M. Willeit

Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference.

Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness–eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n=177) and diurnal preference (n=92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case–control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (χ2=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (χ2=6.61, Bonferroni corrected P=0.050). Period3 647 Val/Gly was associated with self-reported morningness–eveningness scores (n=92, one-way ANOVA: F=4.99, Bonferroni corrected P=0.044), with higher scores found in individuals with at least one glycine allele (t=3.1, Bonferroni corrected P=0.013). A second, population-based sample of individuals selected for high (n=127) or low (n=98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case–control material (n=177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference.

Novel 5-HTTLPR Allele Associates with Higher Serotonin Transporter Binding in Putamen: A [11C] DASB Positron Emission Tomography Study

BACKGROUND The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.

Seasonal Variation in Human Brain Serotonin Transporter Binding

CONTEXT It is a common experience in temperate zones that individuals feel happier and more energetic on bright and sunny days and many experience a decline in mood and energy during the dark winter season. Brain serotonin is involved in the regulation of physiologic functions, such as mating, feeding, energy balance, and sleep. Although these behaviors and serotonin-related conditions show a clear seasonal pattern in humans, the molecular background of seasonal changes in serotonin function is entirely unknown. The serotonin transporter is a key element in regulating intensity and spread of the serotonin signal. OBJECTIVES To detect seasonal variations in serotonin transporter binding in the living human brain and to detect correlations between serotonin transporter binding and duration of daily sunshine. DESIGN Regional serotonin transporter binding potential values, an index of serotonin transporter density, were assessed from December 1, 1999, to December 9, 2003, in a consecutive sample of healthy volunteers. Binding potential values were related to meteorologic data. SETTING Tertiary care psychiatric hospital. PARTICIPANTS Volunteer sample of 88 drug-naive healthy individuals. INTERVENTION Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile positron emission tomography. MAIN OUTCOME MEASURE Regional serotonin transporter binding potential values. RESULTS Serotonin transporter binding potential values were significantly higher in all investigated brain regions in individuals investigated in the fall and winter compared with those investigated in the spring and summer (P = .01 to .001). Moreover, binding potential values showed negative correlations with average duration of daily sunshine in all brain regions (rho = -0.21 to -0.39; P = .05 to <.001), such that higher values occurred at times of lesser light. CONCLUSIONS Serotonin transporter binding potential values vary throughout the year with the seasons. Since higher serotonin transporter density is associated with lower synaptic serotonin levels, regulation of serotonin transporter density by season is a previously undescribed physiologic mechanism that has the potential to explain seasonal changes in normal and pathologic behaviors.

Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography

[11C]‐(+)‐PHNO (4‐propyl‐9‐hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high‐affinity states of the D2 receptors (D2‐high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]‐(+)‐PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]‐(+)‐PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre‐treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB‐277011) antagonists indicated that [11C]‐(+)‐PHNO binding in striatum is specific to D2 receptors. Within‐subject comparisons showed that [11C]‐(+)‐PHNO BP in striatum was almost 2.5‐fold higher than that measured with [11C]‐(–)‐NPA ([11C]‐(–)‐N‐propyl‐norapomorphine). Comparison of the dose‐effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]‐(+)‐PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [11C]‐(+)‐PHNO BP and only up to 56 ± 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]‐(+)‐PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]‐(+)‐PHNO in brain, its high signal‐to‐noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]‐(+)‐PHNO has highly suitable characteristics for probing the D2‐high with PET.

Bright-Light Therapy in the Treatment of Mood Disorders

Bright-light therapy (BLT) is established as the treatment of choice for seasonal affective disorder/winter type (SAD). In the last two decades, the use of BLT has expanded beyond SAD: there is evidence for efficacy in chronic depression, antepartum depression, premenstrual depression, bipolar depression and disturbances of the sleep-wake cycle. Data on the usefulness of BLT in non-seasonal depression are promising; however, further systematic studies are still warranted. In this review, the authors present a comprehensive overview of the literature on BLT in mood disorders. The first part elucidates the neurobiology of circadian and seasonal adaptive mechanisms focusing on the suprachiasmatic nucleus (SCN), the indolamines melatonin and serotonin, and the chronobiology of mood disorders. The SCN is the primary oscillator in humans. Indolamines are known to transduce light signals into cells and organisms since early in evolution, and their role in signalling change of season is still preserved in humans: melatonin is synthesized primarily in the pineal gland and is the central hormone for internal clock circuitries. The melatonin precursor serotonin is known to modulate many behaviours that vary with season. The second part discusses the pathophysiology and clinical specifiers of SAD, which can be seen as a model disorder for chronobiological disturbances and the mechanism of action of BLT. In the third part, the mode of action, application, efficacy, tolerability and safety of BLT in SAD and other mood disorders are explored.

The effects of light therapy on mini-mental state examination scores in demented patients

BACKGROUND Preliminary evidence suggests that demented patients may experience beneficial effects of light therapy. The authors tested whether bright light therapy (BLT) is capable of improving cognitive functions in patients with Alzheimer-type dementia (AD) or vascular dementia (VD). METHODS Twenty-three patients with AD or VD were randomly assigned to either evening BLT or dim light therapy (DLT). Effects of light therapy on cognitive functions were assessed before and after light therapy using Mini-Mental State Examination (MMSE) scores. Body temperature rhythm (BTR) was additionally recorded pre- and posttreatment. RESULTS Irrespective of their diagnosis, patients treated with BLT (p =.0012) but not with DLT (p =.73) showed a statistically significant increase in MMSE total scores after light therapy. Evening BLT simultaneously induced a significant phase delay of 56 min on BTR (p =.025). CONCLUSION Our preliminary results suggest that short-term evening BLT may exert beneficial effects on cognitive functioning in patients with dementia.

