Cardiovascular Adverse Reactions During Antipsychotic Treatment: Results of AMSP, A Drug Surveillance Program Between 1993 and 2013.

BACKGROUND: Cardiovascular diseases are still the leading cause of global mortality. Some antipsychotic agents can show severe cardiovascular side effects and are also associated with metabolic syndrome. METHODS: This observational study was based on data of AMSP (Arzneimittelsicherheit in der Psychiatrie), a multicenter drug surveillance program in Austria, Germany and Switzerland, that recorded severe drug reactions in psychiatric inpatients. RESULTS: A total of 404 009 inpatients were monitored between 1993 and 2013, whereas 291 510 were treated with antipsychotics either in combination or alone. There were 376 cases of severe cardiovascular adverse reactions reported in the given timespan, yielding a relative frequency of 0.13%. The study revealed that incidence rates of cardiovascular adverse reactions were highest during treatment with ziprasidone (0.35%), prothipendyl (0.32%), and clozapine (0.23%). The lowest rate of cardiovascular symptoms occurred during treatment with promethazine (0.03%) as well as with aripiprazole (0.06%). The most common clinical symptoms were orthostatic collapse and severe hypotonia, sinustachycardia, QTc prolongation, myocarditis, and different forms of arrhythmia. The dosage at the timepoint when severe cardiovascular events occurred was not higher in any of the given antipsychotics than in everyday clinical practice and was in average therapeutic ranges. In terms of subclasses of antipsychotics, no significant statistical difference was seen in the overall frequencies of adverse reactions cases, when first-generation high potency, first-generation low potency, and second-generation antipsychotics were compared. Thirty percent of adverse events among second-generation antipsychotics were induced by clozapine. CONCLUSIONS: Our findings on cardiovascular adverse reactions contribute to a better understanding of cardiovascular risk profiles of antipsychotic agents in inpatients.

Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program.

BACKGROUND: Drug-induced liver injury is a common cause of liver damage and the most frequent reason for withdrawal of a drug in the United States. The symptoms of drug-induced liver damage are extremely diverse, with some patients remaining asymptomatic. METHODS: This observational study is based on data of Arzneimittelsicherheit in der Psychiatrie, a multicenter drug surveillance program in German-speaking countries (Austria, Germany, and Switzerland) recording severe drug reactions in psychiatric inpatients. Of 184234 psychiatric inpatients treated with antidepressants between 1993 and 2011 in 80 psychiatric hospitals, 149 cases of drug-induced liver injury (0.08%) were reported. RESULTS: The study revealed that incidence rates of drug-induced liver injury were highest during treatment with mianserine (0.36%), agomelatine (0.33%), and clomipramine (0.23%). The lowest probability of drug-induced liver injury occurred during treatment with selective serotonin reuptake inhibitors ([0.03%), especially escitalopram [0.01%], citalopram [0.02%], and fluoxetine [0.02%]). The most common clinical symptoms were nausea, fatigue, loss of appetite, and abdominal pain. In contrast to previous findings, the dosage at the timepoint when DILI occurred was higher in 7 of 9 substances than the median overall dosage. Regarding liver enzymes, duloxetine and clomipramine were associated with increased glutamat-pyruvat-transaminase and glutamat-oxalat-transaminase values, while mirtazapine hardly increased enzyme values. By contrast, duloxetine performed best in terms of gamma-glutamyl-transferase values, and trimipramine, clomipramine, and venlafaxine performed worst. CONCLUSIONS: Our findings suggest that selective serotonin reuptake inhibitors are less likely than the other antidepressants, examined in this study, to precipitate drug-induced liver injury, especially in patients with preknown liver dysfunction.

Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010.

BACKGROUND: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. METHODS: Of 169,278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. RESULTS: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. CONCLUSIONS: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.

The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme.

