Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression

BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.     

A longitudinal study of apolipoprotein-E genotype and depressive symptoms in community-dwelling older adults.

The Apolipoprotein-E (APOE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD) and cognitive decline in older adults. Depression may also be a risk factor for dementia, and depression is important in the differential diagnosis of dementia. The authors performed a 5-year longitudinal study of APOE genotype and change in Geriatric Depression Scale scores in 113 community-dwelling older adults. No association was observed between APOE genotype and change in depressive symptoms. These results do not support the hypothesis that the APOE epsilon 4 allele is associated with depression. Important objections have been raised to APOE genotyping in the diagnosis of AD. However, the specificity of APOE genotyping in AD diagnosis would not appear to be compromised by an association with depression.     

The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder

The apolipoprotein E (APOE) polymorphism is associated with neurodegenerative diseases. Its role regarding psychiatric disorders is controversial. It has been suggested to affect antidepressant treatment response and response to electroconvulsive therapy (ECT). In the present study, the association between APOE polymorphism and response to ECT in 119 patients with major depressive disorder was investigated. Moreover, a relation between APOE polymorphism and the age of onset of depression as well as the cognitive outcome of ECT was studied. In the whole population, no association was found between APOE polymorphism and response to ECT. However, in nonpsychotic patients, the epsilon2 allele tended to be more frequent in responders than nonresponders. Earlier onset of depression was observed in the patients with epsilon4 allele in late-life depression. There was no association between the APOE genotype and the cognitive change caused by ECT in the population as a whole. In women, however, epsilon2 allele may play a protective and epsilon4 allele a deleterious role in cognition during ECT.     

Association analysis between variants of the interleukin-1beta and the interleukin-1 receptor antagonist gene and antidepressant treatment response in major depression

This study investigated the possible association of the interleukin-1 beta (IL-1beta) C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra) (86bp)(n) variable number of tandem repeats (VNTR) polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1beta-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1beta-511C allele carriers. No association was found for the IL-1beta C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1beta C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bp)(n) VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1beta C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.     

APOE genotype predicts depression in women with Alzheimer's disease: a retrospective study

OBJECTIVE: The association between the APOE epsilon4 allele and depression was investigated in a retrospective study of 323 AD patients. METHODS: Patients were divided into demographically comparable groups based on the presence or absence of depression. RESULTS: Results showed that the frequency of APOE epsilon4 allele was significantly higher in the depressed vs non-depressed AD patients (72% and 58%, respectively), and an interaction revealed that women possessing the APOE epsilon4 allele were almost four times more likely to be depressed than those without the epsilon4 allele. CONCLUSION: Results are consistent with recent suggestions that the APOE epsilon4 genotype may be over-represented among depressed women with AD and highlight the need for additional research investigating the links between APOE genotype, mood, and gender.     

Association of APOE genetic polymorphism with cognitive function and suicide history in geriatric depression

Apolipoprotein E (APOE) has been associated with a variety of late-life neuropsychiatric disorders, including geriatric depression. This study determined whether APOE genotypes affect vulnerability to geriatric depression. We also tested the effect of the presence of the APOE epsilon4 (APOE4) allele on age of onset, suicide attempt history and cognitive function in geriatric depressed patients. We genotyped APOE in 111 elderly inpatients diagnosed as having major depression and 144 normal controls. The depressed patients were evaluated at baseline using the Hamilton Rating Scale for Depression and the Mini-Mental State Examination (MMSE) after admission. Age of onset of depression and suicide attempt history in the depressed group were evaluated by interview and medical record. We found no association between APOE genotypes and geriatric depression (p = 0.342) or APOE4 status and age of onset of depression (p = 0.281). However, compared with depressed subjects lacking the APOE epsilon4 allele, depressed subjects who were also APOE4 carriers showed significantly lower MMSE scores (p = 0.021) and an increased suicide attempt history (p = 0.012). The APOE genotype may contribute to cognitive performance and suicidality in geriatric depression, rather than being a specific risk factor for the disorder.     

Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients

OBJECTIVE: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. METHODS: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. RESULTS: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. CONCLUSION: The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation.     

