Claus Normann

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Enhanced Long-Term Synaptic Depression in an Animal Model of Depression

BACKGROUND A growing body of evidence suggests a disturbance of brain plasticity in major depression. In contrast to hippocampal neurogenesis, much less is known about the role of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) regulate the strength of synaptic transmission and the formation of new synapses in many neural networks. Therefore, we examined the modulation of synaptic plasticity in the chronic mild stress animal model of depression. METHODS Adult rats were exposed to mild and unpredictable stressors for 3 weeks. Thereafter, long-term synaptic plasticity was examined in the hippocampal CA1 region by whole-cell patch clamp measurements in brain slices. Neurogenesis was assessed by doublecortin immunostaining. RESULTS Exposure to chronic mild stress facilitated LTD and had no effect on LTP. Chronic application of the antidepressant fluvoxamine during the stress protocol prevented the facilitation of LTD and increased the extent of LTP induction. Neurogenesis in the dentate gyrus was impaired after chronic stress. CONCLUSIONS In addition to neurogenesis, long-term synaptic plasticity is an important and ubiquitous form of brain plasticity that is disturbed in an animal model of depression. Facilitated depression of synaptic transmission might impair function and structure of brain circuits involved in the pathophysiology of major depression. Antidepressants might counteract these alterations.

Long-term plasticity of visually evoked potentials in humans is altered in major depression.

BACKGROUND Long-term synaptic plasticity is a ubiquitous form of neuronal plasticity that regulates the strength of synaptic transmission in many brain areas. However, most data on long-term potentiation and long-term depression rely on research in animal brain slices. The role of synaptic plasticity in physiology and pathology of the functioning human brain remains obscure. Considering recent studies that provided evidence for a dysfunction of brain plasticity as the neurobiological basis of affective disorders, we assessed neural transmission and its plastic modulation in the visual pathway in healthy control subjects and patients with major depression. METHODS Recordings of visually evoked potentials (VEPs) in humans. RESULTS Prolonged visual presentation of checkerboard reversals resulted in a sustained amplitude modulation of early components of subsequent VEPs. After a 10-min block of visual stimulation (two checkerboard reversals per second), the C1 component was reduced, whereas P1 and N1 were both significantly increased for >30 min. Chronic application of the selective serotonin reuptake inhibitor sertraline in healthy control subjects augmented these effects, whereas the polarity of the modulation was inverted in patients with severe major depression. Moreover, early VEP amplitudes were decreased in depressed patients when compared with matched control subjects and increased in normal control subjects after chronic intake of an antidepressant. CONCLUSIONS Our results demonstrate that stimulus-induced response plasticity of VEPs can be induced in the human brain and is sharing properties with hebbian forms of synaptic plasticity. Major depression and antidepressant treatment of healthy control subjects differentially modulate amplitude and plasticity of evoked potentials. This study provides direct evidence in humans for a central role of synaptic plasticity in the pathophysiology of depression.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Learning as a Model for Neural Plasticity in Major Depression

BACKGROUND The neuroplasticity hypothesis of depression proposes that a dysfunction of neural plasticity-the basic ability of living organisms to adapt their neural function and structure to external and internal cues-might represent a final common pathway underlying the biological and clinical characteristics of the disorder. This study examined learning and memory as correlates of long-term synaptic plasticity in humans to further test the neuroplasticity hypothesis of depression. METHODS Learning in three tasks, for which memory consolidation has been shown to depend on local synaptic refinement in areas of interest (hippocampus-dependent declarative word-pair learning, amygdala-dependent fear conditioning, and primary-cortex-dependent visual texture discrimination), was assessed in 23 inpatients who met International Classification of Disease, 10th Revision, criteria for severe unipolar depression and 35 nondepressed comparison subjects. RESULTS Depressed subjects showed a significant deficit in declarative memory consolidation and enhanced fear acquisition as indicated by skin conductance responses to conditioned stimuli, in comparison with nondepressed subjects. Depressed subjects demonstrated impaired visual discrimination at baseline, not allowing for valid group comparisons of gradual improvement, the plasticity-dependent phase of the task. CONCLUSIONS The results of the study are consistent with the neuroplasticity hypothesis of depression, showing decreased synaptic plasticity in a dorsal executive network that comprises the hippocampus and elevated synaptic plasticity in a ventral emotional network that includes the amygdala in depression. Evaluation of further techniques aimed at modulating synaptic plasticity might prove useful for developing novel treatments for major depressive disorder.

Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.

The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions.

Neuroenhancement: status quo and perspectives

Neuroenhancement is a pharmacological attempt to increase cognitive performance in healthy humans. Strategies to improve learning and memory aim at plasticity pathways in the brain; phosphodiesterase inhibitors such as rolipram and NMDA-modulating drugs like donepezil and d-cycloserine have been tested in clinical trials. Modafinil and methylphenidate are used to increase attention and vigilance. Other fields of intense research include mood, social interaction and sexual performance. So far, all clinical trials of neuroenhancing drugs have either failed or demonstrated only very limited efficacy. However, the high demand for neuroenhancement and the intense research efforts might come up with more efficacious drugs in the near future implying the need for an extended ethical discussion in society.

An open label study of gabapentin in the treatment of acute mania

Recent anecdotal single case reports have suggested that the new antiepileptic drug gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of bipolar disorder. In the present open trial, 14 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were treated with gabapentin as add-on medication and 8 patients were treated with a high dose of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination with other drugs such as lithium and valproic acid. All patients in the add-on group and 4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8 to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that gabapentin monotherapy might be useful in selected patients to treat modest but not severe manic states. In addition, gabapentin in conjunction with other effective mood stabilisers seems to be safe and efficacious in the treatment of severe mania.

Selective modulation of Ca2+ influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus

Both long-term potentiation (LTP) and long-term depression (LTD) can be induced in the Schaffer collateral-CA1 synapse of the hippocampus either by repetitive stimulation of afferent fibres with the frequency of the stimulation determining the polarity of the response or by associative pairing of pre- and postsynaptic activity. An increase in postsynaptic intracellular Ca(2+) concentration is an important signal for the induction of long-term synaptic plasticity. In patch-clamp experiments on hippocampal brain slices, we tested the modulation of different forms of synaptic plasticity by the neurotransmitter serotonin (5-HT) which is known to inhibit high-voltage activated Ca(2+) channels. 1 microM of 5-HT inhibited homosynaptic LTD induced by low frequency stimulation. This effect of 5-HT could be blocked by the selective 5-HT(1A) antagonist WAY 100635. Low frequency-induced LTD is both dependent on Ca(2+) influx through NMDA receptors and high-voltage activated Ca(2+) channels. It was blocked by the NMDA-receptor antagonist D-AP5 and by the N-type Ca(2+) channel antagonist omega-conotoxin GIVA. Tetanus induced LTP was not affected by low concentrations of 5-HT, whereas depotentiation of LTP by asynchronous pairing of EPSPs and postsynaptic action potentials was completely abolished with 5-HT in the bath solution. We conclude that those forms of plasticity which depend on Ca(2+) influx via high-voltage activated Ca(2+) channels are subject to modulation by 5-HT. This might be a relevant mechanism by which 5-HT modifies basic network properties in the brain.

Feasibility and Outcome of Cognitive Behavioral Analysis System of Psychotherapy (CBASP) for Chronically Depressed Inpatients: A Pilot Study

