Maximilian Pilhatsch

Lithium’s Emerging Role in the Treatment of Refractory Major Depressive Episodes: Augmentation of Antidepressants

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants.

Fasting levels of ghrelin covary with the brain response to food pictures

Ghrelin figures prominently in the regulation of appetite in normal‐weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central‐nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75‐g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty‐six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food‐cue reactivity in a bilateral network of visual processing‐, reward‐ and taste‐related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food‐cue‐reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues.

Functional neuroanatomy of emotion processing in major depressive disorder is altered after successful antidepressant therapy

Major Depressive Disorder (MDD) is associated with impaired processing and regulation of emotions. A vast body of research has elucidated the altered neural processes that occur in response to emotional stimuli, while little is known about anticipatory processes. Here we used functional magnetic resonance imaging (fMRI) to investigate neural activation during the presentation and anticipation of negative stimuli. Furthermore, we examined the effects of an 8-week antidepressant treatment with escitalopram. We matched 12 unmedicated MDD patients and 12 healthy control participants to perform a task involving affective pictures. The design of our event-related task consisted of presenting positive, negative, and neutral pictures from the International Affective Picture System (IAPS) across two runs and under opposite conditions. For the ‘expected’ condition, the pictures were cued by a word indicating their emotional valence; whereas the ‘unexpected’ condition had a combination of random letters precede the emotion picture. MDD patients displayed greater amygdala activation when anticipating negative pictures and greater prefrontal activation when confronted with them without the anticipatory cues. After antidepressant treatment, both amygdala and prefrontal activation decreased significantly in the treated MDD patients relative to controls. These findings show that the neural mechanisms of emotion anticipation and processing are altered in patients with MDD and that these alterations are able to normalize after treatment with an antidepressant.

MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice.

In Parkinsons disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brains capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.

Increased depressive behaviour in mice harboring the mutant thyroid hormone receptor alpha 1

Clinical evidence indicates that hypothyroidism contributes to mood disorders. The present study tested if the mutant thyroid hormone receptor alpha 1 (TRalpha1) that causes a receptor-mediated hypothyroidism in the brain affects depressive and anxious behaviour in mice. Mice heterozygous for the TRalpha1 allele (TRalpha1+/m), yielding a receptor protein with a 10-fold reduced affinity to triiodothyronine (T3), and wildtype (wt) mice were subjected to several paradigms specifically testing depressive and anxious behaviour. Mutant and wt mice were either treated with T3 or vehicle. Untreated TRalpha1+/m animals displayed reduced locomotion, higher rates of helplessness in the shuttle box-, greater levels of anxiety in the startle response- and dark light box behavioural paradigms when compared to wt mice. Continuous T3-substitution therapy was effective in alleviating anxious and depressive behaviour without affecting locomotion in mutant mice. Notably, continuous T3-substitution reduced overall locomotion and increased helpless behaviour in wt mice when compared to untreated wt mice. The data suggest that receptor-mediated hypothyroidism caused by an unliganded thyroid hormone receptor alpha 1 leads to a depressive and anxious phenotype in mice, which is responsive to continuous T3-substitution and that an iatrogeneously induced hyperthyreoidism by continuous T3-administration leads to a hypolocomotive and depressive phenotype.

Relationship among latitude, climate, season and self-reported mood in bipolar disorder

OBJECTIVE Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood. METHOD 360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month. RESULTS No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month. CONCLUSION Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

Utility of the WHO‐five well‐being index as a screening tool for depression in Parkinson's disease

Beck depression inventory (BDI‐1A) is the gold standard screening tool for Parkinsons disease (PD) depression, but as a result of its complexity, it is of limited suitability as a quick and easy screening device. We, therefore, validate the 5‐item WHO‐Five Well‐being Index (WHO‐5) as a screening tool for PD depression. Two hundred thirteen of 215 recruited PD patients (99.1%) completed the WHO‐5. Receiver operating characteristic plots were used to calculate sensitivity/specificity for all cut‐off scores for the detection of depression and combined depression/dysthymia as assessed by an independent investigator using the Mini International Neuropsychiatric Interview (MINI). Internal consistency of the WHO‐5 was good (Cronbachs α = 0.83). WHO‐5 showed high validity with adequate detection of depression without differences in the validity indices compared to BDI‐1A (P = 0.234). The optimal cut‐off value for detection of depression was 12 of 13 points. WHO‐5 is a useful, brief, and easy instrument for identifying PD subjects with depression in daily practice.

Gender differences in thyroid system function: relevance to bipolar disorder and its treatment

Thyroid hormones play a critical role in the functioning of the adult brain, and thyroid diseases impair both mood and cognition. This paper reviews gender differences in thyroid system function that are relevant to the diagnosis and treatment of bipolar disorder.

Alcohol-Induced Impairment of Inhibitory Control Is Linked to Attenuated Brain Responses in Right Fronto-Temporal Cortex

BACKGROUND A self-enhancing loop between impaired inhibitory control under alcohol and alcohol consumption has been proposed as a possible mechanism underlying dysfunctional drinking in susceptible people. However, the neural underpinnings of alcohol-induced impairment of inhibitory control are widely unknown. METHODS We measured inhibitory control in 50 young adults with a stop-signal task during functional magnetic resonance imaging. In a single-blind placebo-controlled cross-over design, all participants performed the stop-signal task once under alcohol with a breath alcohol concentration of .6 g/kg and once under placebo. In addition, alcohol consumption was assessed with a free-access alcohol self-administration paradigm in the same participants. RESULTS Inhibitory control was robustly decreased under alcohol compared with placebo, indicated by longer stop-signal reaction times. On the neural level, impaired inhibitory control under alcohol was associated with attenuated brain responses in the right fronto-temporal portion of the inhibition network that supports the attentional capture of infrequent stop-signals and subsequent updating of action plans from response execution to inhibition. Furthermore, the extent of alcohol-induced impairment of inhibitory control predicted free-access alcohol consumption. CONCLUSIONS We suggest that during inhibitory control alcohol affects cognitive processes preceding actual motor inhibition. Under alcohol, decreased brain responses in right fronto-temporal areas might slow down the attentional capture of infrequent stop-signals and subsequent updating of action plans, which leads to impaired inhibitory control. In turn, pronounced alcohol-induced impairment of inhibitory control might enhance alcohol consumption in young adults, which might promote future alcohol problems.

Hypothyroidism and mood disorders: integrating novel insights from brain imaging techniques

Thyroid hormones play a critical role in brain development but also in the adult human brain by modulating metabolic activity. Hypothyroid states are associated with both functional and structural brain alterations also seen in patients with major depression. Recent animal experimental and preclinical data indicate subtle changes in myelination, microvascular density, local neurogenesis, and functional networks. The translational validity of such studies is obviously limited. Clinical evidence for neurobiological correlates of different stages and severities of hypothyroidism and effects of pharmacological intervention is lacking but may be achieved using advanced imaging techniques, e.g. functional and quantitative MRI techniques applied to patients with hypothyroidism before and after hormone replacement therapy.