Journal of Affective Disorders 151 (2013) 605–610

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Journal of Affective Disorders

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Research report

Depression with psychotic features is influenced by the polymorphism

of the serotonin transporter gene
T.J. Stamm a,n, J. Stingl b, K. Wiethoff a, R. Ricken a, A. Heinz a, M. Bauer c,
G. O'Malley d, M. Adli a
a
Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
b
Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany
c
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
d
School of Psychology, University College Dublin, Ireland

ar t ic l e i nf o a b s t r a c t

Article history: Introduction: Current diagnostic classifications regard psychotic symptoms during depressive episodes as
Received 28 June 2012 indicators of depression severity. However, growing evidence suggests that depression with psychotic
Received in revised form symptoms (MDP) may represent a distinct subtype of depression. In the course of the search for
3 July 2013
discriminating factors we tested the hypothesis that the serotonin transporter gene (5-HTTLPR) may
Accepted 6 July 2013
Available online 12 August 2013
interact with the manifestation of psychotic symptoms in acute depression.
Methods: 112 inpatients (61 female) with a depressive episode (16 bipolar, 86 unipolar) at admission
Keywords: were genotyped for 5-HTTLPR variants. Psychotic symptoms und general psychopathology were
Major depression evaluated comprehensively using the Manual of the Association for Methodology and Documentation
Psychotic features
in Psychiatry (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie, 1981). For
Psychopathology
statistical analysis a chi-square test and a logistic regression model was used.
Serotonin transporter gene
Results: 16 (14.3%) out of 112 patients were currently presenting with psychotic symptoms. The primary
finding of our study was the higher prevalence of the s-allele of the 5-HTTLPR within the group of MDP
patients (Pearson χ² ¼7.87; df¼ 2; po 0.03). Secondly, in a logistic regression model, 5-HTTLPR was found
to significantly contribute to the diagnosis of MDP (χ² ¼ 6.5; df¼ 1; p¼ 0.01). This effect was even more
pronounced upon comparing only severely depressed patients with MDP patients. From a psychopatho-
logical perspective, MDP patients showed higher AMDP hostility and apathy scores but equal AMDP
depression scores.
Discussion: This is the first study to show an influence of 5-HTTLPR on psychotic symptoms in acutely
depressed patients.
Limitations: The lack of a control group and the relatively small sample size limits the present study's
findings, thus replication in a larger sample is necessary.
& 2013 Elsevier B.V. All rights reserved.

1. Introduction (Maj et al., 2007; Ohayon and Schatzberg, 2002). MDP differs from
non-psychotic major depression in terms of neurobiological,
Increasing evidence suggests that major depression with psy- epidemiological and psychopathological features. It shows a
chotic symptoms (MDP) represents a distinct subtype of depres- higher rate of dysregulation of the hypothalamus–pituitary–adre-
sion. In current diagnostic manuals, the presence of psychotic nocortical (HPA) system (Bond et al., 1986; Nelson and Davis, 1997;
symptoms is regarded as an indicator of the severity of depressive Posener et al., 2000), altered cerebral dopaminergic activity
symptoms (American Psychiatric Association, 1994). However, (Meyers et al., 1999) and specific differences have been described
recent epidemiological data suggest that there is also a subgroup for the ventricle-to-brain ratio (Targum et al., 1983). Psychotic
of mildly to moderately depressed patients who demonstrate depressive syndromes are also characterized by higher rates of
psychotic symptoms, while most severely depressed patients do relapse and hospitalization, more courses of treatment refractory,
not develop psychotic symptoms in the course of their disease and overall longer episodes than is the case in non-psychotic
syndromes (Baethge et al., 2005; O'Neal et al., 2000).
Furthermore, a longstanding discussion as to whether
n
Corresponding author. Tel.: +49 30 450517009; fax: +49 30 450517953. there might be a diagnostic and pathophysiological overlap
E-mail address: thomas.stamm@charite.de (T.J. Stamm). between MDP and Bipolar Disorder is ongoing: Patients with

