Peter Pregelj

The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide

BACKGROUND Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNF polymorphism (BDNF Val66Met) was reported to influence the effects of stressful life events or childhood adversity on depression and suicidal behaviour in various psychopathologies. The study evaluated the association between BDNF Val66Met variants and suicide, committed with violent or non-violent methods, in victims with or without stressful childhood experience. METHODS BDNF Val66Met polymorphism was genotyped on 560DNA samples from 359 suicide victims and 201 control subjects collected on autopsy from unrelated Caucasian subjects and subdivided according to gender, method of suicide, and influence of childhood adversity. RESULTS A similar frequency of BDNF Val66Met variants was found between all included suicide victims and the control groups, and also between the male groups. The frequency of the combined Met/Met and Met/Val genotypes and the homozygous Val/Val genotype was significantly different between the female suicide victims and female controls, between the female suicide victims who used violent suicide methods and female controls, and between all included suicide victims with or without stressful life events. The combined Met/Met and Met/Val genotypes contributed to this significance. LIMITATION A small group of suicide victims with available data on childhood adversity was studied. CONCLUSIONS The combined Met/Met and Met/Val genotypes of the BDNF Val66Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. These results confirm a major role of BDNF in increased vulnerability to suicide.

Relationship of suicide rates to economic variables in Europe: 2000-2011

BACKGROUND It is unclear whether there is a direct link between economic crises and changes in suicide rates. AIMS The Lopez-Ibor Foundation launched an initiative to study the possible impact of the economic crisis on European suicide rates. METHOD Data was gathered and analysed from 29 European countries and included the number of deaths by suicide in men and women, the unemployment rate, the gross domestic product (GDP) per capita, the annual economic growth rate and inflation. RESULTS There was a strong correlation between suicide rates and all economic indices except GPD per capita in men but only a correlation with unemployment in women. However, the increase in suicide rates occurred several months before the economic crisis emerged. CONCLUSIONS Overall, this study confirms a general relationship between the economic environment and suicide rates; however, it does not support there being a clear causal relationship between the current economic crisis and an increase in the suicide rate.

TPH2 polymorphisms and alcohol-related suicide

Substantial evidence from family, twin, and adoption studies corroborates implication of genetic and environmental factors, as well as their interactions, on suicidal behavior and alcoholism risk. Serotonergic disfunction seems to be involved in the pathophysiology of substance abuse, and has also an important role in suicidal behavior. Recent studies of the tryptophan hydroxylase 2 showed mild or no association with suicide and alcohol-related suicide. We performed SNP and alcohol analysis on 388 suicide victims and 227 controls. The results showed association between suicide (Pχ²=0.043) and alcohol-related suicide (Pχ²=0.021) for SNP Rs1843809. A tendency for association was determined also for polymorphism Rs1386493 (Pχ²=0.055) and alcohol-related suicide. Data acquired from psychological autopsies in a subsample of suicide victims (n=79) determined more impulsive behavior (Pχ²=0.016) and verbal aggressive behavior (Pχ²=0.025) in the subgroup with alcohol misuse or dependency. In conclusion, our results suggest implication of polymorphisms in suicide and alcohol-related suicide, but further studies are needed to clarify the interplay among serotonergic system disfunction, suicide, alcohol dependence, impulsivity and the role of TPH2 enzyme.

The Role of Muscle Activation Pattern and Calcineurin in Acetylcholinesterase Regulation in Rat Skeletal Muscles