Apolipoprotein E genotypes in hospitalized elderly patients with vascular dementia

BACKGROUND: Polymorphism in the apolipoprotein E (APOE) gene is the major genetic risk factor associated with late-onset Alzheimer's Disease (AD). However, it is still unclear if a relationship exists between the APOE epsilon4 allele and vascular dementia (VaD) in elderly subjects. OBJECTIVES: To evaluate the prevalence of APOE alleles in elderly patients with VaD compared to AD patients and to control subjects with no cognitive impairment (NoCI). PATIENTS AND METHODS: We evaluated 396 consecutive patients aged > or =65 years with definite or suspected cognitive impairment with a clinical (Mini-Mental State Examination, Clinical Dementia Rating, Geriatric Depression Scale), functional (Activities of Daily Living, Instrumental Activities of Daily Living), comorbidity (Cumulative Illness Rating Scale) and instrumental (CT scan, NMR) assessment. Diagnosis of dementia was made according to NINCDS-ADRDA and NINDS-AIREN Work Group and the DSM-IV. APOE genotypes were analyzed by a recently described method resulting in positive/negative chain reaction products for each APOE genotype. Statistical analysis was carried out using the Pearson chi(2), the Kruskal-Wallis test and the ANOVA post hoc comparisons. RESULTS: A total of 287 elderly patients (males = 138, females = 149, mean age = 77.8 +/- 6.9 years, range = 65-98) with diagnoses of VaD (n = 97), AD (n = 82) or NoCI (n = 108) were included in the study. A significantly higher APOE epsilon4 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects, while no differences were found between VaD patients and subjects with NoCI (AD = 24.3%, VaD = 10.3, NoCI = 8.7, p < 0.05). Furthermore, a significantly lower APOE epsilon3 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects but not between VaD and NoCI patients (AD = 71.3%, VaD = 80.9, NoCI = 83.4, p < 0.05). No significant differences were observed in the APOE epsilon2 allele (VaD = 8.8%, AD = 4.4, NoCI = 7.9, p = n.s.) among the 3 groups. CONCLUSIONS: In this population, the frequency of the APOE epsilon4 allele is lower in VaD than in AD.     

Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease

BACKGROUND: Psychiatric symptoms occur frequently in the course of AD, are a frequent contributor to institutionalization, predict cognitive decline and death, and often require treatment with psychotropic medications. Previous studies investigating the association between APOE genotype and psychiatric symptomatology in AD have reported contradictory results. OBJECTIVE: To determine whether APOE genotype predicts incident psychiatric symptomatology in patients with AD. METHODS: Eighty-seven patients with AD at early stages and no psychiatric history were followed semiannually for up to 9.3 years (mean 5.5 years) for development of delusions, illusions, hallucinations, behavioral symptoms, and depression. Cox proportional hazards models were used to examine the relative risk for incident psychiatric symptomatology (outcome) in relation to APOE genotype (predictor). RESULTS: The presence of one epsilon4 allele carried a 2.5-fold risk, whereas the presence of two epsilon4 alleles carried a 5.6-fold risk for development of delusions. The associations remained significant even when age, ethnicity, sex, education, duration of disease, and cognitive and functional performance were controlled for. The presence of two epsilon4 alleles was associated with reduced risk for developing hallucinations in the adjusted analysis only. No significant associations were detected between APOE genotype and the incidence of illusions, behavioral symptoms, or depression. CONCLUSION: The presence of one or more epsilon4 alleles is a significant predictor for the incidence of delusions in the course of AD.     

Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression

OBJECTIVE: Current clinical knowledge holds that antidepressants have a delayed onset of efficacy. However, the delayed onset hypothesis has been questioned recently by survival analytical approaches. We aimed to test whether early improvement under antidepressant treatment is a clinically useful predictor of later stable response and remission. METHOD: We analyzed data from a randomized double-blind controlled trial with mirtazapine and paroxetine in patients with major depression (DSM-IV). Improvement was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score reduction of > or = 20%. Stable response was defined as > or = 50% HAM-D-17 score reduction at week 4 and week 6, and stable remission as a HAM-D-17 score of < or = 7 at week 4 and week 6. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Improvement occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. CONCLUSION: Our results strongly suggest that early improvement predicts later stable response with high sensitivity. These empirically derived data question the delayed onset hypothesis for both antidepressants tested and provide important clinical clues for an individually tailored antidepressant treatment.     

