European Archives of Psychiatry and Clinical Neuroscience

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.

Implication of serotonergic system in suicide and suicide attempts has been discussed for several years. One of the most abundant serotonin receptors in the mammalian brain is the receptor 1A (5-HT1A); studies of its polymorphisms and suicide have provided very inconsistent results so far. The suggestion that the G allele depresses HTR1A autoreceptor expression, and therefore reduces serotonergic neurotransmission that might predispose to depression and suicide, made the promoter polymorphism -1019C>G a very promising candidate gene. In our study we analyzed promoter polymorphism -1019C>G on 323 suicide victims and 190 controls (all of Slovenian origin), taking into account sex, suicide method, and in case of suicide victims also stressful life events. Differences in the distributions of genotype and allele frequencies were not statistically significant between suicide victims and control group, and the same was found for distributions according to sex and suicide method. For 62 suicide victims information about stressful life events in the month prior to the suicide and in childhood was provided. For analysis we combined CG/GG genotypes and compared them to the CC genotype. More stressful life events in the month prior to the suicide were reported for the subgroup with CC genotype (mean number of events = 2.53; SD = 1.50) in comparison to subgroup with CG/GG genotypes (mean number of events = 1.58; SD = 1.32; P < 0.05). However, subgroups of suicide victims with CC or CG/GG genotypes did not differ regarding numbers of reported stressful life events in childhood (P > 0.05). Our study provides no evidence for the implication of HTR1A promoter polymorphism in suicide in general, but it suggests further studies that would take into account the interconnected network of suicide completion, genetic background and stress, beside other risk factors.

We introduce a diagnostic map that was calculated by robust non-metric multidimensional scaling based on AMDP symptom profiles of patients with schizophrenic and affective disorders to demonstrate a possibility to combine the categorical and the dimensional perspective at the same time. In the diagnostic map, a manic, a depressive, and a non-affective cluster clearly emerged. At the same time, the mania dimension (r = 0.82), the depression dimension (r = 0.68), and the apathy dimension (r = 0.74) showed high multiple regression values in the map. We found substantial overlaps of the diagnostic groups with regard to the affective spectrum but irrespective of the ICD-10 classification. Within this sample, we found the association and quality of mood symptoms to be a structuring principle in a diagnostic map. We demonstrate that this approach represents a promising way of combining the categorical and the dimensional perspective. As a practical implementation of these findings, a multidimensional diagnostic map could serve as an automated diagnostic tool based on psychopathological symptom profiles.

Development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) has been ongoing since 1994, though official release will not occur for another 4 years. Potential revisions are being derived from multiple sources, including building on perceived limitations of DSM-IV; broad-based literature reviews; secondary and primary data analyses; and discussions between global members of the mental health community. The current focus on aligning DSM with the International Classification of Diseases-11 (ICD-11) speaks to the importance of creating a unified text that embraces cross-cutting issues of diagnostics, such as developmental, age-related, and cultural phenomena. International discourse is vital to this process and has been fostered by a National Institutes of Health-sponsored conference series on diagnosis-specific topics. From this series, the DSM-V Task Force developed the following set of revision principals to guide the efforts of the DSM-V Work Groups: grounding recommendations in empirical evidence; maintaining continuity with previous editions of DSM; removing a priori limitations on the amount of changes DSM-V may incur; and maintaining DSM's status as a living document. With work group formation complete, members are currently carrying out the research and revision recommendations proposed during the conference series. Ongoing activities include adding specialized advisors to each work group; completing literature reviews and planning data analyses; and forming study groups to discuss integration of cross-cutting issues (e.g., developmental lifespan factors; formation of diagnostic spectra). The road to DSM-V and ICD-11 has been challenging, but members continue to work diligently in their goal of constructing the most harmonious, scientifically sound, and clinically relevant DSM to date.

This study examined the extent to which fathers' and infants' interaction behavior were related to children's externalizing behavior problems at age 8 and 11 years. In a prospective longitudinal study of children at risk for later psychopathology, 72 fathers and their 3-month-old children were videotaped and evaluated during a standardized playing and nursing situation. Externalizing behavior problems at age 8 and 11 years were assessed using Achenbach's Child Behavior Checklist. In the high externalizing group, fathers were found to be less responsive and less sensitive (the latter only with respect to girls) during early interaction than fathers of the low externalizing group, while children were more positive with their fathers. Furthermore, low scores on the interaction pattern of "sensitive fathering/negative infant" and high scores on the "nonresponsive fathering or active infant" pattern were associated with more externalizing problems. These findings suggest that father and infant interaction behaviors during early infancy may predict later problem behaviors at school age, although the mechanisms underlying this relationship have yet to be identified.

To describe the prevalence and correlates of post-traumatic stress disorder (PTSD), depressive and anxiety disorders, or any other mental disorder among adult victims treated in a hospital at different points in time after the 11 March 2004 terrorist attacks in Madrid. A random sample of 56 individuals injured in the attacks was interviewed in person at one, six, and twelve months after the attacks. Current DSM-IV mental disorders: depressive disorders and anxiety disorders (PTSD, generalised anxiety, agoraphobia, social phobia, and panic disorder) were assessed with the Spanish version of the MINI (Mini International Neuropsychiatric Interview), a structured, lay-administered psychiatric interview. PTSD was the most prevalent psychiatric disorder (35.7% at month 1, 34.1% at month 6, and 28.6% at month 12), followed by major depression (28.6%, 22.7%, and 28.6%, respectively). Others relevant conditions were suicide risk, generalised anxiety disorder (GAD), agoraphobia, and panic disorder. No significant differences in the prevalence of the disorders were found between the different assessment times. Patients with a psychiatric history prior to 11 March had a higher prevalence of PTSD, major depression, GAD, and panic disorder at month 1. Females had higher prevalence of PTSD, agoraphobia, and panic disorder at month 1. The only predictive factor for PTSD at month 12 was PTSD at month 6 (OR = 14.007). The only predictive factor for major depression at month 12 was major depression at month 6 (OR = 15.847). The prevalence of PTSD and major depression was high and remained stable between month 1, month 6, and month 12. The only predictive factor for PTSD at month 12 was PTSD at month 6.