Hyponatraemia (HN) can be a life-threatening medical condition which may lead to severe neurological and psychiatric symptoms. The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicentre drug surveillance programme that assesses severe or new adverse drug reactions during psychopharmacological treatment in psychiatric inpatients. We report on a total of 263 864 psychiatric inpatients monitored from 1993 to 2007 in 80 psychiatric hospitals in Germany, Switzerland and Austria. During this period plasma sodium levels below 130 mmol/l (severe HN according to AMSP) were reported in 93 patients (relative frequency 0.04%). On average, the plasma sodium levels of all cases were 119.7 mmol/l (±5.8 s.d.); median 121 mmol/l (range 104-129 mmol/l). Patients who showed no clinical signs (n=65, 70%) had a mean sodium level of 121.3 mmol/l (±5.0 s.d.); median 122 mmol/l (range 114-129 mmol/l). By contrast, patients with clinical symptoms (n=28, 30%) had a mean sodium level of 116.0 mmol/l (±6.0 s.d.); median 117 mmol/l (range 104-125 mmol/l). HN was mainly observed during treatment with selective serotonin reuptake inhibitors (SSRIs) (0.06%), Serotonin noradrenaline reuptake inhibitors (SNRIs) (0.08%), carbamazepine (0.10%) and oxcarbazepine (1.29%); the highest rate was found for oxcarbazepine. Antipsychotics, mirtazapine and tricyclic antidepressants were only rarely involved in HN (0.003-0.005%). Combinations of several drugs known to induce HN significantly increased the risk of HN, e.g. more than 10-fold for SSRI+diuretics+ACE inhibitors (0.37%) vs. SSRI given alone (0.02%). This is clinically relevant because such combinations, e.g. SSRI+diuretics may occur especially in elderly patients, who are in general at higher risk of developing HN.

Switching antidepressant class does not improve response or remission in treatment-resistant depression.

OBJECTIVE: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak. This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class). METHODS: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included. RESULTS: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders. CONCLUSIONS: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate.

Technical note: further development of a resolution modification routine for the simulation of the modulation transfer function of digital x-ray detectors.

PURPOSE: This paper proposes the further development of a resolution modification routine which is used to simulate the presampling modulation transfer function (pMTF) of digital x-ray detectors. METHODS: It suggests a method to reconstruct anisotropic two dimensional (2D) pMTF matrices from the experimentally measured horizontal and vertical 1D pMTFs. In this study, the horizontal dimension of the detector is 17.3 cm, while the vertical one is 24 cm. This matrix is multiplied with the 2D Fourier transform of the super-sampled ideal input image to simulate blurring. Then, the restored image is sampled to form the pixels of the digital image. The authors suggest convolution with the comb function instead of the rectangular function to avoid the correction with the sinc function required by the latter. It is demonstrated that this correction is avoided when the comb function is used. Moreover, this study suggests a way to effectively sample the images in the case when the ratio between the "analog" pitch of the super-sampled input image and the pixel pitch of the digital x-ray detector is a semi-integer. RESULTS: The validation of the simulation algorithm demonstrated that when the comb function was used the average absolute difference between the pMTF measured from the output images and the input ones was less than 1%, while this was of 13% when the rectangular function was used. When a sinc correction was applied in the latter case the difference decreased again to less than 1%. CONCLUSIONS: The developed modification routine provides the means to simulate the spatial resolution of digital x-ray detectors under a wider range of conditions.

Technical Note: modification of the standard gain correction algorithm to compensate for the number of used reference flat frames in detector performance studies.

PURPOSE: The x-ray performance evaluation of digital x-ray detectors is based on the calculation of the modulation transfer function (MTF), the noise power spectrum (NPS), and the resultant detective quantum efficiency (DQE). The flat images used for the extraction of the NPS should not contain any fixed pattern noise (FPN) to avoid contamination from nonstochastic processes. The "gold standard" method used for the reduction of the FPN (i.e., the different gain between pixels) in linear x-ray detectors is based on normalization with an average reference flat-field. However, the noise in the corrected image depends on the number of flat frames used for the average flat image. The aim of this study is to modify the standard gain correction algorithm to make it independent on the used reference flat frames. METHODS: Many publications suggest the use of 10-16 reference flat frames, while other studies use higher numbers (e.g., 48 frames) to reduce the propagated noise from the average flat image. This study quantifies experimentally the effect of the number of used reference flat frames on the NPS and DQE values and appropriately modifies the gain correction algorithm to compensate for this effect. RESULTS: It is shown that using the suggested gain correction algorithm a minimum number of reference flat frames (i.e., down to one frame) can be used to eliminate the FPN from the raw flat image. This saves computer memory and time during the x-ray performance evaluation. CONCLUSIONS: The authors show that the method presented in the study (a) leads to the maximum DQE value that one would have by using the conventional method and very large number of frames and (b) has been compared to an independent gain correction method based on the subtraction of flat-field images, leading to identical DQE values. They believe this provides robust validation of the proposed method.

A comparison of the Major Depression Inventory (MDI) and the Beck Depression Inventory (BDI) in severely depressed patients.