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jad.2013.07.005
606 T.J. Stamm et al. / Journal of Affective Disorders 151 (2013) 605–610

MDP have been shown to display a higher risk of developing 2. Methods

(hypo)mania than non-psychotic patients (Maj et al., 2007; Tohen
et al., 2012). 2.1. Sample characteristics
From a psychopathological perspective, patients with MDP
have been found to display more anxiety, less illness-related Of the 148 depressed patients that took part in phase II of the
insight, a higher incidence of guilt feelings, more ruminative and German Algorithm Project (GAP-2) (Bauer et al., 2009), 112 inpa-
referential ideas, and stronger agitation than their non-delusional tients of central European origin (61 females, 51 males) gave their
depressed counterparts (Baethge et al., 2005). informed written consent for genetic analysis. The German Algo-
The unique biological, epidemiological and psychopathological rithm Project was conducted between 1990 and 2006 to test and
profile of MDP thus far indicated within the research has lead to a implement an algorithm-guided, pharmacological treatment of
surge of interest within the field regarding the potential role of depression. In GAP-1 (Adli et al., 2002), the feasibility and effec-
certain genetic entities in MDP. A promising candidate gene here tiveness of the treatment regime was tested in an open design.
may be the polymorphism within the promotor region of the GAP-2 was a prospective, randomized controlled study that com-
serotonin transporter gene. pared a standardized stepwise treatment regime (SSTR) to treat-
The gene coding for the serotonin transporter (5-HTT) has been ment as usual (TAU) at the then Department of Psychiatry of the
located on chromosome 17q11.2 (Lesch et al., 1994). A polymorphic Freie Universität Berlin. The institution's local ethical committee
region (5-HTTLPR) has been identified upstream of the transcrip- approved the study. Patients with a depressive syndrome consecu-
tion starting point. It generally consists of either 14 or 16 repeated tively hospitalized between June 1, 1997, and May 31, 2000, were
elements generating a long (l) or a short (s) allele. The short allele screened for study eligibility by means of a clinical interview.
is associated with lower gene expression activity in vitro (Heils Patients with an ICD-10 diagnosis of a major depressive episode
et al., 1996; Lesch et al., 1996) and in vivo, at least in non-smokers with or without psychotic features and bipolar depression were
(Heinz et al., 2000; Kobiella et al., 2011). Meta-analytical research invited to participate. Diagnoses were confirmed with the Compo-
has reported a significant association between the s-allele and site International Diagnostic Interview, a fully structured diagnostic
bipolar disorder (Lasky-Su et al., 2005). Somewhat similarly, three interview for the assessment of mental disorders, which provides
meta-analytical studies reported an association between the s- current diagnoses in line with the approved ICD-10 criteria. (WHO,
allele and unipolar depression (Furlong et al., 1998; López-León 1993). Exclusion criteria included organic mental disorders, schi-
et al., 2008; Lotrich and Pollock, 2004). However, it is notable that zoaffective disorders, alcohol or substance dependence, substance-
two other studies concluded there to be no association (Anguelova related affective disorders, and ongoing prophylactic medication
et al., 2003; Willis-Owen et al., 2005). This may be explained by with a mood stabilizer (i.e., lithium, valproate or carbamazepine)
the heterogeneity of inclusion criteria for the analyses (Cohen- that could not be discontinued (where the decision was made by
Woods et al., 2013). the treating physician).
Literature on the influence of 5-HTTLPR on psychotic symptoms
in affective disorders is controversial; Table 1 shows the relevant 2.2. Clinical assessment
results from studies using varying methodologies with samples of
patients of central European origin. However, the mostly retro- In case of pharmacological pretreatment, medication was
spective and medical record-based operationalization of psychotic tapered off before commencing the GAP-2 protocol. 38 patients
symptoms may confound these partially contradicting findings, as (33.9%) had no psychopharmacological medication at admission,
has previously been discussed by others (Mihalopoulos et al., 34 (30.4%) had one, 30 (26.8%) had two, and 10 patients (8.9%) had
2000; Seemüller et al., 2011). more than two psychoactive drugs that had to be tapered off. Upon
For these reasons, we utilized a cross-sectional methodological admission to the hospital, all subjects underwent a comprehensive
design in this study that reflects a thorough evaluation of current psychopathological interview conducted by the treating physician
psychopathology in MDP in order to adequately test the hypoth- using the Manual of the Association for Methodology and Doc-
esis whether the s-allele of the 5-HTTLPR genotype presents more umentation in Psychiatry (Arbeitsgemeinschaft für Methodik und
frequently in MDP patients. Secondly, we aimed to investigate Dokumentation in der Psychiatrie, 1981). The AMDP is a docu-
whether 5-HTTLPR significantly contributes to the occurrence of mentation system used for structured anamnestic data and psy-
the diagnosis of MDP and whether the psychopathological profile chopathology based on classical symptoms, as described by Jaspers
of MDP patients is different from that of non-delusional depressed (1946) and compiled by the German–Swiss–Austrian Association
patients. for Methodology and Documentation in Psychiatry