Acetylcholinesterase (AChE) expression in fast rat muscles is approximately fourfold higher than in slow muscles. We examined whether different muscle activation patterns are responsible for this difference and whether the calcineurin signaling pathway is involved in AChE regulation. The slow soleus and fast extensor digitorum longus (EDL) muscles were directly or indirectly stimulated by a tonic low-frequency or a phasic high-frequency pattern of electric impulses. The phasic, but not tonic, stimulation increased the AChE mRNA levels in denervated soleus muscles to those in the normal EDL and maintained high levels of AChE mRNA in denervated EDL muscles. Therefore, muscle activation pattern is the predominant regulator of extrajunctional AChE expression in rat muscles. Indirect phasic stimulation of innervated muscles, imposed on their natural pattern of neural activation, did not increase the AChE transcript levels in the soleus, whereas a 30% reduction was observed in the EDL muscles. A low number of impulses per day is therefore prerequisite for high AChE expression. Treatment by tacrolimus and cyclosporin A, two inhibitors of calcineurin (but not by a related substance rapamycin, which does not inhibit calcineurin), increased the levels of AChE transcripts in the control soleus muscles and in tonically electrically stimulated soleus and EDL muscles, even to reach those in the control EDL muscles. Therefore, tonic muscle activation reduces the extrajunctional levels of AChE transcripts by activating the calcineurin signaling pathway. In denervated soleus and EDL muscles, tacrolimus did not prevent the reduction of AChE mRNA levels, indicating that a calcineurin-independent suppressive mechanism was involved.

Role of load bearing in acetylcholinesterase regulation in rat skeletal muscles.

Slow antigravity muscles differ from fast muscles with regard to load bearing performed during contraction. We examined the importance of load bearing in regulation of acetylcholinesterase (AChE) expression in slow and fast rat muscles. The levels of AChE mRNA in the slow soleus muscles are about 30% of those in the fast extensor digitorum longus (EDL) muscles. In the soleus muscles unloaded for 8 days by hindlimb suspension, AChE mRNA levels were not significantly different from those in the control soleus muscles. In the suspended animals, AChE transcripts in the EDL muscles decreased to about 80% of control levels. Reduction of the resting muscle tension by joint fixation did not significantly affect the levels of AChE mRNA in the unloaded soleus muscles. Phasic high‐frequency electrical stimulation of the unloaded soleus muscles via the sciatic nerve increased their AChE mRNA levels to about 50% of those in the EDL muscles. The levels observed after phasic stimulation were significantly higher than those after low‐frequency tonic stimulation, indicating the importance of muscle activation pattern for AChE regulation also in the absence of load bearing. The AChE mRNA levels in the soleus muscles overloaded for 8 days by synergist muscle ablation increased significantly to about 50% of those in the EDL muscle. The load bearing during muscle contraction seems to be a relatively unimportant extrinsic factor in the regulation of the AChE mRNA levels in muscle fibers, except when an increased load induces muscle hypertrophy accompanied by the fusion of satellite cells with the muscle fibers.

Availability of mental health service providers and suicide rates in Slovenia: a nationwide ecological study.

Aim To investigate the influence of socioeconomic factors, mental health service availability, and prevalence of mental disorders on regional differences in the suicide rate in Slovenia. Methods The effects of different socioeconomic factors, mental health service availability, and mental disorders factors on suicide rates from 2000-2009 were analyzed using a general linear mixed model (GLMM). Pearson correlations were used to explore the direction and magnitude of associations. Results Among socioeconomic factors, unemployment rate ranked as the most powerful predictor of suicide and an increase of one unit in the unemployment rate increased regional suicide rate by 2.21 (β = 2.21, 95% confidence intervals [CI] = 1.87-2.54, P < 0.001). On the other hand, higher marriage/divorce ratio was negatively related to the suicide rate and an increase of one unit in marriage/divorce ratio reduced regional suicide rate by 1.16 (β = -1.16, 95% CI = -2.20 to -0.13, P < 0.031). The most influential mental health service availability parameter was higher psychiatrist availability (4 psychiatrists and more working at outpatient clinics per 100 000 inhabitants), which was negatively correlated with the suicide rate and reduced regional suicide rate by 2.95 (β = -2.95, 95% CI = -4.60 to -1.31, P = 0.002). Another negatively correlated factor was the antidepressant/anxiolytic ratio higher than 0.5, which reduced the regional suicide rate by 2.32 (β = -2.32, 95% CI = -3.75 to -0.89, P = 0.003). Among mental health disorders, only the prevalence of alcohol use disorders was significantly related to the regional suicide rates and an increase of one unit in the prevalence of alcohol use disorders per 1000 inhabitants increased the regional suicide rate by 0.02 (β = 0.02, 95% CI = 0.01- 0.03, P = 0.008). Conclusions Besides unemployment, which was a very strong predictor of suicide rates, unequal availability of mental health services and quality of depressive disorder treatment may contribute to variations in suicide rates in different regions.

