Wolfgang Sperling

The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes

It is established that cannabis consumption cannot only trigger transient psychotic episodes but also predisposes for the development of lasting paranoid schizophrenia in a dose dependent manner (Moore et al., 2007; Muller-Vahl and Emrich, 2008). Patients with a positive family history are at a higher risk for such drug induced schizophrenic disorders (Fergusson et al., 2006; Morgan and Curran, 2008). Crossreactions between different drugs to trigger recurrence of schizophrenic episodes are rare (Huffman et al., 2008). We present the case of a 25 year old man who had a history of cannabis induced recurrent psychotic episodes and an acute reactivation of symptoms after abuse of the synthetic cannabinoid “Spice”.

Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.

Chronic alcohol consumption can induce brain atrophy, whereby the exact mechanism of brain damage in alcoholics remains unknown. There is evidence that chronic alcoholism is associated with hyperhomocysteinemia. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative injury in vitro and in vivo. The present volumetric magnetic resonance imaging study included 52 chronic alcoholics and 30 non-drinking healthy controls. Patients were active drinkers and had an established diagnosis of alcohol dependence. We investigated the influence of different variables on the hippocampal volume of patients suffering from chronic alcoholism. We observed that pathological raised levels of plasma homocysteine showed the most significant correlation to hippocampal volume reduction (P<0.001, multiple regression analysis). Raised plasma levels of homocysteine are associated with hippocampal (brain) atrophy in alcoholism.

Homocysteine as a neurotoxin in chronic alcoholism.

There is evidence from in vitro and in vivo studies that homocysteine induces neuronal damage and cell loss by both excitotoxicity and different apoptotic processes. Clinical evidence suggest a strong relationship between higher plasma homocysteine levels and brain atrophy in healthy elderly subjects as well as in elderly at risk of and with Alzheimers disease. Chronic alcoholism leads to elevated plasma homocysteine levels, as shown by clinical investigations and animal experiments. In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of alcoholism-associated brain atrophy. Furthermore, taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anticonvulsive therapy could prevent this severe complication. Homocysteine plays a role in a shared biochemical cascade involving overstimulation of N-methyl-D-aspartate (NMDA) receptors, oxidative stress, activation of caspases, DNA damage, endoplasmic reticulum and mitochondrial dysfunction. These mechanisms are believed to be important in the pathogenesis of both excitotoxicity and apoptotic neurotoxicity. Prospective intervention studies may show whether the incidence of complications of alcohol withdrawal or alcoholism-associated disorders can be reduced by therapeutic measures with early lowering of elevated homocysteine levels (e.g. folate administration). The most important pathophysiological and pathobiochemical features of glutamatergic neurotransmission and of ethanol-induced hyperhomocysteinaemia are reviewed in relation to their excitotoxic and apoptotic potential.

Managing an effective treatment for neuroleptic malignant syndrome

IntroductionNeuroleptic malignant syndrome (NMS) is a rare, but sometimes fatal, adverse reaction to neuroleptics characterized principally by fever and rigor. The aim of this study was to prove the efficacy of different NMS treatment strategies, focusing on the efficacy of dantrolene.MethodsAltogether, 271 case reports were included. These cases were categorized into four treatment groups and compared to each other according to effectiveness of therapy within 24 hours, mortality, complete time of remission in days, effectiveness due to increase of dosage, relapse on the basis of decrease of dosage, and improvement of symptoms.ResultsBetween the four treatment groups, the complete time of remission was significantly different (analysis of variance, F = 4.02; degrees of freedom = 3; p = 0.008). In a logistic regression with adjustment for age, gender, and severity code, no significant predictor of the treatment for the complete time of remission (dichotomized by median) could be found. However, if the premedication was a monotherapy with neuroleptics, the complete time of remission was significantly shorter with dantrolene monotherapy (t = -2.97; p = 0.004).ConclusionThe treatment of NMS with drugs that are combined with dantrolene is associated with a prolongation of clinical recovery. Furthermore, treatment of NMS with dantrolene as monotherapy seems to be associated with a higher overall mortality. Therefore, dantrolene does not seem to be the evidence-based treatment of choice in cases of NMS but might be useful if premedication consisted of a neuroleptic monotherapy.

Sex hormone activity in alcohol addiction: integrating organizational and activational effects.

There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brains reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.

Cortical activity associated with auditory hallucinations.

Auditory hallucinations are one the most enigmatic and hampering symptoms associated with schizophrenia. Non-invasive functional imaging techniques have begun to delineate the underlying neuronal basis. We investigated the spontaneous magnetoencephalographic activity in a 33-year-old male schizophrenic patient and compared the results to those obtained from 13 healthy controls. Despite current neuroleptic medication (clozapine) the patient was still suffering from auditory hallucinations. Using the dipole density method, we were able to demonstrate an increase of fast MEG activity (12.5–30 Hz) in the left auditory cortex associated with hallucinations. This activity was absent in healthy controls. We conclude that an increase in fast MEG activity in the auditory cortex is a neurophysiologic correlate for auditory hallucinations in schizophrenia.