Patients received optimized pharmacotherapy in addition to the CBASP program in compliance with current national and international guidelines for depression treatment [13, 14] and according to clinical expert supervision ( table 1 ). Ten inpatients with severe chronic depression according to DSM-IV were included in this pilot study. Exclusion criteria were limited to a history of bipolar I disorder, comorbid substance dependence with less than 3 months of abstinence, and mental disorders due to organic factors. The SCID I and II [15, 16] were used for diagnosis. Early trauma and life events were assessed by using the Childhood Trauma Questionnaire (CTQ) [17, 18] . Follow-up data were collected 6 months after discharge. Table 1 summarizes the baseline demographics and characteristics of the 10 inpatients. Concerning feasibility, all patients completed the treatment. Self-rating questionnaires for evaluating the experience and acceptance of the program revealed that patients found the overall concept ‘helpful’ or ‘very helpful’. Satisfaction with the CBASP group therapy was rated as ‘high’ or ‘very high’. In addition, the acceptance of the CBASP concept by the treatment team was high. The CBASP concept proved to be feasible and there were no major difficulties integrating the concept into the daily clinical routine. The 24-item version of the Hamilton Depression Rating Scale (HAMD) [19] served as the primary outcome measure and the Beck Depression Inventory (BDI) [20] as the secondary measure. T tests for paired samples revealed significant improvements and large effect sizes in the primary outcome HAMD-24 (HAMD pre : 31.80 8 4.87; HAMD post : 14.90 8 9.40; ES pre-post : d = 2.26, T(9) = 6.33, p = 0.000) and in the BDI (BDI pre : 35.50 8 6.16; BDI post : 17.88 8 11.21; ES pre-post : d = 1.95; T(7) = 4.75, p = 0.002). Treatment response was defined a priori as a reduction in symptom severity of at least 50% on the HAMD, and remission was defined as a score of 10 or less on the HAMD scale. Figure 1 a illustrates the treatment response for each patient, demonstrating that no patient deteriorated. Six out of the 10 patients were classified as responders and 4 of these fulfilled the remission criterion. Exploratory analyses revealed that the nonresponders had a significantly higher number of personality disorders ( M = 3.25) than responders ( M = 0.66; U = 2.00; p = 0.038). In addition, the Impact Message Inventory (IMI-R) [21, 22] was used to assess the stimulus character of a patient rated by the therapist before and after treatment. The mean scores of the IMI-R are illustrated in figure 1 b and showed that the patients could change their stimulus character to be more friendly and dominant. Finally, the 6-month naturalistic follow-up assessments were completed by 9 out of the 10 patients. Outpatient psychotherapy was continued by 6 patients (CBASP: 3, cognitive-behavioral therapy: 2, schema therapy: 1), 9 patients were still on pharmacotherapy, and 6 patients regularly attended the CBASP support group. In figure 1 a, the HAMD follow-up scores for each patient in relaCognitive behavioral analysis system of psychotherapy (CBASP) was initially developed as an outpatient treatment for chronic depression [1, 2] . It integrates cognitive-emotional, behavioral, interpersonal, and psychodynamic theories and strategies by addressing directly the specific psychopathology of chronic depression. In most of the studies being conducted in outpatient settings CBASP proved to be an effective treatment [3–5] , especially in patients with early onset [5] , early trauma [4] , and in combination with medication [3] . The recently published REVAMP trial found no difference between CBASP, brief supportive therapy, or continued optimized pharmacotherapy for augmentation of antidepressant nonresponse; however, the validity of these findings is limit ed by the low number of therapy sessions used in this study [6, 7] . Given the high degree of suicidality, comorbidity, and therapy resistance in chronic depression [8–11] , however, many of these patients require inpatient treatment [12] . Here, we report on a first specialized program for chronic depression adapting CBASP to an inpatient setting. The aim of this study was to evaluate the feasibility and shortas well as long-term outcome of this program. The CBASP inpatient treatment was established at our department in 2008 and is based on the outpatient CBASP concept by McCullough [1, 2] . However, we modified his approach by implementing a multidisciplinary structured treatment program combining individual and group therapies. The manualized CBASP inpatient treatment is limited to 3 months (24 individual sessions). The new CBASP group therapy focuses on a modified approach for conducting situation analysis and on Kiesler’s circle training with the extensive use of role playing and shaping. The entire treatment team was trained in CBASP; regular workshops and weekly supervisions for both the team and the individual therapists were conducted. Specific CBASP elements were also implemented in other accompanying treatments such as nurse encounters, physiotherapy, music therapy, and occupational group therapy. A patient support group was established to avoid relapse after discharge. Received: February 3, 2010 Accepted after revision: August 26, 2010 Published online: March 10, 2011