Mood disorders included into the bipolar spectrum are increasing, and overactivity (increased goal-directed activity) has reached the status of mood change for the diagnosis of hypomania in the recent studies by Angst and Akiskal. was to find frequency of bipolar spectrum in remitted depressed outpatients by including sub-syndromal hypomania. 111 depression-remitted outpatients were interviewed for history of hypomania and hypomanic symptoms with the Structured Clinical Interview for DSM-IV-Clinician Version (a partly semistructured interview), as modified by Benazzi and Akiskal. Bipolar I patients were not included. All past hypomanic symptoms (especially overactivity) were systematically assessed. Wording of the questions could be changed to increase/check understanding. Subsyndromal hypomania was defined as an episode of overactivity (increased goal-directed activity) plus at least 2 hypomanic symptoms. Frequency of bipolar II (BPII) was 68/111 (61.2%, 95% confidence interval 52% to 69.8 %), frequency of major depressive disorder (MDD) was 43/111. The most common hypomanic symptom was overactivity. In the MDD sample, sub-syndromal hypomania was present in 39.5% (15.3% of the entire sample), and had 4 median symptoms. Bipolar spectrum frequency was 76.5% (95% confidence interval 67.9% to 83.5 %). Overactivity had higher sensitivity than elevated mood for predicting BPII diagnosis. Single interviewer. By systematic probing more focused on past overactivity than mood change, and by inclusion of sub-syndromal hypomania, bipolar spectrum frequency was higher than the near 1 to 1 ratio versus MDD reported up to now (Angst et al.). Given the wide confidence interval, the value in the depression population should be around 70%. Better probing skills by clinicians, and use of semi-structured interviews could much reduce the current high underdiagnosis of BPII and related disorders in usual clinical practice.

Anxiety disorders (AD) are associated with an increase in physical comorbidities, but the effects of these diseases on hospital-based mortality are unclear. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital-based mortality differed between individuals with and without AD during a 12.5-year observation period in general hospital admissions. During 1 January 2000 and 30 June 2012, 11,481 AD individuals were admitted to seven General Manchester Hospitals. All comorbidities with a prevalence ≥1 % were compared with those of 114,810 randomly selected and group-matched hospital controls of the same age and gender, regardless of priority of diagnoses or specialized treatments. Comorbidities that increased the risk of hospital-based mortality (but not mortality outside of the hospital) were identified using multivariate logistic regression analyses. AD individuals compared to controls had a substantial excess comorbidity, but a reduced hospital-based mortality rate. Twenty-two physical comorbidities were increased in AD individuals compared with controls, which included cardiovascular diseases and their risk factors. The most frequent physical comorbidities in AD individuals were hypertension, asthma, cataract, and ischaemic heart disease. Risk factors for hospital-based mortality in AD individuals were lung cancer, alcoholic liver disease, respiratory failure, heart failure, pneumonia, bronchitis, non-specific dementia, breast cancer, COPD, gallbladder calculus, atrial fibrillation, and angina. The impact of atrial fibrillation, angina, and gallbladder calculus on hospital-based mortality was higher in AD individuals than in controls. In contrast, other mortality risk factors had an equal or lower impact on hospital-based mortality in sample comparisons. Therefore AD individuals have a higher burden of physical comorbidity that is associated with a reduced risk of general hospital-based mortality. Atrial fibrillation, angina, and gallbladder calculus are major risk factors for general hospital-based mortality in AD individuals.

Eighteen depressive outpatients were investigated using single-photon emission computerized tomography (SPECT) with a high-affinity dopamine (DA) and serotonin transporter (SERT) specific radioligand, (123)I-labeled beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)-tropane). The patients were tested at the beginning of the study and on follow-up after six months. The severity of depression was evaluated using the 17-item Hamilton Rating Scale of Depression (HRSD). Eight of the eighteen patients had an HRSD score below the median (12 points) on follow-up, and they had a significantly greater increase in (123)I-beta-CIT binding in the midbrain region compared with those patients who did not recover (ANCOVA: F = 8.12; df = 1, 14; p = 0.013). These results indicate that recovery from depression is associated with an increase in (123)I-beta-CIT binding in the midbrain.

The in vivo assessment of brain serotonergic function might be of clinical relevance in neuropsychiatry. The loudness dependence of auditory evoked potentials (LD) has been proposed as an indirect indicator of cortical serotonergic activity, whereas single photon emission computed tomography (SPECT) and [123I]ADAM allow the selective assessment of brain serotonin transporters (SERT). The aim of this study was to investigate LD and SERT availability as independent variables of the brain serotonergic system in healthy volunteers. Fifteen (six male, nine female) subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analyzed using dipole source analysis. SPECT was performed four hours after injection of 137 +/- 11.4 MBq [123I]ADAM. As a measure of SERT availability specific ADAM brainstem binding was used. LD correlated significantly with SERT availability (Pearson's correlations: rho = -0.57, p < 0.05). The correlations remained significant after controlling for the effects of age or gender (partial correlations: rho = -0.60, p < 0.05) but were pronounced in the female group (rho = -0.83, p < 0.01). Associations between LD and SERT availability contribute to the understanding of the central serotonergic system and further validate the use of neurophysiological approaches as indirect measures of neurochemical brain activity.