Monoaminergic function in the pathogenesis of seasonal affective disorder.

Seasonal affective disorder/winter type (SAD) is characterized by recurrent depressive episodes during autumn and winter alternating with non-depressive episodes during spring and summer. Light therapy with full-spectrum, bright white light has been shown to be effective for this condition. Several hypotheses have been discussed in the literature about the pathogenesis of SAD. The most prominent includes disturbances in central monoaminergic transmission. Evidence can be inferred from studies showing a seasonal rhythm of central and peripheral serotonergic functioning which may be a predisposing factor for SAD. Some of the symptoms of SAD are believed to represent an attempt to overcome a putative deficit in brain serotonergic transmission. Moreover, 5-HT receptor challenge studies suggest altered activity at or downstream to central 5-HT receptors. Monoamine depletion studies support hypotheses about serotonergic and catecholaminergic dysfunctions in SAD and suggest that light therapy may well compensate for this underlying deficit. Further, albeit indirect, support for the importance of monoaminergic mechanisms in SAD and its involvement in the mechanism of the action of light therapy comes from studies showing antidepressant efficacy of serotonergic and noradrenergic antidepressants in the treatment of SAD. Altogether, disturbances in brain monoaminergic transmission seem to play a key role in the pathogenesis of SAD; monoaminergic systems may also play an important role in the mechanisms of the action of light therapy.

Direct Effect of Sunshine on Suicide

IMPORTANCE It has been observed that suicidal behavior is influenced by sunshine and follows a seasonal pattern. However, seasons bring about changes in several other meteorological factors and a seasonal rhythm in social behavior may also contribute to fluctuations in suicide rates. OBJECTIVE To investigate the effects of sunshine on suicide incidence that are independent of seasonal variation. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of data on all officially confirmed suicides in Austria between January 1, 1970, and May 6, 2010 (n = 69 462). Data on the average duration of sunshine per day (in hours) were calculated from 86 representative meteorological stations. Daily number of suicides and daily duration of sunshine were differentiated to remove variation in sunshine and variation in suicide incidence introduced by season. Thereafter, several models based on Pearson correlation coefficients were calculated. MAIN OUTCOMES AND MEASURES Correlation of daily number of suicides and daily duration of sunshine after mathematically removing the effects of season. RESULTS Sunshine hours and number of suicides on every day from January 1, 1970, to May 6, 2010, were highly correlated (r = 0.4870; P < 10-9). After differencing for the effects of season, a mathematical procedure that removes most of the variance from the data, a positive correlation between number of suicides and hours of daily sunshine remained for the day of suicide and up to 10 days prior to suicide (rmaximum = 0.0370; P < 10-5). There was a negative correlation between the number of suicides and daily hours of sunshine for the 14 to 60 days prior to the suicide event (rminimum = -0.0383; P < 10-5). These effects were found in the entire sample and in violent suicides. CONCLUSIONS AND RELEVANCE Duration of daily sunshine was significantly correlated with suicide frequency independent of season, but effect sizes were low. Our data support the hypothesis that sunshine on the day of suicide and up to 10 days prior to suicide may facilitate suicide. More daily sunshine 14 to 60 days previously is associated with low rates of suicide. Our study also suggests that sunshine during this period may protect against suicide.

Effects of sunshine on suicide rates

OBJECTIVES Seasonal spring peaks of suicide are well described in epidemiological studies, but their origin is poorly understood. More recent evidence suggests that this peak may be associated with the increase in the duration of sunshine in spring. We investigated the effect of number of sunshine hours per month on suicide rates in Austria between 1996 and 2006. METHODS Suicide data, differentiated by month of suicide, sex, and method of suicide (violent vs nonviolent methods), were provided by Statistics Austria. Data on the average number of sunshine hours per month were calculated from 39 representative meteorological stations (provided by the Austrian Central Institute for Meteorology and Geodynamics). For statistical analysis, analysis of variance tests, Kruskal-Wallis tests, and Pearson correlation tests were used. RESULTS A total of 16,673 suicides with a median of 126 ± 19.8 suicides per month occurred in the examined period. A clear seasonal pattern was observed, with suicide frequencies being highest between March and May and lowest between November and January (df = 11, F = 5.2, P < .0001) for men (df = 11, F = 4.9, P < .0001) and women (df = 11, F = 2.4, P = .008). The average number of sunshine hours per month was significantly correlated with the number of suicides among both sexes (r = .43, P < .0001), violent methods (r = .48, P < .0001) but not with nonviolent methods (r = .03, P = .707). CONCLUSIONS This study shows that seasonal changes in sunshine account for variations in the number of suicides and especially violent suicides. We propose that sunshine, via interactions with serotonin neurotransmission, may trigger increased impulsivity and promote suicidal acts. However, because of the hypothesis-generating design of this study, more research is needed to further clarify the role of sunshine in triggering neurobiologic changes, which might contribute to suicidal behavior.

Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning

It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS− conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS− condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS− compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS− in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia.