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Serotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic serotonin-1A receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of serotonin-1A receptor binding in the living human brain.
Thirty-six healthy, drug-naïve subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional serotonin-1A receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined.
Correlation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation.
Seasonal factors such as exposure to global radiation influence postsynaptic serotonin-1A receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.
Many experience low mood and energy during winter. Brain serotonin is involved in the regulation of many physiologic and pathologic functions that vary with season. Seasonal variations in peripheral serotonergic markers have been described in clinical and nonclinical populations, and a postmortem study shows seasonal differences in hypothalamic serotonin concentration.
We investigated the molecular background of seasonal changes in serotonin function by conducting a series of studies on serotonin transporter (5-HTT) density and function in depression and health.
In a large study in drug-free patients with seasonal affective disorder (SAD) we aimed at detecting state-related alterations in 5-HTT-mediated inward and outward transport in platelets. Another study in healthy subjects aimed at detecting seasonal variations in 5-HTT binding in the living human brain using [11C] DASB positron emission tomography. Regional 5-HTT binding, an index of 5-HTT density, was assessed in a large sample of drug-naïve healthy volunteers, and was related to meteorological and astronomical data.
In patients with SAD we showed that the 5-HTT is in a hyperfunctional state during winter depression, and normalizes after light therapy and in natural summer remission. In healthy subjects, 5-HTT binding was higher in autumn/winter as compared to spring/summer. Regional 5-HTT binding correlated negatively with daily sunshine, such that higher values occurred at times of lesser light.
Since high 5-HTT density is associated with low synaptic serotonin levels, regulation of 5-HTT density and 5-HTT function by light is a mechanism that may explain seasonal changes in normal and pathologic behaviours.
Tranylcypromine, an irreversible monoamine-oxidase (MAO) inhibitor, has been frequently used to treat the most challenging mood disorders since 1950s. Due to dietary restrictions as well as feared drug interactions, tranylcypromine has been increasingly replaced by modern antidepressants lacking such challenging pharmacology. Ketamine, a high-affinity non-competitive antagonist at the N-methyl-D-aspartate receptor, has been increasingly appreciated as rapid-acting antidepressant with good anti-suicidal properties. Previous in-vitro and ex-vivo studies suggested that ketamine acts as a monoamine-reuptake inhibitor. Since inhibition of monoamine-reuptake with concurrent blockade of MAO should have the potential to precipitate a sympathomimetic crisis, a combination of ketamine and tranylcypromine is considered hazardous.
Here we report on a 43-year-old, 120 kg female patient suffering from treatment-resistant depression with recurrent severe suicidal crises, who was treated with tranylcypromine. Because of elective surgery requiring general anaesthesia, tranylcypromine was discontinued for two weeks. After reinstating tranylcypromine 10 mg p.o.q.d., she became acutely suicidal again. Hence, intravenous S-ketamine 12.5 mg was slowly administered under cardiovascular monitoring. We observed good anti-suicidal effects, while no relevant changes in blood pressure or heart rate occurred during or after s-ketamine infusion. Under plasma level monitoring tranylcypromine was increased to 80 mg p.o.q.d., and intravenous S-ketamine up to 75 mg was repeatedly administered.
This report is believed to be the first to demonstrate repeated concomitant administration of S-ketamine and tranylcypromine as antidepressant treatment in humans lacking any relevant changes in cardiovascular parameters. Hence, we put serious doubt on whether monoamine-reuptake inhibition is a relevant pharmacological effect of ketamine in humans.
There is evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality.
To evaluate the association between local lithium levels in drinking water and suicide mortality in Austria.
A nationwide sample of lithium measurements was examined for association with suicide rates across Austrian districts. Multivariate regression models were adjusted for socioeconomic factors. Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results.
The overall suicide rate as well as the suicide mortality ratio were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors.
In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.
A spring peak in suicide rates that is paralleled by an increase in daily sunshine has been observed in many countries of the northern hemisphere. However, seasons bring about changes in other meteorological factors and a seasonal rhythm in social behavior may also contribute to fluctuations in suicide rates.
We investigated direct effects of sunshine on suicide incidence in Austria. Data on all confirmed suicides between 1970 and 2010 (n = 69 462) were correlated with data on the average duration of sunshine per day (in hours) after mathematically removing the effects of season.
Sunshine hours and number of suicides in Austria were highly correlated (r = 0.4870; P < 10-9). After differencing for the effects of season, a positive correlation between number of suicides and hours of daily sunshine remained for the day of suicide and up to 10 days prior (rmaximum = 0.0370; P < 10-5). There was a negative correlation between the number of suicides and hours of daily sunshine for the 14 to 60 days prior to the suicide (rminimum = −0.0383; P < 10-5). These effects were found in the entire sample and in violent suicides.
Daily sunshine was significantly correlated with suicide frequency independent of season. Sunshine on the day of suicide and up to 10 days prior may facilitate suicide. More daily sunshine 14 to 60 days previously was associated with low rates of suicide suggesting that sunshine during this period may protect against suicide.