A study was carried out involving 134 neurotic-depressive inpatients (according to ICD-9) treated with cognitive behaviour therapy and in a subgroup additionally with antidepressants. Using standardized rating instruments, a large set of potential predictor variables was tested. After cross-validation according to the split-half technique, only very few of these proved to be suitable as predictors for the main outcome criteria. These predictors included certain aspects of social functioning before index admission, intensity of depressive symptoms at admission and the degree of self-evaluated mood disturbances three weeks after admission. Several predictors known from the literature could not be reproduced in this study, demonstrating the well-known instability of most predictor findings. On the other side, the predictor profile of the neurotic-depressive patients was quite similar to that found in endogenous depressives, a result which might--together with other findings, such as the response of neurotic depressives to antidepressants--question the traditional subclassification of functional depressive states into these subgroups.

Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.

This report from the WHO project on Psychological Problems in General Health Care examines the relevance in primary care of the concept of recurrent brief depression (RBD) proposed by Jules Angst. RBD refers to brief, severe depressive episodes that recur frequently, i.e. nearly once a month over a 1-year period, according to Angst. Using a structured interview (CIDI), RBD was assessed in patients not meeting the criteria for depressive episodes lasting at least 2 weeks, as defined in the ICD-10 (DE). A substantial proportion of primary care seekers were identified as presenting RBD without other depressive disorders, 3.7% with a formal RBD diagnosis and 2.7% with frequent but not monthly depressive episodes. These two subgroups were found to differ very little in terms of sociodemographic characteristics, severity, disability, and comorbidity with other diagnoses. However, in patients with a formal diagnosis of RBD, a higher rate of history of suicide attempts was found (14.0%), similar to that observed in patients meeting the criteria for DE. Most of the severity and disability indicators show that RBD is a severe condition, associated with substantial impairment, even if they show a higher degree of severity for DE. About one RBD patient out of three is recognized by general practitioners as presenting a psychological disorder, a majority of whom are actually treated. Our results confirm the relevance of the concept of RBD in primary care, and the need to further explore the pertinence of the restrictive recurrence criterion proposed by Angst.

The traumatic loss of an unborn child after TOP due to fetal malformation and/or severe chromosomal disorders in late pregnancy is a major life-event and a potential source of serious psychological problems for those women. To obtain information on the course of grief following a traumatic loss, 62 women who had undergone TOP between the 15th and 32nd gestational week were investigated in a longitudinal study design and compared with 65 women after spontaneous delivery of a full-term healthy child. Grief, posttraumatic stress, depression, anxiety and psychiatric disorders were evaluated 14 days, 6 months and 14 months after the event, implementing validated self-report and clinician rated instruments. Compared to women after spontaneous delivery, women after induced TOP were significantly more stressed regarding all psychological outcomes at all three measuring points. Especially, 14 months after TOP 13.7% of the women fulfilled all criteria of a complicated grief diagnoses following Horowitz et al. (1997, Am J Psychiat 154:7904-7910). 16.7% were diagnosed as having a manifest psychiatric disorder according to DSM-IV. All in all, 25% of these women were critically affected by the traumatic loss. TOP for fetal anomaly is to be seen as a major life event, which causes complicated grief reactions and psychiatric disorders for a substantial number of women.

Stepwise multiple logistic regression was used in an attempt to develop a statistical model which would predict "recovery" in a group of 1471 depressives admitted to a tertiary care hospital. Six variables identified by this approach included: Electroconvulsive therapy, personality disorder, chronicity, anxiety disorder, organic mental disorder, and dysthymia. The meaning and significance of the findings are discussed.

The question of how to define a therapeutically adequate electroconvulsive therapy (ECT) has been under discussion since the early days of ECT. Although convention has asserted a demand for minimum seizure times, the complex electrophysiological conditions involved in developing a generalized seizure make it problematic for therapeutic efficacy of ECT to be linked only with seizure duration. Within the framework of an open clinical study of 40 patients, selected parameters of the ictal electroencephalogram (EEG) have now been examined with respect to differentiation between therapeutically effective and ineffective treatments. For this purpose a rating scale covering both quantitative and qualitative features of the ictal EEG was used. Although this study recorded no correlations between seizure duration and clinical improvement, correlations were established between clinical improvement, on the one hand, and the frequency of epileptic discharges and their slowing during the spike-wave phase as well as the stereotypy of the discharge or a "stable" pattern of rhythmic spike-wave or sharp wave complexes, on the other. The results suggest that several of these EEG parameters might be combined to form a marker for therapeutically adequate ECT, and that treatment might be controlled accordingly.

Few data are available about the diagnostic yield of the lactate stress test (LST) in a large group of patients with mitochondriopathy (MCP). Serum lactate was determined once before, three times during, and once after a 15-minute, constant 30W workload on a bicycle in 62 controls, aged 17 to 84 years, 155 patients with MCP, aged 17 to 87 years, and 31 patients with neurological disorders other than MCP. Lactate's upper reference limits at rest, 5, 10, 15 minutes after starting, and 15 minutes after finishing the exercise were 2.0, 2.1, 2.1, 2.1 and 1.8 mmol/l respectively. The test was regarded abnormal if more than two of the five lactate values exceeded the cut-off levels. Among the 103 patients with abnormal LST, 64 (62 %) had normal resting lactate. The sensitivity of the test was 67% and the specificity 94%. The LST proved to have a high sensitivity and specificity in the detection of patients with MCP, being thus a simple but powerful tool to assess the impaired oxidative metabolism in MCP patients.