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage

OBJECTIVES: To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Neuropsychological assessments were conducted with 70 SAH survivors derived from a consecutive series of neurosurgical admissions. Outcomes, including cognitive tests, health questionnaires and Glasgow Outcome Scale at a mean of 16 months after SAH, were compared with presence or absence of the epsilon4 allele. RESULTS: There was no evidence that SAH survivors possessing the epsilon4 allele had poorer outcome. The only suggestion of an association between the epsilon4 allele and outcome was in a subgroup of patients with a Fisher grade 4 haemorrhage, although this trend did not reach statistical significance. CONCLUSIONS: Overall, possession of the APOE epsilon4 allele is not significantly associated with neuropsychological outcome following SAH. However, there may be an effect amongst those with a Fisher grade 4 haemorrhage.     

Apolipoprotein E epsilon4 allele differentiates the clinical response to donepezil in Alzheimer's disease

The existence of an association between apolipoprotein E (APOE) and Alzheimer's disease (AD) has been reported in several studies. The possession of an ApoE epsilon4 allele is now considered a genetic risk factor for sporadic AD. There has been a growing agreement about the role exerted by the ApoE epsilon4 allele on the neuropsychological profile and the rate of cognitive decline in AD patients. However, a more controversial issue remains about a possible influence of the APOE genotype on acetylcholinesterase inhibitor therapy response in AD patients. In order to address this issue, 81 patients diagnosed as having probable AD were evaluated by a complete neuropsychological test battery at the time of diagnosis (baseline) and after 12-16 months (retest). Patients were divided into two subgroups: (1) treated with donepezil at a dose of 5 mg once a day (n = 41) and (2) untreated (n = 40). Donepezil therapy was started after baseline evaluation. The APOE genotype was determined according to standardized procedures. We evaluated the possible effect of the APOE genotype on the neuropsychological tasks in relation to donepezil therapy. The statistical analysis of the results showed a global worsening of cognitive performances for all AD patients at the retest. Differences in the clinical outcome were analysed in the four subgroups of AD patients for each neuropsychological task. ApoE epsilon4 carriers/treated patients had improved or unchanged scores at retest evaluation for the following tasks: visual and verbal memory, visual attention and inductive reasoning and Mini Mental State Examination. These results indicate an effect of donepezil on specific cognitive domains (attention and memory) in the ApoE epsilon4 carriers with AD. This might suggest an early identification of AD patients carrying at least one epsilon4 allele as responders to donepezil therapy.     

No association between subjective memory complaints and apolipoprotein E genotype in cognitively intact elderly

OBJECTIVE: This cross-sectional study examined the relationship between subjective memory complaints and the apolipoprotein epsilon 4 allele (epsilon4), a genetic risk factor for Alzheimer's disease (AD), among cognitively normal subjects identified from a community memory screening. DESIGN: The sample comprised 232 consecutive white non-Hispanic older adults who presented to a free community-based memory-screening program at a University affiliated memory disorders center. Participants were classified as cognitively normal based on scores on the age and educated adjusted Folstein Mini-Mental Status Exam (MMSAdj) and a brief Delayed Verbal Recall Test (DRT). Subjects were assessed for APOE genotype, subjective memory complaints (Memory Questionnaire, MQ), depressive symptoms (Hamilton Depression Rating Scale, HDRS), and history of four major medical conditions that have been associated with memory loss (stroke/transient ischemic attack [TIA], atherosclerotic heart disease, hypertension, and diabetes). A hierarchical regression analysis was performed to examine the association between APOE genotype and memory complaints after controlling for a host of potential confounding factors. RESULTS: The APOE epsilon4 allele frequency for cognitively normal subjects was 0.13. Subjective memory complaints were predicted by depressive symptoms and a history of stroke/TIA. They were not associated with APOE genotype, MMSAdj score, DRT score, age, education, gender, and reported history of atherosclerotic heart disease, hypertension, or diabetes. CONCLUSION: The results did not suggest an association between subjective memory complaints and the APOE epsilon4 allele in this sample of cognitively intact subjects. This indicates that memory complaints may confer risk for future dementia through pathways independent of APOE genotype. The results also show that older adults with memory complaints are at increased risk for underlying depression.     