BACKGROUND: We set out to examine the psychometric properties of the MDI in comparison to the BDI in a mixed group of patients with primary depression. METHODS: At the Department of Biological Psychiatry in Vienna currently depressed inpatients with either a depressive or a schizo-affective disorder filled out both MDI and BDI on day of admission and at a time-point two weeks later during their treatment. Furthermore the Hamilton Depression Scale (HAM-D) was administered by the treating clinician at both time-points. RESULTS: In total, 51 patients were included in the study. The non-parametric item response analysis was preferred to the classical Cronbach coefficient α as the latter is influenced by the number of items in a questionnaire. MDI obtained a Mokken analysis coefficient above 0.40, indicating unidimensionality. To determine external validity severely depressed patients with psychotic symptoms (N = 10) were compared to the remaining non-psychotic depressed patients (N = 41). Although BDI and MDI showed a lower score for psychotic than for non-psychotic inpatients, the standard deviations for both were greater for psychotic inpatients. On the intercorrelations between the different scales, MDI showed for all coefficients values above 0.70. On the other hand BDI and MDI both showed the same degree of linear relationship as the usual versions of HAM-D. CONCLUSION: Our results demonstrate that the MDI had the highest coefficients values and was sufficient as a measure for depressive disorders in psychiatric patients.

MAMMO_QC: Free software for quality control (QC) analysis in digital mammography and digital breast tomosynthesis compliant with the European guidelines and EUREF/EFOMP protocols.

Quality Control (QC) tests in mammography are very important, since mammograms have been used as a population-based screening test for more than 30 years and QCs lead to better image quality and radiation safety for patients. European guidelines, EUREF and EFOMP protocols provide comprehensive QC guidelines for digital mammography (DM) and digital breast tomosynthesis (DBT) units, respectively. We developed a novel, fast, free and platform independent software (named MAMMO_QC) for QC performance tests in DM and tomosynthesis, based on the aforementioned guidelines. MAMMO_QC consists of a series of ImageJ plugins for DM and DBT. It does not require any programming knowledge and can be used to evaluate several performance parameters, such as pre-sampled modulation transfer function (pMTF), normalised noise power spectrum (NNPS), detective quantum efficiency (DQE), contrast-detail analysis based on the CDMAM 3.4 and 4.0 test tools, homogeneity and artefacts, automatic exposure control (AEC) performance. The user can use MAMMO_QC for acceptance, commissioning and routine QC performance analysis based on the European guidelines. We validated our results against well-established software products used in mammography and DBT (i.e., COQ, OBJ_IQ_reduced and Artinis CDMAM Analyzer). All the average relative differences were within 5.5%, and several years of usage and testing allows us to consider MAMMO_QC as an accurate and reliable tool for QC on DM and DBT systems. Our developed software for DM and DBT computes almost all the parameters stated in the European, EUREF and EFOMP guidelines. To the best of our knowledge, no such software has been developed so far.

Urological adverse drug reactions of psychotropic medication in psychiatric inpatients - A drug surveillance report from German-speaking countries.

Urological adverse drug reactions (UADR) are common during treatment with psychotropic medication. The aim of this study was to provide a systematic description of the differential profile of UADR of psychotropic drugs in a large naturalistic population. Data stems from psychiatric hospitals collected by AMSP (Arzneimittelsicherheit in der Psychiatrie), a continuous multi-center pharmacovigilance program in Austria, Germany, and Switzerland. 171 cases of severe UADR (0.037%) among a total population of 462 661 inpatients treated with psychotropic drugs in 99 psychiatric hospitals between 1993 and 2016 were examined. Urinary retention (129 cases, 0.028%) was the most common UADR followed by incontinence (23 cases, 0.005%) and nocturnal enuresis (16 cases, 0.003%). Risk of UADR was higher in patients with mania than in other diagnostic groups. Promethazine and haloperidol were the antipsychotics with the highest rate of UADR. Tricyclic antidepressants had a higher and selective serotonin reuptake inhibitors a lower risk for UADR than the respective other antidepressants. Amitriptyline and clomipramine were the most common causes of urinary retention and clozapine of urinary incontinence. This research improves our knowledge of the urological risk profiles of psychotropic drugs in inpatients and highlights compounds associated with higher or lower risk.

On the Response of a Micro Non-Destructive Testing X-ray Detector.