Table 1
5- HTTLPR and psychotic symptoms in affective disorders: research overview.

Authors Sample Design Evaluation of Main Results

psychotic symptoms

Seretti et al. (1999a) 67 MDD 65 BP Cross-sectional current HDRS s-Allele associated with psychic anxiety
psychopathology but not with “delusional items”
Seretti et al. (1999b) 80 MDD BP 160 Retrospective lifetime OPCRIT No association
Seretti et al. (1999c) SCH 162 MDD 83 BP 152 Retrospective lifetime OPCRIT No association
Ho et al. (2000) 139 MDD 131 BP Retrospective lifetime SADS -L s-Allele associated with psychosis
Ospina-Duque et al. (2000) 103 BP I 112 Controls Retrospective lifetime DIGS s-allele associated with psychosis
Serretti et al. (2002) SCH 259 MDD 667 BP 789 66 Retrospective lifetime OPCRIT No association
Mendlewicz et al. (2004) 539 MDD 572 BP Retrospective lifetime SADS -L No association
De Pradier et al. (2010) 137 BP Retrospective lifetime DIGS s-Allele associated with psychosis

MDD: major depressive disorder; BP: bipolar disorder; SCH: schizophrenia; HDRS: Hamilton Rating Scale for Depression; OPCRIT: the operational criteria checklist for
psychotic and affective illness; SADS-L: Schedule for Affective Disorders and Schizophrenia—Lifetime version; DIGS: Diagnostic Interview for Genetic Studies.
 T.J. Stamm et al. / Journal of Affective Disorders 151 (2013) 605–610 607

