Karsten Henkel

Impairment in episodic and chronic cluster headache

Despite being an excruciating headache, little is known about the burden of cluster headache (CH) regarding its various subtypes. In a multicentre, prospective study, patients with chronic CH (n = 27), with episodic CH in the active (n = 26) and outside the active period (n = 22), migraine patients (n = 24) and healthy controls (n = 31) were included. Epidemiological data, the German version of the Headache Disability Inventory (HDI) and a screening for psychiatric complaints were applied. About 25% of chronic CH patients in our study received invalidity allowance due to CH. HDI scores (total and subscales emotion and function) indicated a severe headache-specific disability (one-way ANOVA: P < 0.01). Patients with chronic and active episodic CH were significantly more affected than patients with inactive CH and migraine. Healthy volunteers were significantly less affected than all headache patients. Symptoms suggestive of psychiatric co-morbidity were found predominantly in chronic CH: depressive symptoms (56%), signs of agoraphobia (33%) and suicidal tendencies (25%) were frequently reported. Patients with chronic and active episodic CH were severely impaired in non-economic and economic domains such as disability, working life and psychiatric complaints. Remarkably, psychiatric co-morbidity was highest in chronic CH. Thus, especially chronic CH warrants special medical and further supportive care.

The impact of dopamine on aggression: an [18F]-FDOPA PET Study in healthy males.

Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[18F]-fluoro-l-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain (r = −0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.

Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [18F]fluorodopamine ([18F]FDOPA)-PET in conjunction with the inlet–outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [18F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [18F]FDOPA (K; dopamine synthesis capacity) as well as the [18F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (−22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [18F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers

BACKGROUND There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. METHODS We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. RESULTS Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. CONCLUSIONS The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.

Aggressiveness in different presentations of cluster headache: Results from a controlled multicentric study:

Background: The hypothalamus has been discussed as a pivotal structure for both cluster headache (CH) and aggressiveness, but little is known about the extent of self-reported aggressiveness in patients with CH. Patients and methods: Twenty-six patients with chronic, 25 with active episodic and 22 with episodic CH outside the active period were examined interictally with a validated questionnaire quantifying factors of aggression and compared with 24 migraine patients and 31 headache-free volunteers. Results: The ANOVA was significant for the subscale ‘self-aggression/depression’ (F4, 123 = 5.771, p < 0.001) with significant differences between chronic and episodic CH and healthy volunteers. No significant changes were found for other subscales and the sum scale (F4, 123 < 1.421, p > 0.230). Especially in the clinically most affected group of patients (chronic CH and active episodic CH), high levels of “self-aggression/depression” correlate with higher prevalence of depressive symptoms and higher impairment measured on an emotional and functional level. Discussion: Self-aggressive and depressive cognitions with highest scores in chronic CH seem to be reactive as they correlate with depressive symptoms and impairment. They should be considered as an important therapeutic target since they impair the patient’s life significantly.

MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behavior in males.

A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening sample, strictly case-matched groups of 2×12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening sample MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie; MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism.

Cluster headache and neuropsychological functioning

Background: Despite significant advances in unravelling the pathophysiology of cluster headache (CH), little is known about neuropsychological functioning. Apart from neuroimaging studies indicating involvement of posterior hypothalamic and other areas frequently involved in nociception, some studies suggest involvement of prefrontal areas. Among others, these mediate executive functioning (EF). Methods: Therefore, three neuropsychological tests (Trail Making Test (TMT), Go/Nogo Task and Stroop Task) were completed by four headache patient samples (chronic CH, episodic CH in the active or inactive period, and migraine patients) and compared to healthy controls. Results: Analyses revealed that patients especially with chronic and active episodic CH were particularly impaired in tests relying more on intact EF (i.e. TMT-B, Stroop interference) than on basal cognitive processes (i.e. TMT-A, Stroop naming). Within the CH groups performance decreased linearly with increasing severity. Discussion: These findings are in line with a recently proposed involvement of prefrontal structures in CH pathophysiology as patients performed worse on neuropsychological tasks relying on these structures. Impaired EF could also result from medication and sleep disturbances due to active CH. Because the decreased performance was also present outside the attacks it may hint at generally altered brain functions, but do not necessarily reflect clinically relevant behaviour.

Sicherheits- und Nebenwirkungsprofil der EKT

Patienten, bei denen die Durchfuhrung einer Elektrokonvulsionstherapie indiziert ist, leiden meistens an einer schweren therapieresistenten psychiatrischen Erkrankung. Jedoch sollte wie bei anderen Therapieformen eine detaillierte Nutzen-Risiko-Analyse individuell fur jeden Patienten durchgefuhrt werden. Eine umfassende Aufklarung des Patienten, von dessen Angehorigen und des gesetzlichen Betreuers muss innerhalb juristischer Vorgaben erfolgen und das Verhaltnis von Wirkung zur Nebenwirkungen berucksichtigen. Die Elektrokonvulsionstherapie gilt heutzutage als sicheres Verfahren. Dennoch konnen, wie auch bei jedem anderen Therapieverfahren, Nebenwirkungen auftreten. Im vorliegenden Kapitel wird uber mogliche akute und persistierende Nebenwirkungen und als Sonderstellung uber die kognitiven Nebenwirkungen durch die Elektrokonvulsionstherapie berichtet.

Plasma levels and cerebrospinal fluid penetration of venlafaxine in a patient with a nonfatal overdose during a suicide attempt.

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EKT im internationalen Vergleich

Die EKT hat in den verschiedenen Regionen der Welt einen unterschiedlichen Stellenwert. Insbesondere unterscheiden sich das Indikationsspektrum, der medizinische Standard und die Behandlungsrate. In Westeuropa, Nordamerika, Australien, Neuseeland und einigen Schwellenlandern wird die EKT vornehmlich zur Behandlung therapierefraktarer Depressionen eingesetzt. Die Patienten sind oft alter und weiblichen Geschlechts. Die Behandlung erfolgt in einem modifizierten Setting mit Kurznarkose, Muskelrelaxation, meist mit Rechteckstimulation und EEG-Monitoring. Die hochsten Behandlungsraten finden sich in Australien und Skandinavien. Hingegen kommt die EKT in Osteuropa, weiten Teilen Asiens und, sofern verfugbar, in Lateinamerika und Afrika hauptsachlich zur Therapie der Schizophrenie, auch bei jungeren und mannlichen Patienten, zum Einsatz. In diesen Regionen gibt es einen erheblichen Anteil unmodifizierter Behandlungssettings. Die Behandlungsraten pro Zentrum divergieren weltweit erheblich.