Treatment resistant depression (TRD) affecting approximately 10–30% of all depressed patients often remains misdiagnosed and undertreated, leading to a higher risk of relapse and suicide. Electroconvulsive therapy (ECT) and sub-anesthetic ketamine have repeatedly shown to be effective in the TRD population. Administering ketamine as an anesthetic component to augment antidepressant efficacy of ECT has been proven inconclusive, while a combination of alternating ECT and ketamine has not been investigated yet.
We present a severely depressed and chronically suicidal female inpatient who failed multiple antidepressant treatment attempts, requiring frequent psychiatric admissions. Since available conventional as well as non-conventional antidepressant treatment strategies were nearly exhausted, we employed a combination of ECT (bilateral stimulation up to 150%) 2–3 times/week, while intravenous racemic ketamine (up to 75 mg per infusion) was administered on ECT free days 2–3 times/week. Consequently, robust anti-suicidal and antidepressant effects could be observed already during the first treatment week. The temporarily occurring subjective forgetfulness disappeared after the last ECT. Summarizing, we employed 9 ECT treatments and 7 ketamine infusions leading to a stable psychopathological state even after discharge from psychiatric inpatient care. In order to prevent relapse a maintenance-therapy comprising ECT once monthly and 2 ketamine infusions (up to 100 mg per infusion) administered on the day before and after ECT was established.
In our patient alternating ECT and intravenous racemic ketamine were proven safe and long-term effective after numerous failed antidepressant trials including ECT and ketamine alone. We may hence encourage clinicians to widen their therapeutic armamentarium in severe TRD.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
It has been shown that patients with schizophrenia are super-sensitive towards dopamine-releasing agents such as amphetamine. Here, we studied the effects of amphetamine sensitization on amphetamine-induced dopamine release in healthy subjects.
To measure d-amphetamine-induced dopamine release as measured with the D2,3 agonist radioligand [11C]-(+)-PHNO-PET via change in non-displacable binding potential (BPND) and behavioral measures of d-amphetamine effects with drug effects questionnaire (DEQ) and subjective states questionnaire (SSQ).
To study d-amphetamine-induced sensitization in healthy subjects on a behavioral and neurochemical level with [11C]-(+)-PHNO-PET in order to gain more knowledge on sensitization-induced changes in the dopaminergic system.
Twelve stimulant-naïve healthy male subjects underwent three 90-min [11C]-(+)-PHNO-PET-scans and four oral administrations of d-amphetamine. After a naïve baseline scan, subjects underwent a PET scan with previous ingestion of 0.4 mg/kg bodyweight of d-amphetamine 90–120 minutes before scanning. Subsequently, subjects were sensitized to d-amphetamine with the same dose on two separate days. Thereafter, they underwent another PET scan with previous d-amphetamine ingestion. DEQ and SSQ were administered before, 60 min, 90–120 min, and 210 min after amphetamine ingestion.
We found significant sensitization effects on a behavioral level and on a neurochemical level after four administrations of amphetamine. Items of the SSQ, which showed significant sensitization effects were “outgoing”, “energetic”, “lively”, “alert” and “focused”.
We were able to induce significant behavioral and neurochemical sensitization in healthy humans, which were measured with [11C]-(+)-PHNO-PET for the first time. This sensitization model will be useful for studying the neurobiology of schizophrenia.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case–control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.
Method. One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets.
Results. No association between 5-HTTLPR and SAD was found in the new case–control material, in the combined analysis of all samples, or when only including 316 patients with controls (N=298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2·24 (1·03–4·91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set.
Conclusions. These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.
Background. During recent years hypotheses about the pathophysiology of seasonal affective disorder/winter type (SAD) have focused monoaminergic mechanisms. There is substantial evidence that serotonergic systems play an important role. The potential role of catecholaminergic pathways has not been fully explored.
Methods. Eleven drug-free, symptomatic depressed patients with SAD and 11 healthy age- and gender-matched healthy controls were invited to participate in a 123Iβ-CIT single photon emission computed tomography (SPECT) study to assess striatal density of dopamine transporters (DATs). The cerebellum was used as reference region. Ratios were calculated between mean counts in left and right striatum and cerebellum. These ratios minus 1 represent specific/non-displaceable binding and are assumed to be directly related to DAT availability at the time of binding equilibrium.
Results. Displaceable 123Iβ-CIT binding in the area corresponding to the left striatum was significantly reduced in SAD patients compared to healthy controls (10·49±0·91 v. 11·95±1·54, respectively; 2-tailed P = 0·017, Mann–Whitney U test).
Conclusions. These data suggest reductions in the availability of striatal DAT binding sites in untreated symptomatic depressed SAD patients. It remains unclear whether these reductions represent a primary defect or an attempt to overcome a state of possible lowered dopamine availability in the synaptic cleft during a depressive episode of SAD. However, these findings provide evidence that brain dopaminergic systems may be involved in the pathophysiology of SAD.
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