(Arbeitsgemeinschaft fuer Methodik und Dokumentation in der agarose gel electrophoresis and stained with ethidiumbromide for
Psychiatrie). The symptom spectrum comprises of affective, beha- UV visualization. The genotypic distribution of the bi-allelic poly-
vioral, cognitive, psychotic, sensory, and social dimensions of morphism satisfied Hardy–Weinberg equilibrium in the whole
psychopathology. Based on a multitude of empirical studies, the sample as well as in the respective subgroups of psychotic and
AMDP is considered a well-established manual for which relia- non-psychotic patients.
bility and validity are reported as good to very good (Baumann and
Stieglitz, 1997). Symptom items are rated by clinicians on a scale 2.4. Statistical analysis
from 0 (no symptom), to 1 (mild), 2 (moderate) or 3 (severe).
Factor analytical findings by Pietzcker et al. (1983) have revealed Statistical analyses were carried out using SPSS (Statistical
several subscales presenting distinct psychopathological syn- Package for the Social Sciences) Software, Version 17.0. The
dromes: The “paranoid–hallucinatory”, “manic”, “psycho–organic”, genotype distribution and the presence of the Hardy–Weinberg
“depressive”, “apathetic”, “hostile”, “somatic” and “compulsive equilibrium were tested with the χ² test, as well as the distribution
syndrome”, were all used in this study. of psychotic and non-psychotic depressed patients. With 112
Further, severity of depressive symptomatology was assessed genotyped patients we had a power of 0.68 and an alpha error
by a psychologist using the Bech–Rafaelsen Melancholia Scale of 0.05 to detect a middle to low (effect size 0.3) impact of the
(BRMS) (Bech and Rafaelsen, 1986). genotype of 5-HTTLPR on MDP. A logistic regression was used
For both measures, two experienced, independent raters were measuring the contribution of 5-HTTLPR together with sex, age,
responsible for scoring. Both received extensive and frequent number of episodes, length of current episode, and diagnosis of
training in the systematic use of the AMDP and BRMS. bipolar versus unipolar disorder to the diagnosis of MDP to
Major depression with psychotic features (MDP) was operatio- exclude possible confounds. Mean scores were compared using
nalized dependent on results yielded from assessment using the t-test and one-factorial ANOVA.
AMDP: all symptoms of the categories “delusions” and “hallucina-
tions” were used as indicators for psychotic symptoms. The
operationalization of MDP via the AMDP was, on all accounts, in 3. Results
line with the original diagnosis made for the patient by the
treating physician. Out of 112 depressed patients, 16 (14.3%) were found to present
with at least one psychotic symptom, as measured by the AMDP,
2.3. Genotyping which will now be referred to as the MDP group for clarity. All
psychotic patients showed delusional thought disorders, mostly
A blood sample was obtained from each individual (along with with mood-congruent content: delusions of guilt (n ¼8), delusions
written informed consent) for several genetic analyses in addition of poverty (n ¼ 3), hypochondriacal delusions (n ¼2), delusions of
to the German Algorithm Project. The analysis of 5-HTTLPR was reference (n ¼1), and delusions of persecution (n ¼2). In addition,
determined following the previously reported method (Kaiser three patients reported hallucinations of voices with mood-
et al., 2002). High-molecular-weight genomic DNA was prepared congruent content.
using the standard phenol chloroform method for extraction of Most of the clinical and epidemiological variables did not differ
DNA. The laboratory staff was blind with regard to the psychiatric between psychotic versus non-psychotic patients (see Table 2).
observations. Amplification reaction for the 5-HTTLPR deletion/ Subjects diagnosed with bipolar disorder presented significantly
insertion was performed in a total volume of 25 mL, containing more frequently with a psychotic depressive syndrome than
100 ng DNA, 200 mM dATP, dCTP, dTTP, 150 mM dGTP, and 50 mM unipolar patients (χ²¼ 9.35; df ¼ 1; p ¼0.002).
7-deaza-GTP (Boehringer Mannheim, Roche, Germany), 1 mM of The distribution of the three genotypes of the 5-HTTLPR
each of the primers, 1  buffer 1 and 2.8 units of mixed showed no significant deviation from the Hardy–Weinberg Dis-
polymerase (Taq- and Pwo-polymerases) from the Expand™ Long tribution (LL 36.6%, LS 42.9%, SS 20.5%). Age, number of episodes,
Template PCR-System Kit (Boehringer Mannheim, Roche, Ger- length of current episode, BRMS score at admission and the
many). These deviations from the standard reaction conditions polarity of the affective disorder were all equally distributed across
described by Lesch et al. (1996) may prevent the selective the three genotypes.
amplification of alleles (Kaiser et al., 2002). Regarding our primary objective, the presence of psychotic symp-
The primer sequences applied were GGC GTT GCC GCT CTG AAT toms presented significantly more frequently in patients who had one
GC (forward) and GAG GGA CTG AGC TGG ACA ACC AC (reverse) for or more s-alleles: only two out of 41 patients (4.9%) homozygous for
the 5-HTTLPR insertion/deletion polymorphism. The PCR program the l-allele showed psychotic symptoms, while seven out of 48 (14.6%)
of the reaction consisted of 35 cycles, an initial denaturation at ls-allele and seven out of 23 (30.4%) ss-allele carriers were diagnosed
94 1C for 2 min, and a final extension period of 72 1C using a as having MDP (Pearson χ²¼7.87; df¼2; p¼0.02).
Mastercycler PCR machine (Eppendorf, Hamburg, Germany). The Secondly, in the logistic regression model, only 5-HTTLPR and the
conditions of the cyclic PCR reactions were as follows: 95 1C: 30 s, diagnosis of bipolar disorder carried over as significant predictors to
62 1C: 30 s, 72 1C: 1 min. All PCR products were separated by 3.5% MDP. In the overall sample, 5-HTTLPR in the first step contributed

Table 2
Clinical characteristics and distribution of 5-HTTLPR genotype.