Variation in the val(158)met polymorphism of the COMT gene has been found to be associated with cognitive performance. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal areas. Given the complex modulation and functional heterogeneity of frontal lobe systems, further specification of COMT gene-related phenotypes differing in prefrontally mediated cognitive performance are of major interest. Eighty healthy individuals (54 men, 26 women; mean age 23.3 years) performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (fMRI). COMT val(158)met genotype was determined and correlated with brain activation measured with fMRI during the task. Although there were no differences in performance, brain activation in the left inferior frontal gyrus [Brodmann area 10] was positively correlated with the number of val alleles in the COMT gene. COMT val(158)met status modulates brain activation during the language production on a semantic level in an area related to executive functions.

Efficacy and tolerability of Hypericum LI 160 was compared to fluoxetine and placebo in mild to moderate Major Depression (DSM-IV) in a 4-week randomized, double-blind trial. One hundred and sixty-three outpatients from 15 general practitioner centers received either 900 mg Hypericum LI 160, 20 mg fluoxetine, or placebo daily. Amelioration was measured by the Hamilton and the Montgomery-Asberg Depression scales. Response and remission rates and global ratings by investigators and patients were measured. Adverse event reports, laboratory screening, vital signs, physical exams and ECG were collected. No significant differences could be observed regarding efficacy measures except for remission rate (Hypericum 24%; fluoxetine 28%; placebo 7 %). Hypericum was significantly better tolerated than fluoxetine. Hypericum LI 160 or fluoxetine were not more effective in short-term treatment in mild to moderate depression than placebo.

Hippocampal pyramidal neuron size was determined in all Cornu Ammonis subregions - CA1-CA4 - in five chronic schizophrenic men and compared with eight controls matched with respect to age and sex. Four out of five probands and the same eight controls had been examined in a previous study showing a significantly lower cell count and disorientation of pyramidal cells in the CA1- CA3 subregions of the schizophrenics. There was also a negative correlation between the total number of cells and the number of disoriented cells. In this study it was shown that the schizophrenic probands also had significantly smaller neurons in all subregions. There was a significant negative correlation between pyramidal neuron size and the number of disarrayed neurons in each subregion, and there was a significant positive correlation between neuron size and the total number of pyramidal cells in CA1 and CA2, but not in CA3 and CA4. The consistency of hippocampal anomalies in these schizophrenics is, thus, demonstrated by the statistical relations between the different parameters examined.

Depression rating scales play a decisive role in the assessment of the severity of depression and the evaluation of the efficacy of antidepressant treatments. The Hamilton Depression Rating Scale (HAMD) is regarded as the 'gold standard'; nevertheless, studies suggest that the Inventory of Depressive Symptomatology (IDS) is more sensitive to detect symptom changes. The aim of the present study was to investigate whether the IDS is more sensitive in detecting changes in depression symptoms in patients with mild major, minor or subsyndromal depression (MIND). Biweekly IDS-C(28) and HAMD(17) data from 340 patients of a 10-week randomized, placebo-controlled trial comparing the effectiveness of sertraline and cognitive-behavioural therapy in patients with MIND were analysed. We investigated sensitivity to change for both scales (1) from assessment-to-assessment, (2) in relation to depression severity level, and (3) in relation to DSM-IV depression criterion symptoms. The IDS-C(28) was more sensitive in detecting changes in depression symptomatology over the treatment course as well as for different severity levels, especially in patients with a low depression severity. It assesses the DSM-IV criteria more thoroughly, is better able to track the change of cognitive symptoms and to identify residual symptoms. Both scales are well able to assess depressive symptomatology. However, the IDS-C(28) surpasses the HAMD(17) in detecting small changes especially in the core symptoms of depression. This is important for an optimal treatment by capturing early improvements, enabling prompt reactions and detecting residual symptoms.

In the 1980s, we assessed Greek adolescents living in Germany and Greek adolescents living in Greece. Data from this earlier study supported the hypothesis of selective migration with higher psychopathology self-rating scores in Greek adolescents in Greece as compared to Greek adolescents in Germany. The current study uses the same design and instruments so that the comparison of the mental health of populations in the same areas, almost two decades apart, becomes possible. In 1980, a total of 2631 Greek adolescents were assessed in Munich, Germany or Veria, Greece. In 1998, 2920 Greek adolescents were assessed in Munich, Germany and Veria, Greece. The General Health Questionnaire (GHQ-28) was used to assess mental health status at both times. 1) GHQ-28 scores showed a significant increase from 1980 to 1998 in both locations. 2) While in 1980, Greeks in Veria, Greece had higher psychopathology scores than Greek adolescents in Munich, Germany, this (with the exception of depression) was no longer true for 1998. 3) At both times and both locations adolescent girls scored higher in the GHQ-28 than adolescent boys. While the 1980 data supported the selective migration hypothesis, this was no longer true for the 1998 data. The increase in psychopathology in both locations is alarming and deserves further exploration.

Of 118 child and adolescent schizophrenic patients (ICD-9: 295.x; mean onset age 16.0 years), 97 (82.2%) could be completely investigated at follow-up (mean interval 7.4 years; mean age 23.1 years). At follow-up 30% of the patients were semi-dependent or dependent, 72% still required psychiatric treatment, 44% were at least moderately impaired with regard to educational/occupational functions and 58% with regard to social functions; 73% had experienced at least one further schizophrenic episode. Comparison with schizophrenia beginning in adulthood showed that the impairment in social function was much greater in the younger group of patients. These results support the belief that schizophrenic psychoses starting in adolescence have a worse outcome than those beginning in adulthood. The most efficient indicators for a worse outcome were long duration of inpatient treatment at first admission, a high number of symptoms and low social competence at discharge.