Certain imaging performance metrics are examined for a state-of-the-art 20 µm pixel pitch CMOS sensor (RadEye HR), coupled to a Gd2O2S:Tb scintillator screen. The signal transfer property (STP), the modulation transfer function (MTF), the normalized noise power spectrum (NNPS) and the detective quantum efficiency (DQE) were estimated according to the IEC 62220-1-1:2015 standard. The detector exhibits excellent linearity (coefficient of determination of the STP linear regression fit, R2 was 0.9978), while its DQE peaks at 33% and reaches 10% at a spatial frequency of 3 cycles/mm, for the measured with a Piranha RTI dosimeter (coefficient of variation CV = 0.03%) exposure value of 28.1 µGy DAK (detector Air Kerma). The resolution capabilities of the X-ray detector under investigation were compared to other commercial CMOS sensors, and were found in every case higher, except from the previous RadEye HR model (CMOS-Gd2O2S:Tb screen pair with 22.5 µm pixel pitch) version which had slightly better MTF. The present digital imager is designed for industrial inspection applications, nonetheless its applicability to medical imaging, as well as dual-energy is considered and certain approaches are discussed in this respect.

Cascaded systems analysis of a-Se/a-Si and a-InGaZnO TFT passive and active pixel sensors for tomosynthesis.

Medical imaging systems like full field digital mammography (FFDM) and digital breast tomosynthesis (DBT) commonly use amorphous selenium (a-Se) based passive pixel sensor (PPS) direct conversion x-ray detectors. On one hand, direct conversion detectors inherently offer better resolution characteristics in terms of a higher modulation transfer function (MTF), in comparison to the indirect CsI:Tl PPS x-ray imager. On the other hand, especially at lower doses, this superior performance of the direct imager is seldom retained in its detective quantum efficiency (DQE) curves. It is well known that a-Se PPS x-ray imagers suffer from high additive electronic noise originating from the from the amorphous silicon (a-Si) thin film transistor (TFT) array that is being used in the current back-plane technology. This degrades the noise power spectrum (NPS) and subsequently the overall DQE. To address this deficiency, we propose to replace the PPS back-plane by active pixel sensor (APS) back-plane technology, which has the potential to reduce the back-plane electronic noise by amplifying the input signal, especially at low doses. The proposed APS is based on amorphous In-Ga-Zn-O (a-IGZO) TFT technology, which can offer high mobility (5-20 cm2 V-1 s-1), low leakage current (<10-13 A) and low flicker noise (Hooge's parameter α H ~ 1.5 [Formula: see text] 10-3), leading to better imager noise performance. To test our hypothesis, we used linear cascaded systems analysis to model the imaging performance (MTF, NPS and DQE) of the PPS and APS a-Se direct imagers. This model was first validated using experimentally measured data obtained for a 85 µm pixel pitch a-Se/a-Si TFT PPS imager. Using this model, we analyzed the noise performance of the direct a-Se and indirect CsI:Tl x-ray a-IGZO APS imagers at different dose and electronic noise levels. Obtained results clearly showed that lowering back-plane electronic noise can significantly improve the performance of the a-Se/a-IGZO TFT APS imager. Our simulated results showed that a higher DQE at lower radiation doses (maximum DQE of 0.6 can be achieved at an exposure level of 1 µGy) can be achieved with the a-Se detector, thereby making this combination a promising candidate for low dose applications like DBT.

Venous thromboembolism during treatment with antipsychotics: Results of a drug surveillance programme.

OBJECTIVES: Venous thromboembolism (VTE) can be a life-threatening medical condition that may lead to leg swelling, respiratory distress and death. METHODS: The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a continuous multicentre drug surveillance programme that assesses severe adverse drug reactions during treatment of psychiatric inpatients. We report on a total of 264,422 inpatients who were treated with antipsychotics (APs) and monitored from 1993 to 2011 in 99 psychiatric hospitals. RESULTS: During this period VTE events were reported for 89 inpatients, corresponding to an occurrence rate of 34 cases per 100,000 inpatient admissions treated with APs or 43 cases per 10,000 person-years. The occurrence of VTE was greatest in patients over the age of 65 years of age with mood disorders. The chemical class of butyrophenones (48/100,000) followed by atypical APs (36/100,000) showed the highest occurrence rate for VTE compared to thioxanthenes (23/100,000), which were less associated with VTE. If imputed alone, pipamperone (61/100,000) and risperidone (55/100,000) were most frequently associated with VTE. In general, there was no difference in occurrence rate of VTE between high- and low-potency APs. CONCLUSIONS: These results suggest that clinicians should consider AP drug exposure as a potential risk factor for VTE for patients older than 65 years. Additionally, the diagnosis of an affective disorder seems to increase the risk for VTE.