Patients with depressive syndrome at admission N ¼ 112 Psychotic depression N¼ 16 (14.3%) Non-psychotic depression N ¼ 96 (85.7%) Statistics

Diagnosis (unipolar:bipolar) 10:6 86:10 χ2 p o 0.01

Sex (female:male) 7:9 54:42 χ2 n.s.
5-HTTLPR: ll:ls:ss 2:7:7 39:41:16 χ2 p o 0.03
Mean age 52.8 (SD 12.2) 47.1 (SD 13.8) t-test; n.s.
Mean age at onset 44.5 (SD 14.3) 39.5 (SD 13.4) t-test; n.s.
Mean number of episodes (depressive) 2.5 (SD 1.4) 2.6 (SD 2.2) t-test; n.s.
Mean length of current episode (in days) 141.7 (124.0) 179.4 (202.7) t-test; n.s.
608 T.J. Stamm et al. / Journal of Affective Disorders 151 (2013) 605–610

significantly to the presence of psychotic symptoms (χ²¼6.50; df¼ 1; (Seretti et al., 1999a) did not address MDP as a categorical entity, but
p¼ 0.01), and accounted for 10.4% of the variance. After step 2, i.e., the rather used mean scores of clusters from the Hamilton Rating Scale for
addition of the diagnosis of bipolar versus unipolar disorder, variance Depression (HRDS). The authors compiled a “delusional cluster” made
accounted for rose to 20.6% (χ²¼13.26; df¼2; p¼ 0.001). When we up of a number of HRDS items (item 2: guilt; item 15: hypochondria;
excluded mildly and moderately depressed patients without psychotic item 20: paranoid symptoms) and compared the three genotypes
symptoms, the impact of 5-HTTLPR on MDP was even more pro- regarding the mean scores of this cluster. The present study, however,
nounced: Variance accounted for by Nagelkerkes R-quadrate was established categories reflective of the presence or absence of psycho-
19.6% for the genotype alone (χ²¼8.62; df¼ 1; p¼0.003), and tic symptoms using the AMDP and then measured the contribution of
increased to 34.2% after including the second significant contributor, the 5-HTTLPR genotype to MDP's occurrence. While the HRDS was not
namely, the diagnosis of bipolar disorder (χ²¼ 15.94; df¼ 2; po0.001). designed to assess MDP as a categorical diagnostic entity, it is
Mean BRMS score was higher at admission in the MDP group noteworthy that there was in fact a clear statistical trend towards
(M¼24.6 versus M¼ 20.7; po0.001), as well as the AMDP subscales higher mean “delusional” scores in the ss-genotype group in Serretti
“paranoid–hallucinatory syndrome”, “hostility syndrome” and “apa- et al.'s study (Seretti et al., 1999a).
thetic syndrome” (all p'so0.05). Interestingly, there was no difference From the psychopathological perspective, it is important to note
between groups regarding the core symptoms of depression measured that MDP patients had higher scores than the non-delusional
by the AMDP “depressive syndrome” (M¼ 61.3 versus M¼ 60.0; n.s.). patients on the BRMS but not on the AMDP's “depressive syndrome”
To exclude the possibility that the presence of mildly and moderately subscale. This might reflect the fact that the BRMS includes symp-
depressed patients without psychotic symptoms could have acted as a toms such as retardation (verbal and motor), anxiety and thoughts of
confounding variable, a separate analysis was conducted comparing guilt. These symptoms are not part of the AMDP “depressive
MDP patients with the subgroup of severely depressed patients syndrome” subscale, because factor analysis in the original AMDP
without psychotic features. As shown in Table 3, no change in the cohort of more than 2000 patients with various psychiatric disorders
syndrome profile occurred after the exclusion of mildly and moder- could not identify them as core depressive symptoms. The differ-
ately depressed patients. entiated evaluation of current psychopathology by use of the AMDP
in this study endorsed the hypothesis of a distinct diagnostic entity of
MDP: depressive core symptoms, measured by the AMDP “depres-