Mirtazapine monotherapy versus combination therapy with mirtazapine and aripiprazole in depressed patients without psychotic features: a 4-week open-label parallel-group study.

BACKGROUND: There is preliminary evidence that the atypical antipsychotic aripiprazole, which is a partial agonist at D(2) and 5-HT(1A) receptors and a potent antagonist at 5-HT(2A) receptors, may be useful as an augmentation strategy in treatment-resistant depression. METHOD: In this 4-week open-label non-randomized parallel-group study, the safety and efficacy of aripiprazole as add-on treatment strategy in patients suffering from non-delusional depression was investigated. Forty drug-free depressed inpatients without psychotic symptoms (13 men, 27 women), suffering from a major depressive episode or bipolar disorder, depressive state (DSM-IV criteria), were included in the study. The patients were treated either with mirtazapine monotherapy (45 mg/day) or combination therapy (mirtazapine 45 mg/day plus aripiprazole 15 mg/day) for 4 weeks. Safety and efficacy were assessed weekly using the Hamilton Depression Rating Scale, the Simpson-Angus Scale and the Barnes Akathisia Scale. RESULTS: Mirtazapine monotherapy and combined treatment with mirtazapine and aripiprazole showed comparable antidepressant effects as assessed at the endpoint of the study period. However, additional administration of aripiprazole accelerated the onset of antidepressant action in patients suffering from treatment-resistant depression. Additive use of aripiprazole reduced the mirtazapine-induced increase in the body mass index. Moreover, mirtazapine had favourable effects on aripiprazole-induced akathisia. No other extrapyramidal side effects were seen in the combination therapy group. CONCLUSION: Combined therapy with mirtazapine and aripiprazole is a safe and well-tolerated treatment option which may be useful especially in treatment-resistant depression. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole in depressed patients.     

Cholesterol and APOE genotype interact to influence Alzheimer disease progression

In this retrospective analysis of 443 Alzheimer disease (AD) patients from a 30-week tacrine trial, change in Alzheimer's Disease Assessment Scale score from baseline to final value was significantly associated with a total serum cholesterol/APOE genotype interaction. Disease progression in the no-APOE epsilon4 allele/high-cholesterol subgroup was greater than in the normal-cholesterol subgroups with or without epsilon4. Cholesterol levels and APOE genotype may interact to affect AD progression. The results are consistent with preclinical data on cholesterol's effects in AD.     

Factors associated with depressive symptoms in non-demented community-dwelling elderly.

OBJECTIVE: We examined the risk for depressive symptoms associated with age, education, ethnicity, gender, marital status, apolipoprotein E genotype (APOE) and memory complaints among non-demented elderly (> or = 60 years). DESIGN: Cross-sectional study of geriatric patients recruited from a free memory screening offered to the community. SAMPLE: This investigation included 506 community-residing elderly subjects who were screened for cognitive impairment and classified as non-demented based on age and education-adjusted Folstein Mini-Mental State Exam (MMSAdj) scores of 24 or greater. RESULTS: The prevalence of significant depressive symptoms (Hamilton Depression Rating Scale > or = 12) was 12.1% (N = 61). Increased risk for depression was associated with female gender (OR = 2.3; 95% CI = 1.1-4.8; p < 0.05), Cuban American ethnicity (OR = 4.9; 95% CI = 2.3-10.4; p < 0.0001) and memory complaints (OR = 1.3; 95% CI = 1.2-1.4; p < 0.0001). The APOE allele frequencies in the current sample were 0.07, 0.80 and 0.13 for the epsilon 2, epsilon 3 and epsilon 4 alleles, respectively. CONCLUSIONS: The results suggest that signs and symptoms of depression are common among non-demented elderly subjects in the community. In this study, mood disturbances were associated with Cuban American ethnicity, female gender and more memory complaints. Factors that were not confirmed by this study include age, education, marital status and APOE genotype. The observed APOE, epsilon 4 allele frequency of 0.13 supports the normal cognitive classification of the sample.     

Prospective study of apolipoprotein E genotype and functional outcome following ischemic stroke

BACKGROUND: The apolipoprotein E (APOE) epsilon 4 allele is a marker of adverse outcome following head injury and intracerebral hemorrhage. Transgenic animal data in a focal cerebral ischemia model suggest that the epsilon 4 allele increases infarct size and functional impairment. OBJECTIVE: To determine if APOE genotype is associated with functional recovery from ischemic stroke. DESIGN: Prospective study. SETTING: Stroke service at a university teaching hospital. PATIENTS: Patients with clinical and neuroimaging findings (computed tomography or magnetic resonance imaging) compatible with an acute ischemic stroke. MAIN OUTCOME: Functional outcome by Barthel index (BI) and modified Rankin scale (mRS) was compared for epsilon 3/epsilon 3 patients vs epsilon 4 carriers and vs epsilon 2 carriers at 1 and 3 months. Univariate predictors of 3-month outcome were examined in a multivariate analysis. RESULTS: One hundred eighty nine patients were enrolled: 100 women, 89 men (mean +/- SD age, 69.4 +/- 11.0 years). There were 25 epsilon 2 alleles (frequency, 0.07), 292 epsilon 3 alleles (0.77), and 61 epsilon 4 alleles (0.16). Baseline National Institutes of Health Stroke Scale scores and Oxfordshire Community Stroke Project classifications were similar in all groups (epsilon 3/epsilon 3, epsilon 4, and epsilon 2 carriers). One-month (BI, P = .64; mRS, P = .59) and 3-month (BI, P = .87; mRS, P = .73) outcomes were not associated with possession of either epsilon 4 or the epsilon 2 allele. Baseline National Institutes of Health Stroke Scale scores (P < .001) and age (P = .002) were significant predictors of 3-month BI and mRS outcomes in multivariate analyses. CONCLUSIONS: Although there is a robust influence of APOE polymorphism on functional recovery after some types of brain injury in humans, it does not exert a major influence on injury severity or functional recovery following ischemic stroke. Arch Neurol. 2000;57:1480-1484     

Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients.

OBJECTIVE: Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks). METHODS: Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events. RESULTS: Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events. CONCLUSION: During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.     

A monoamine oxidase B gene variant and short-term antidepressant treatment response

Genetic differences among patients suffering from Major Depression are likely to contribute to interindividual differences in medication treatment response. Thus, the identification of gene variants affecting drug response is needed in order to be able to predict response to psychopharmacological drugs. This study analyzed a possible association of the common A644G single nucleotide polymorphism (SNP) within intron 13 of the monoamine oxidase B (MAOB) gene with antidepressant treatment response. The study population consisted of n = 102 patients with major depression (criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; DSM-IV) participating in a randomized double-blind controlled clinical trial, conducted at 50 centers in Germany, comparing the efficacy of mirtazapine and paroxetine during 6 weeks of treatment. Overall, female patients homozygous for the A-allele had a significantly faster and more pronounced antidepressant treatment response than AG/GG-carriers. In paroxetine-treated females these differences remained statistically significant. In mirtazapine-treated females homozygous for the A-allele compared to AG/GG-carriers, HAMD-17 scores during the study period were constantly and markedly lower, but not statistically different. In males, we found no association between the MAOB A644G intron 13 SNP and antidepressant treatment response. Our data provide first suggestive evidence that the MAOB A644G SNP is involved in the outcome of treatment with mirtazapine or paroxetine in females with major depression. To confirm the role of the MAOB A644G gene variant in antidepressant treatment response, independent replications are needed. If replicated, the MAOB A644G polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.     

Pharmacogenetics of antidepressant medication intolerance

OBJECTIVE: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). METHOD: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. RESULTS: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. CONCLUSIONS: Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.