Agomelatine in the treatment of seasonal affective disorder.

RATIONALE: The novel antidepressant agomelatine acts as a melatonergic (MT(1) and MT(2)) receptor agonist and as a serotonin-2C receptor antagonist. Previous studies showed that agomelatine is able to restore disrupted circadian rhythms, which were implicated in the pathophysiology of seasonal affective disorder (SAD). OBJECTIVES: The aim of this study was to investigate the efficacy and tolerability of agomelatine in the treatment of SAD. MATERIALS AND METHODS: Thirty-seven acutely depressed SAD patients were included in an open study with agomelatine (25 mg/day in the evening) over 14 weeks. Efficacy assessments included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD), the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I), the Circscreen, a self-rating scale for the assessment of sleep and circadian rhythm disorders, and the Hypomania Scale. RESULTS: Agomelatine led to a progressive and statistically significant decrease of SIGH-SAD, CGI-S, and CGI-I scores from week 2 onward (p < 0.001). Furthermore, scores on the Circscreen improved significantly during the study (p < 0.001). Treatment with agomelatine over 14 weeks yielded a response rate of 75.7% (SIGH-SAD <50% of baseline value) and a remission rate (SIGH-SAD <8) of 70.3% in the intention to treat sample. Scores on the Hypomania Scale were consistently low during the study. Agomelatine showed good overall tolerability: throughout the study only one adverse event (mild fatigue) was related to the study drug. CONCLUSIONS: The results of this study suggest that seasonal depression may be effectively and safely treated with agomelatine.

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

The impact of serotonin receptor 1A and 2A gene polymorphisms and interactions on suicide attempt and suicide risk in depressed patients with insufficient response to treatment--a European multicentre study.

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P<0.05) could be found between any SNP and neither suicide risk nor personal history of suicide attempts. Interactions between 5HTR1A rs6295 and 5HTR2A rs6313 in suicide risk, and 5HTR1A rs6295 and 5HTR2A rs643627 in a personal history of suicide attempts have been reported (P=0.027 and 0.036, respectively); however, the results did not survive multiple testing correction. In conclusion, our study shows no association between 5HTR1A or 5HTR2A gene polymorphisms and both current suicide risk and personal history of suicide attempts. In addition, epistatic effects of 5HTR1A and 5HTR2A genes on suicidal behaviour were not significant, although sample size limitations do not allow definitive conclusions.

Actigraphy in patients with seasonal affective disorder and healthy control subjects treated with light therapy.

BACKGROUND: Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. METHODS: Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. RESULTS: SAD patients had 33% lower total (p = .031) and 43% lower daylight activity (p = .006) in week 1 compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6% in patients (p = .025); they were phase delayed by 55 minutes (p = .023) and had significantly lower sleep efficiency (p = .030). Total (p = .002) and daylight activity (p = .001) increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) in patients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). CONCLUSIONS: Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT might also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season.

A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.

Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.

Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression.

BACKGROUND: Evidence suggests that serotonin transporter gene promoter polymorphism (5HTTLPR)-dependent low transcriptional activity of the human serotonin transporter gene may be a genetic susceptibility factor for depression. We studied the behavioral responses to tryptophan depletion (TD) in healthy women with and without a first-degree family history of depression and examined the relationship to 5HTTLPR alleles. METHODS: Twenty-four healthy women with a negative family history of depression and 21 women with a positive family history of depression were genotyped for the polymorphism of the 5HTTLPR and then entered a double-blind, placebo-controlled, randomized crossover TD study. The effects of these interventions were assessed with measures of depression and plasma tryptophan levels. RESULTS: The TD induced a robust decrease of plasma tryptophan levels in all women irrespective of family history of depression or 5HTTLPR genotypes. The s/s genotype of the 5HTTLPR was associated with an increased risk of developing depressive symptoms during TD irrespective of family history. In contrast, individuals with the l/l genotype did not develop depressive symptoms, irrespective of family history. Finally, s/l subjects without family history showed a mood response that was intermediate between the s/s and l/l subjects, while s/l subjects with a family history of depression showed the same depressiogenic effect of TD as seen in the s/s subjects. CONCLUSIONS: The results of the present study suggest that the s-allele of the 5HTTLPR and a positive family history of depression are additive risk factors for the development of depression during TD.