4. Discussion sive syndrome” item, were not quantitatively different across psy-
chotic and non-psychotic patients, however psychotic patients
To the best of our knowledge, this has been the first study to showed more symptoms in the “paranoid–hallucinatory”, “hostile”
investigate the influence of 5-HTTLPR on the occurrence of MDP and “apathetic syndromes” domains.
within a sample of acutely depressed patients. 5-HTTLPR variants seem to be a factor modulating stress vulner-
14.3% of the patients in our sample showed psychotic symp- ability and personality-associated traits. Vulnerability studies indicate
toms. Thus, the frequency of MDP in our sample is in line with that this polymorphism increases stress reactivity and therefore
naturalistic data on the epidemiology of psychotic features within increases the risk of suffering from depression if stressful life events
major depressive episodes. Furthermore, similar to other studies, occur concurrently (Caspi et al., 2010). In healthy subjects, anxiety-
we also encountered substantial overlap between MDP and bipolar related traits and neuroticism scores are higher in s-allele carriers
disorder (Maj et al., 2007; Tohen et al., 2012), (Gonda and Bagdy 2006; Lesch et al., 1996; Schinka et al., 2004).
Most notably, our results may indicate a significant influence of Furthermore, meta-analytical findings indicate that, independent of
5-HTTLPR on the occurrence of MDP: carrying one or two s-alleles psychiatric diagnosis and severity of psychiatric disease, suicidal
significantly increases the risk of suffering from psychotic symptoms behavior can be more aggressive in s-allele carriers of 5-HTTLPR
during a depressive episode. This is in line with some previous (Anguelova et al., 2003). In a study of close relatives of patients with
findings from studies utilizing a retrospective design by defining endogenous psychosis, carriers of the s-allele showed an increase in
MDP as a lifetime trait (DePradier et al., 2010; Ho et al., 2000; tension, suspicion, detachment and attention difficulties, symptoms
Ospina-Duque et al., 2000). Contradictory data exists, however, it that could be regarded as precursor symptoms or even endopheno-
must be considered that all studies reporting negative results were types of depression and major psychosis (Alfimova et al., 2008).
conducted within the European Collaborative Project on Affective Functional MRI studies in healthy subjects demonstrated higher
Disorders. Therefore, a substantial proportion of patient samples will amygdala activation in s-allele carriers who were confronted with
have overlapped, and as such, the findings of these studies are not fearful pictures, which may be indicative of gene-dependent differ-
independent (Mendlewicz et al., 2004; Seretti et al., 1999a, 1999b, ences in brain regions associated with emotional processing (Heinz
1999c, 2002). The only other study to utilize a cross-sectional design et al., 2007).

Table 3
Psychopathologic Syndromes: BRMS++AMDP subsyndromes (T- scores).

Patient subsamples Psychotic depression N ¼ 16 Non-psychotic depression N ¼ 96 Non-psychotic depression: severe N ¼46

nn
BRMS score at admission 24.6 (SD 5.5) 18.8 (SD 4.4) 20.7 n (SD 4.3)
AMDP depressive syndrome 61.3 (SD 3.9) 60.0 (SD 4.4) 61.1 (SD 4.1)
AMDP paranoid–hallucinatory syndrome 53.6 (SD 9.9) 44.2n (SD 3.1) 44.2nn (SD 3.2)
AMDP manic syndrome 49.1 (SD 9.3) 46.3 (SD 7.0) 46.4 (SD 6.9)
AMDP psycho–organic syndrome 50.9 (SD 7.4) 48.2 (SD 7.6) 47.9 (SD 7.3)
AMDP apathetic syndrome 62.2 (SD 4.7) 57.2nn (SD 6.0) 57.6n (SD 5.8)
AMDP hostile syndrome 52.0 (SD 8.6) 45.1nn (SD 6.9) 45.0nn (SD 6.7)
AMDP vegetative syndrome 47.1 (SD 8.7) 50.2 (SD 10.2) 51.0 (SD 10.1)
AMDP compulsive syndrome 57.2 (SD 18.3) 51.0 (SD 11.2) 52.1 (SD 13.5)