The translocator protein (18kD) (TSPO) plays a crucial role for the synthesis of neurosteroids by promoting the transport of cholesterol to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Neurosteroids are allosteric modulators of GABA(A) receptor function, which plays an important role in the pathophysiology of anxiety disorders. The TSPO ligand XBD173 enhances GABAergic neurotransmission by promoting neurosteroidogenesis without direct effects at the GABA(A) receptor. In humans, XBD173 shows potent antipanic efficacy without sedation and withdrawal after 7 days of treatment. XBD173 therefore appears to be a promising compound for rapid anxiolytic efficacy with a favorable side-effect profile. Furthermore, TSPO ligands show neuroprotective and antiinflammatory effects in experimental models of peripheral neuropathies and traumatic brain injury. These compounds might therefore also be valuable for the treatment of neurologic diseases with inflammation-related pathophysiology.

Hypercortisolemia and increased levels of hyperphosphorylated tau proteins in cerebrospinal fluid (CSF) are common features with pathogenic relevance in Alzheimer;s disease (AD). Experimental studies point to an influence of cortisol on Abeta and tau pathology in AD. Association of both parameters have not yet been described in a sample of AD patients. In the present study, serum levels of cortisol were determined in 26 patients with mild AD dementia and 20 age-matched healthy elderly controls by ELISA. In addition, we measured in AD patients CSF levels of cortisol, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau 181), tau protein phosphorylated at threonine 231 (P-tau 231) and beta-Amyloid (Abeta) 1-42 and determined T-tau/Abeta 1-42 ratios in CSF. We found in AD patients significantly increased cortisol serum levels (551.4 +/- 146.1 nmol/l; P = 0.002) as compared to healthy controls (435.3 +/- 83.9 nmol/l). In AD patients, cortisol serum levels were significantly inversely correlated with T-tau (r = -0.496; P = 0.01), P-tau 181 (r = -0.558; P = 0.003) and P-tau 231 (-0.500; P = 0.009) protein levels and T-tau/Abeta 1-42 ratios (r = -0.450; P = 0.021) in CSF. In addition, cortisol serum levels showed a trend of positive correlation with Abeta 1-42 CSF levels (r = 0.386; P = 0.052). However, no significant correlations of cortisol serum with CSF levels as well as cortisol CSF levels with CSF biomarkers could be detected in AD patients. In conclusion, our results show that increased cortisol serum but not CSF levels are associated with minor signs of AD pathology in CSF, indicating a putative neuroprotective effect of moderately elevated cortisol serum levels in patients with mild AD dementia.

An analysis of suicide rates in France from 1826 to 1913 indicated that suicide rates were lower during years of war than during years of peace. This effect was stronger for female suicide rates than for male suicide rates and seemed to hold both for major and minor wars.

Prison suicide rates in France from 1852 to 1913 were strongly correlated with the overall male suicide rate in France. Measures of domestic social integration were associated with both of these suicide rates, but were less successful in accounting for the prison suicide rate than the overall male suicide rate.

At the end of the 19(th) century, male suicide rates in Switzerland were as high as the respective rates in recent decades, whereas female suicide rates were distinctly lower. An age-period-cohort analysis was performed to provide more information about the gender-specific changes over the last century. Suicide mortality has been reported in Switzerland since 1876 when the standardised registration of mortality data began. The analysed data cover the period 1881-2000. The statistical analyses were based on log-linear models and data aggregated by 10-year age-intervals and 10-year period intervals. The results indicate similar age and period effects in males and females. The estimates representing age-specific risk increase steadily with age, with intermediate plateaus in the 20s and the 50s. The period-specific estimates follow the economic cycles. The birth cohort effects are stronger in males and weaker in females. In the males' estimates, there is a peak in cohorts born around 1840 and a low in cohorts born some 60-100 years later. The estimates increased again in generations born after World War II. In females, the birth cohort estimates are low in cohorts born in the first half of the 19(th) century and increase until the first half of the 20(th) century. Birth cohort effects remain an intriguing topic in epidemiology of suicide. A better understanding of birth cohort effects might open new doors to suicide prevention.

This study presents a visual rating scale for the assessment of cerebral [(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography (FDG-PET) scans to characterize typical findings in dementias associated with frontotemporal lobar degeneration (FTLD) and to differentiate individual patients with FTLD compared to Alzheimer's disease (AD) and mild cognitive impairment (MCI). A total of 43 cerebral PET scans from patients with FTLD (n = 16, mean age 58.4 years), AD (n = 16, 59.9 years) and MCI (n = 11, 57.9 years) were analysed. Every PET data set was visually rated for seven brain regions on each hemisphere (frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, thalamus and cerebellum). The extent of the impairment in metabolism was classified as absent, mild, medium or strong. Using this four-stage visual rating scale, characteristic profiles of metabolic impairment in FTLD, AD, MCI and the FTLD-subgroup FTD (n = 9) could be demonstrated. Patients with FTLD showed a significantly lower metabolism in the left frontal lobe and in the left basal ganglia when compared to AD and to MCI. Complementary analyses using statistical parametric mapping (SPM2) supported the findings of the visual analysis. In detecting FTLD with visual rating, sensitivity/specificity was 81/94% compared to AD and 81/64% compared to MCI. Patients with FTD were correctly attributed to a diagnosis of FTLD with a sensitivity of 89%. This visual rating scale may facilitate the differential diagnosis of FTLD in clinical routine.

