs, but also to drugs of abuse. This work reviews evidence to date in support of initial receptor conditions determining response to antipsychotic agents, response to antidepressants, and dependence as a response to alcohol, as conceptual examples.