ANOVA.
n
po 0.01.
nn
p o0.001.
 T.J. Stamm et al. / Journal of Affective Disorders 151 (2013) 605–610 609

Furthermore, pharmacogenetic studies have consistently Dr. Adli has received Grant/Research Support from the German Federal
Ministry of Education and Research, German Federal Ministry of Health, the
shown that response to antidepressant monotherapy is less favor-
Volkswagen-Foundation, Lundbeck, Esparma, and Bristol-Myers Squibb. He has
able in s-allele carriers of central European origin (for a review, see received Speaker Honoraria from Astra Zeneca, Eli Lilly & Company, Lundbeck,
Kirchheiner et al. (2004)), while more aggressive treatment with Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Sanofi,
augmentation strategies including lithium or pindolol seem to Esparma, Wyeth Pharmaceuticals, Gilead, and Deutsche Bank. He has been a
regress out the genotype-dependent differences (Benedetti et al., consultant to Bristol-Myers Squibb, esparma, and Lundbeck

2008; Serretti et al., 2007; Stamm et al., 2008).

Therefore, for healthy subjects, being an s-allele carrier of Acknowledgments
5-HTTLPR might increase the risk of being more anxious, tense and We thank Mrs. Antje Astalosch, who assisted with the preparation and proof-
suspicious. In clinical populations it may increase the risk of depres- reading of the manuscript.
sion following critical life events, the risk of suicidal behavior and the
risk of more aggressive suicide attempts. Carrying the 5-HTTLPR References
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The German Algorithm Project, Phase 2, was supported by unrestricted research serotonin transporter gene polymorphism, cannabis and childhood sexual
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Conflict of interest ter gene polymorphisms in bipolar and unipolar affective disorders. American
Dr. Stamm has received Speaker Honoraria from Astra Zeneca, Lundbeck, Journal of Medical Genetics 81, 58–63.
Bristol-Myers Squibb and Boehringer Ingelheim. He is a consultant to Servier. Gaudiano, B.A., Zimmerman, M., 2010. The relationship between childhood trauma
Dr. Stingl and Dr. Wiethoff reported no possible conflict of interest. history and the psychotic subtype of major depression. Acta Psychiatrica
Dr. Ricken has received congress and travel fee support from Lundbeck and Scandinavica 121, 462–470.
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(Deutsche Forschungsgemeinschaft) and the German Federal Ministry of Education controls. Depression Research and Treatment, 1–7.
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5HTTLPR polymorphism and the symptoms of neuroticism in a healthy
Janssen-Cilag, and Bristol-Myers Squibb.
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Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., Lesch, K.P., 1996.
Research Institute, NARSAD and the European Commission (FP7). He was/is a Allelic variation of human serotonin transporter gene expression. Journal of
consultant for AstraZeneca, Lilly, Servier, Lundbeck, Bristol-Myers Squibb and Neurochemistry 66, 2621–2624.
Otsuka. Heinz, A., Jones, D.W., Mazzanti, C., Goldman, D., Ragan, P., Hommer, D., Linnoila, M.,
Dr. Bauer has received Speaker Honoraria from AstraZeneca, Lilly, GlaxoSmithK- Weinberger, D.R., 2000. A relationship between serotonin transporter genotype
line, Lundbeck, Bristol-Myers Squibb, Servier and Otsuka. and in vivo protein expression and alcohol neurotoxicity. Biological Psychiatry
Mrs. O'Malley reported no possible conflict of interest. 47, 643–649.
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