The role of the amygdala during facial emotion recognition (FER) tasks as well as its clinical implications in schizophrenia patients remains unclear. While most of authors have reported hypoactivation, recently it has been suggested that patients may also exhibit hyperactivation. We studied amygdalar response during a previously validated FER task using (18)[F] fluorodeoxyglucose positron emission tomography ((18)FDG-PET) technique in ten right-handed healthy volunteers and 11 right-handed non acute patients with schizophrenia. Both groups underwent two scans on different days in a random order; each consisted of 17 1/2 min of continuous emotional and control tasks. Statistical Parametric Mapping (SPM) 2 analysis with a region of interest approach was carried out. Left amygdalar hyperactivation among the schizophrenia group was shown in both emotional and control tasks when compared to healthy subjects. The right amygdala showed no differential activation in any of the tasks. Patients diagnosed with schizophrenia exhibit a non-task specific amygdalar hyperactivation during a continuous emotional and non-emotional task when compared to matched healthy controls.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of the left temporo-parietal cortex (LTPC) has been proposed as a useful therapeutic method for auditory hallucinations (AHs). Stereotactic neuronavigation enables the magnetic coil to be targeted according to the individual parameters obtained from neuroimaging. Individualized rTMS neuronavigated according to 18-fluorodeoxyglucose positron emission tomography ((18)FDG PET) allows us to focus the coil explicitly on a given area with detected maxima of specific abnormalities, thus presuming a higher therapeutic effect of the method. The objective of this study is to test clinical efficacy of neuronavigated LF-rTMS administered according to the local maxima of (18)FDG PET uptake of LTPC and to compare it with treatment effects of standard and sham rTMS. In a double-blind, sham-controlled design, patients with AHs underwent a 10-day series of LF-rTMS using (1) (18)FDG PET-guided "neuronavigation," (2) "standard" anatomically guided positioning, and (3) sham coil. The effect of different rTMS conditions was assessed by the Auditory Hallucinations Rating Scale (AHRS) and the Positive and Negative Syndrome Scale (PANSS). Fifteen patients were randomized to a treatment sequence and ten of them completed all three treatment conditions. The intention-to-treat analysis of AHRS score change revealed superiority of the (18)FDG PET-guided rTMS over both the standard and the sham rTMS. The analyses of the PANSS scores failed to detect significant difference among the treatments. Our data showed acute efficacy of (18)FDG PET-guided rTMS in the treatment of AHs. Neuronavigated rTMS was found to be more effective than standard, anatomically guided rTMS.

Grade of Membership (GoM) analysis, a multivariate classification technique based on fuzzy-set mathematics, was applied to the demographic, history, and mental-state data on 53 dementia praecox cases and 134 manic-depressive insanity cases admitted to Kraepelin's University Psychiatric Clinic in Munich in 1908. The original data recorded by Kraepelin and his collaborators on special Zählkarten (counting cards) were rated and coded in terms of the Present State Examination (PSE) Syndrome Check List. The statistical analysis resulted in a high degree of replication of Kraepelin's clinical entities. However, the dichotomy of dementia praecox and manic-depressive insanity was not fully supported. The catatonic syndrome tended to occupy an intermediate position between the two major psychoses. The possibility is discussed that catatonia in Kraepelin's time shared certain clinical features with the later diagnostic groupings of schizoaffective disorder, cycloid psychoses, and other "atypical" forms of psychotic illnesses.

In 1906, Alzheimer presented the first case of the disease which was later named Alzheimer's disease by Kraeplin. While the publication on this case in 1907 is only a relatively short communication, Alzheimer published a very comprehensive paper in 1911 in which he discussed the concept of the disease in detail. This publication focusses on the report of a second patient suffering from Alzheimer's disease, the case of Johann F. The detection of neurohistopathological sections from this patient found among archives at the Institute of Neuropathology of the University of Munich enabled us to reinvestigate this case using modern methods. Neurohistopathologically, the case of Johann F. is "plaque-only" Alzheimer's disease. There is a controversy in the modern literature as to whether these "plaque-only" cases belong to the modern concept of Alzheimer's disease. A careful analysis of all pros and contras in the literature led to the conclusion that plaque-only cases are also an integrative part of the modern Alzheimer disease concept.

An investigation was made of all known cases of mental illness where more than one member of the family entered one of the Ontario Mental Hospitals. The materials is fairly complete for a period of 18 years. Analysis of the resulting data, on pairs of relatives, gave rise to the following conclusions of particular interest. (i) Schizophrenia, affective psychosis, senile psychosis, Huntington's chorea and mental defect are shown to be conditions which remain significantly true to type when mental disease occurs in different members of a family. As a rider to this, however, it is found that schizophrenia and affective psychosis are not very distinct entities and groups of closely related familial cases frequently include both diagnoses. (ii) Schizophrenia is a rare diagnosis in the fathers of patients and occurs in only 8.7% of fathers, as opposed to the 30.7% in the whole sample of relatives: it is not so rare in mothers (24.5%). (iii) The most frequent type of relationship in pairs of patients is sister and sister: next in frequency is the type brother and brother, then brother and sister. Mother and son, mother and daughter, father and daughter and then father and sone come next in order. Less frequent are uncle and nephew or uncle and niece and, again less frequent, aunt and nephew or niece; grandparents and grandchildren were rarely found. (iv) Fathers, diagnosed schizophrenic or first admitted below the age of 35, have more psychotic sons than psychotic daughters, but the reverse is true for mothers in the same categories. (v) Fathers diagnosed as having affective illness or first admitted at the age of 35 or over have more psychotic daughters than psychotic sons, but the reverse is true for mothers in the same categories. (vi) Male subjects with either schizophrenic or affective diagnosis and in early- or late-onset age groups, have more psychotic brothers than psychotic sisters. Similarly, female subjects have more psychotic sisters than psychotic brothers. (vii) Each main diagnosis group has its characteristic first admission age. (viii) The first admission age is earlier in males than in females for schizophrenics, and later in males than in females for affective disorders. (ix) Study of first admission ages in families indicates that parents and, particularly, grandparents are much older than children and, particularly, grandchildren at first admission. This effect is not attributed to progressive degeneration. (x) Male subjects show a significantly wider scatter of first admission ages than do female subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

In spite of the great impact of senile dementia of the Alzheimer type (SDAT) on society, far too little is known about its epidemiology. In this study of a total, normal population from a geographically delimited area in Sweden, Lundby, 2612 persons were examined in 1957 by one psychiatrist (Hagnell). In 1972 the same population was reexamined irrespective of domicile. The incidence and risk of contracting SDAT during the 15 years were calculated. No cases of SDAT were diagnosed before the age of 60 years. The lifetime risk was for men 25.7% and for women 26.2%. When only the very severely impaired were taken into account, the figures were 14.5% in men and 14.6% in women.