Leptin is associated with craving in females with alcoholism

The appetite and weight regulating peptide leptin was associated recently with alcohol craving during withdrawal. Nevertheless, correlations were only significant with craving displayed on the visual analogue scale for maximum craving during the previous week (VAS), and not if assessed with the highly validated Obsessive Compulsive Drinking Scale (OCDS). The objective of the following study, therefore, is to elucidate further the associations between the leptin system and craving concepts during alcohol withdrawal. A sufficiently large sample size should allow multiple statistical subgroup and confounder analyses. We prospectively investigated 102 chronic alcoholic inpatients (23 females, 79 males) during withdrawal on days 0 (admission), 1, 2 and days 7 ‐ 10. In addition to the statistical analysis of the total sample, females and males were to be analysed separately. For detecting associations between leptin levels and craving scores multiple regression analysis was performed. Plasma leptin levels were determined, and craving for ethanol was assessed by both the OCDS and the VAS. Leptin plasma levels significantly increased during alcohol withdrawal compared to day 0, while all craving scores decreased. Body mass corrected leptin plasma levels predicted craving on day 0 in the OCDS total score (R  = 0.55, F  = 7.91, df = 1.19, p  < 0.05) and in the OCDS obsessive subscore (R  = 0.57, F < = 8.48, df = 1.19, p  < 0.05) in females. Neither in males nor in the total population did multiple regression analysis reveal any significant results. Leptin levels seem to change during inpatient alcohol withdrawal. In a multivariate model, correlations between leptin levels and the highly validated craving scores of the OCDS can only be assumed in females. Hence, gender differences have to be taken into account when searching for neurobiological models of alcohol craving.

Low digit ratio 2D:4D in alcohol dependent patients.

The ratio of the lengths of the second and fourth finger (2D∶4D) has been described as reflecting the degree of prenatal androgen exposure in humans. 2D∶4D is smaller for males than females and is associated with traits such as left-handedness, physical aggression, attention-deficit-hyperactivity disorder and a genetic polymorphism of the androgen receptor. All of these traits are known to be correlated to the vulnerability for alcohol dependency. We therefore hypothesized low 2D∶4D in patients with alcohol dependency. In the present study on 131 patients suffering from alcohol dependency and 185 healthy volunteers, we found that alcohol dependent patients had smaller 2D∶4D ratios compared to controls with preserved sexual dimorphism but with reduced right-left differences. The detection of alcohol dependency based on 2D∶4D ratios was most accurate using the right hand of males (ROC-analysis: AUC 0.725, sensitivity 0.667, specificity 0.723). These findings provide novel insights into the role of prenatal androgen exposure in the development of alcohol dependency and for the use of 2D∶4D as a possible trait marker in identifying patients with alcohol dependency.

Alcoholism-Associated Hyperhomocysteinemia and Previous Withdrawal Seizures

BACKGROUND Higher homocysteine levels were found in actively drinking alcoholics as well as in early abstinent patients. Furthermore, it has been shown that high homocysteine levels predicted first-onset alcohol withdrawal seizures. The aim of the present study was to determine plasma homocysteine levels in actively drinking alcoholics and patients with early abstinence in order to evaluate whether there is an additional association between elevated plasma homocysteine levels and a history of alcohol withdrawal seizures. METHODS Two groups of patients with an established diagnosis of alcohol dependence were studied. Group A comprised 56 consecutively admitted alcoholics who had been abstinent from alcohol between 24 to 72 hours before hospitalization. Group B consisted of 144 consecutively recruited alcoholics who were admitted - acutely intoxicated - for withdrawal treatment. Furthermore, groups were divided into two subgroups: patients with and without a history of alcohol withdrawal seizures. RESULTS Alcoholics of GROUP B with a history of withdrawal seizures had significantly (p<.0001) higher homocysteine levels than actively drinking patients without seizures in their history: 42.0 micromol/l (SD 26.4) versus 22.5 micromol/l (SD 11.4). Using a logistic regression analysis, history withdrawal seizures in Group B but not in Group A patients were best predicted by a high homocysteine level at admission (Wald chi2=15.5, p<.0001; odds ratio 1.11, 95% CI 1.05-1.20). CONCLUSIONS Homocysteine levels on admission may be a useful screening method to identify actively drinking patients with a higher risk of alcohol withdrawal seizures.

Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal

The orexins (hypocretins) are neuropeptides deriving from the lateral hypothalamus and may be of importance within the context of drug craving, withdrawal, and relapse. Therefore, the orexin A expression and promoter methylation in peripheral blood cells of 68 patients (41 male and 27 female patients at three different time points during withdrawal and 27 patients during stationary dehabituation therapy) suffering from alcohol dependence were assessed by quantitative reverse transcription-polymerase chain reaction and bisulfite sequencing. There was a statistically significant difference of orexin A expression between the three time points of withdrawal and long-term (LT) abstinence (F=4.16, P=.011). This difference was most prominent in comparison with LT abstinence (t=-3.08, P=.0032). Expression was significantly associated with the severity of withdrawal symptoms measured with the Withdrawal Syndrome Scale for Alcohol and Related Psychoactive Drugs (WSA) (t=2.17, P=.0356). The stronger the withdrawal symptoms, the lower the orexin A expression (F=4.69, P=.036). Body mass index (t=2.15, P=.041), the severity of withdrawal measured with the WSA (t=2.595, P=.0133), craving measured either by the Obsessive Compulsive Drinking Scale (t=2.77, P=.0085) or the Lübecker Craving Questionnaire (t=-2.23, P=.0314) had a significant influence on orexin A expression taking into account mean methylation of the CpG island of the orexin A promoter during withdrawal. Orexin A may be a possible candidate to further elucidate mechanisms of alcohol withdrawal taking into account energy homoeostasis in the circuit of reward and motivation.