Increased libido associated with donepezil treatment: a case report

Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79‐year‐old woman with dementia of the Alzheimers type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6‐year follow‐up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor‐induced increased libido and the current literature on hypersexuality as a side‐effect of donepezil treatment are discussed.

Safety and tolerability of rivastigmine transdermal patch formulation in newly diagnosed patients with Alzheimer's dementia in naturalistic conditions

Aim:  The majority of available data on safety and tolerability issues regarding cholinesterase inhibitors used for the treatment of Alzheimers disease has been available for orally administered formulations. The objective of this prospective, 24 week, observational, non‐interventional post‐marketing surveillance study was to evaluate the safety and tolerability, as well as the efficacy, of the rivastigmine transdermal patch formulation in newly diagnosed patients with Alzheimers dementia in naturalistic conditions.

Reduced Blood Alcohol Concentration in Suicide Victims in Response to a New National Alcohol Policy in Slovenia

Background: Addiction is a major social and health problem. Studies on suicide and alcohol at the individual and aggregated level have confirmed a link between alcohol and suicide. Aim: To assess the impact of the new national alcohol policy in Slovenia on the blood alcohol concentration (BAC) in BAC-positive suicide victims before, during and after the implementation of the new national alcohol policy in 2003. Method: Blood samples were collected by forensic pathologists during medicolegal autopsies of suicide victims in order to establish their BAC levels at the time of death. BAC was measured using two routine independent headspace gas chromatography methods (HSS-GC-FID) and expressed in grams per kilogram. Results: During the period before the implementation of the act which limited the availability of alcohol in Slovenia, the BACs of BAC-positive suicide victims were higher than those tested in the period after the implementation of the act. Conclusion: Despite certain limitations, this study demonstrates that legislation measures restricting alcohol availability may be an effective measure of BAC reduction in BAC-positive suicide victims.

Neural regulation of acetylcholinesterase‐associated collagen Q in rat skeletal muscles

Acetylcholinesterase‐associated collagen Q is expressed also outside of neuromuscular junctions in the slow soleus muscle, but not in fast muscles. We examined the nerve dependence of muscle collagen Q expression and mechanisms responsible for these differences. Denervation decreased extrajunctional collagen Q mRNA levels in the soleus muscles and junctional levels in fast sternomastoid muscles to about one third. Cross‐innervation of denervated soleus muscles by a fast muscle nerve, or electrical stimulation by ‘fast’ impulse pattern, reduced their extrajunctional collagen Q mRNA levels by 70–80%. In contrast, stimulation of fast muscles by ‘slow’ impulse pattern had no effect on collagen Q expression. Calcineurin inhibitors tacrolimus and cyclosporin A decreased collagen Q mRNA levels in the soleus muscles to about 35%, but did not affect collagen Q expression in denervated soleus muscles or the junctional expression in fast muscles. Therefore, high extrajunctional expression of collagen Q in the soleus muscle is maintained by its tonic nerve‐induced activation pattern via the activated Ca2+‐calcineurin signaling pathway. The extrajunctional collagen Q expression in fast muscles is independent of muscle activation pattern and seems irreversibly suppressed. The junctional expression of collagen Q in fast muscles is partly nerve‐dependent, but does not encompass the Ca2+‐calcineurin signaling pathway.