Subtle motor, emotional, cognitive and behavioral abnormalities are often present in apparently healthy children and adolescents who later develop schizophrenia. This suggests that some aspects of causation are established long before psychosis is manifest. We aim to develop a descriptive model of the factors contributing to the development of schizophrenia. Our main focus is on genetic factors, pregnancy and delivery complications, early development and scholastic performance. This is done by reviewing the Northern Finland 1966 Birth Cohort, its scientific activities (publications and work in progress) and selected literature.

National suicide rates differ widely throughout Europe. The reasons for this are still unclear. Besides differences in actual suicide figures, different assessment methods and certification strategies have been suggested. This study examines the ethnic influence on suicide rates of South Tyrol, an Italian province bordering on Austria. The region has historically been under the cultural influence of both countries, with its population composed of three ethnic groups: the German-, Italian- and Ladinian-language groups. The study shows a significant correlation between the male suicide rate and the proportion of the German-language group. The ethnic suicide rates of Italian- and German-speaking people in South Tyrol were found to approximate each other, in comparison with the national rates for Italy and Austria, as a possible result of cultural interaction.

To assess the long-term survival of brain tumor patients, and in particular to evaluate the relation of quality of life (QOL) to survival among low-grade glioma patients. The postoperative survival of 101 brain tumor patients was followed from surgery (1990-1992) until the end of the year 2003. Depression was evaluated by the Beck Depression Inventory (BDI) and QOL with Sintonen's 15D scale before operation and at one year as well as at five years after operation. The mean survival times in years (SD) were significantly related to tumor malignancy, being the shortest, 1.9 (0.6), for patients with high-grade gliomas, while patients with low-grade gliomas or a benign brain tumor had mean survival times of 9.1 (1.0) and 11.6 (0.5), respectively. At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years. A decreased level of QOL in low-grade glioma patients was significantly related to the shorter survival. The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up. Decreased QOL may serve as an indicator for poor prognosis in low-grade glioma patients.

Focusing on recent publications from the 1990s, this article qualitatively reviews the comparative efficacy of the combination of pharmaco- and psychotherapy (COMBI) vs either modality alone. There is only a weak empirical basis recommending the routine use of both psychotherapy and pharmacotherapy in acute treatment of Major Depressive Disorders (MDD). Concerning long-term treatment of MDD patients, the methodologically sophisticated study from Frank et al. shows that a COMBI is superior to interpersonal psychotherapy but not superior to medication alone. However, certain subgroups of patients might benefit substantially from COMBI compared to both psychotherapy and pharmacotherapy alone: 1) acute and long-term treatment of more severe forms of chronic depression, and 2) long-term treatment of older MDD patients. Compared to psychotherapy alone, severely depressed MDD patients profit more and faster when treated with combined psycho-pharmacotherapy.

Evidence was found for the role of social integration in affecting suicide rates both in a time-series analysis and in a regional analysis for the Austro-Hungarian Empire in the nineteenth and early twentieth centuries. The social correlates of the homicide rates were, however, quite different from those of the suicide rates.

Estrogen and serotonin play vital roles in the mechanism of premenstrual dysphoric disorder (PMDD). Cognitive deficit in the premenstrual phase contributes to impaired life function among women with PMDD. The aim of this study was to evaluate the difficulties in cognitive control and working memory (WM) in PMDD and to explore the effects of gonadotropic hormone and polymorphism of serotonin 1A receptor (HTR1A; rs6295) on cognitive deficit in PMDD. Women with PMDD completed diagnostic interviewing, questionnaire assessment, the Go/Nogo task, 2-back and 3-back tasks, and gonadotropic hormone analysis in the premenstrual and follicular phases. Further, they were followed up for two menstrual cycles to confirm two consecutive symptomatic cycles. A total of 59 subjects with PMDD and 74 controls completed all evaluation, fulfilled the criteria, and entered into the final analysis. The results demonstrated cognitive control and WM decline in the premenstrual among women with PMDD. The G/G genotype of HTR1A (rs6295) was found to be associated with impaired WM in the premenstrual phase and premenstrual decline of cognitive function. It also contributed to the vulnerability of cognitive function to the menstrual cycle effect and PMDD effect. As the G/G genotype of HTR1A (rs6295) involves in reducing serotonin neurotransmission, our results provide insight into the serotonin mechanism of cognitive function among women with PMDD.

The role of the C-1019G variant in conferring susceptibility to mood disorders is an object of ongoing debate. In their recent meta-analysis of case-control investigations, Kishi and coworkers have sought to clarify the issue by pooling earlier results. Whether a claimed effect of this variant can be upheld, however, is questionable in view of numerous artefacts.

The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (P allele model = 0.007 and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 3,119 patients and 4,380 controls or BP = 1,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: P allele model = 0.006, P recessive model = 0.01; BP: P dominant model = 0.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (P allele model = 0.0002, P dominant model = 0.0008, and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 1,013 patients and 1,728 controls or BP = 1,051 patients and 2,099 controls), rs878567 was associated with MDD (P allele model = 0.0007 and P dominant model = 0.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs.

The hippocampus, thalamus and basal ganglia are among the brain regions of major interest in schizophrenia. The purpose of this study was to corroborate previous findings of reduced N-acetylaspartate in the hippocampal and thalamic regions and to investigate possible metabolite changes in the putamen in schizophrenia. MRSI study of the thalamus, basal ganglia, and hippocampus in 13 schizophrenic patients under stable medication and age-matched healthy controls. A decrease of the N-acetylaspartate signal was found in the hippocampal region and the thalamus but not in the putamen of patients compared to controls. No significant group differences in the signals from creatine and phosphocreatine, and choline-containing compounds were found in the hippocampal region and the putamen but the signal from choline-containing compounds was decreased in the thalamus of patients. Metabolic processes in the basal ganglia of schizophrenic patients seem to be opposite the hippocampal and thalamus findings.

The human calcium-activated potassium channel gene (hKCNN3, hSKCa3) contains two tandemly arranged, multiallelic CAG repeats located in exon 1 which result in short to moderate polyglutamine stretches of unknown functional significance. Case-control and family-based association studies suggested an association of hKCNN3 repeats with susceptibility for schizophrenia. Twelve multiplex pedigrees with periodic catatonia, a schizophrenia subtype with major gene effect and patterns of anticipation, were genotyped using the multiallelic hKCNN3 repeat polymorphism. Using a dominant model of inheritance with sex- and age-dependent penetrance classes, cumulative results showed exclusion of linkage of hKCNN3 to periodic catatonia under the assumption of genetic homogeneity with lod score of -48.01 at zero recombination fraction. Our results provide evidence that hKCNN3 is not the causative gene in the familial schizophrenia subtype of periodic catatonia. By fluorescent in situ hybridization we confirmed the assignment of hKCNN3 to chromosome 1q21 near the heterochromatin region. Linkage mapping showed segregation with marker D1S498 (theta = 0.05) and placed hKCNN3 in the genetic linkage map in a cluster of genes near the centromeric region of chromosome 1.

In a population of 200 consecutive inpatients with a history of at least 3 months' total cumulative neuroleptic exposure, the prevalence of tardive dystonia (TDt) was 4%, higher than previously reported. The prevalence of tardive dyskinesia (TDk) was 22%. Patients with TDt did not differ in demographic or clinical variables from nondyskinetic patients. In comparison with patients with TDk, patients with TDt were significantly younger, had a more severe movement disorder, and had received neuroleptics for the first time fewer years before. Patients with TDk were significantly older than patients without tardive disorders, both when they were examined and when they had started their first neuroleptic treatment. Furthermore, they had started their first neuroleptic treatment more years before. These results support the distinction between TDt and TDk, and suggest that the previously reported prevalence of TDt might have been underestimated.

To our knowledge, no previous long-term studies of the Leonhardean classification in the whole spectrum of endogenous psychoses have been conducted. This prospective study (n = 276; female patients n = 222; normal control persons n = 54) started in 1967-1976. The same population was followed-up by participation of a "blinded control" psychiatrist in 1997-2002 [patients available at follow-up = 125 (56.3%); available controls = 38 (70.4%)]. Patients for this investigation were selected by two independent diagnosticians from eight nosological groups based on full diagnostic agreement. Diagnostic agreement at follow-up (weighted-kappa) was 0.87. Predictive validity of the diagnostic categories was measured empirically and using a stochastic (Markovian) model, thus combining validity and reliability. Hebephrenias, group of normal persons and of schizophrenias proved to be valid categories, with diagnostic stabilities of 0.94, 0.91, and 0.93, for the three groups, respectively. In addition, bipolar manic-depressive psychoses and cycloid psychoses were also valid (diagnostic stability of 0.77 and 0.76, respectively). Unipolar depression was valid (diagnostic stability = 0.84) only by forming a "nosological family" based on diagnostic stability and on current status and clinical presentation during the period preceding the follow-up with regard to other mood-congruent disorders and outcome-diagnosis "normal control". Validity of systematic paraphrenias (diagnostic stability = 0.69) was in the moderate range. Division of schizophrenias in "systematic versus non-systematic" nosological categories was inconclusive; the categories of affect-laden paraphrenia, periodic catatonia and systematic catatonias could not be confirmed reliably in this study.

Cloninger has developed a novel approach concerning relationships between psychopathological syndromes and personality by his biosocial theory. Increased levels of harm avoidance (HA) were consistently found in unipolar disorders. The present study was conducted to cross-validate, in part, previous findings that high harm avoidance (HA) persisted in the course of disorder and to explore the distinct role of character dimensions. One hundred and twenty-six inpatients with an unipolar depressive disorder and 126 healthy controls, strictly matched for age and gender have been included in the study. Our findings underline that higher harm avoidance among unipolar depressives compared to healthy controls persisted after treatment even if a significant reduction could be observed. Recurrent disorders and comorbidity with anxiety disorders seem to be related to a relatively immature character in terms of consistently lower scores for the character dimensions (e.g. self-directedness and cooperativeness) of the patients classified into these groups both at admission and at discharge compared with their healthy counterparts.

Lithium has been used to augment the efficacy of antidepressant medications for more than 20 years. The present study examines whether evidence exists to support the clinical efficacy of lithium augmentation in refractory, treatment resistant depression. Studies were identified by searching Medline (1980 to August 2002) and by scanning the references of published reviews and standard textbooks. Studies were selected if they were open-labeled or double-blind, placebo-controlled or comparator trials that involved patients who had not responded to conventional antidepressants. 27 prospective studies were identified that included a total of 803 depressed patients displaying the following designs: 10 double-blind, placebo-controlled trials, 2 randomized, double-blind comparator trials, 2 randomized, open comparator trials, and 13 open-label trials. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation in partial and non responders to antidepressant treatment. In the placebo-controlled trials, the response rate in the lithium group was 45% and in the placebo group 18% (p<0.001). Summarizing all open and controlled studies, approximately 50% of patients responded to lithium augmentation within 4 weeks. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression.Therefore, it should be considered a first-line treatment strategy in patients with major depression who do not adequately respond to standard antidepressants.