Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample.

Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.

[Psychotherapy and pharmacotherapy for harmful tobacco use and tobacco dependency]. / Psycho- und Pharmakotherapie bei schädlichem Tabakgebrauch und -abhängigkeit.

Tobacco consumption is one of the major preventable health risk factors. In Germany approximately 110,000 people prematurely die from tobacco-related diseases and approximately 50% of regular smokers are considered to be tobacco dependent. Nevertheless, motivation to quit smoking is low and the long-term abstinence rates after attempts to stop smoking without professional support are far below 10%. As part of the S3 treatment guidelines 78 recommendations for motivation and early interventions for smokers unwilling to quit as well as psychotherapeutic and pharmacological support for smokers willing to quit were formulated after an systematic search of the current literature. More than 50 professional associations adopted the recommendations and background information in a complex certification process. In this article the scientific evidence base regarding the psychotherapeutic and pharmacological treatment options as well as recommendations and further information about indications and treatment implementation are presented. By following these guidelines for treatment of heavy smokers who are willing to quit combined with individual and group therapies on the basis of behavioral treatment strategies and pharmacological support, long-term success rates of almost 30% can be achieved.

[Assessment of possible drug-drug interactions in psychopharmacotherapy after hospital discharge using an interactive database]. / Datenbankgestützte Prüfung von möglichen Psychopharmakainteraktionen nach Entlassung aus stationärem Aufenthalt.

INTRODUCTION: Psychiatry is confronted with increasing requirements in quality management, guidelines and an increasing proportion of elderly, chronic multimorbid patients with psychiatric disorders. The latter give rise to polypharmacy which may lead to drug-drug interactions. Assessment of drug interactions is more and more difficult as the total number of drugs taken increases. In the present study hospital discharge medication was analysed semiautomatically for possible drug-drug interactions. METHODS: In-hospital cases were randomly selected. Discharge medication was analysed using PsiacOnline, a large web-based database for drug interactions. RESULTS: The selection yielded 342 cases from 213 patients (mean age 46.3 years, 53 % females). 86 patients had one psychiatric diagnosis; the other patients had at least two or more diagnoses. The discharge prescription was analysed for 55 different psychotropic drugs from 4 large drug groups (18 antidepressants; 17 antipsychotic drugs; 5 mood stabilisers/epileptic drugs and 13 different hypnotic/anxiolytic drugs). Antipsychotic drugs were the most frequent drugs (n = 334); followed by antidepressants (n = 312) and mood stabilizers (n = 112). 47 patients (13.7 %) were discharged with monotherapy. Mean drug number was 2.7. PsiacOnline revealed 535 hits: 126 (23.6 %) combinations were non-critical, 86 (16.1 %) combinations were critical based on pharmacological properties of the drugs; 232 (43.4 %) combinations were critical according to in vitro studies or animal experiments; critical drug combinations in high-risk patients: 67 × (12.5 %); combinations with reported risks for side effects due to interaction: 17 × (3.2 %) and combinations with documented risks for severe drug interactions: 7 × (1.3 %). CONCLUSION: Although the majority of drug combinations was considered not critical, approximately 3 % of cases had an increased risk for adverse drug actions and a further 1.3 % cases with a severe risk gave evidence that integration of an IT-based pharmacological expert system in a computerised physician order entry (CPOE) should be considered. Suggested beneficial effects need to be shown by an appropriately-designed clinical study.

[Off-label use in psychiatry]. / Off-Label-Use in der Psychiatrie.

In psychiatry, there is an increasing use of drugs Off-Label. Especially antidepressants and antipsychotic drugs are prescribed more often outside approved indications. Main problems with Off-Label Use are drug safety, lack of reimbursement by health care providers and insufficient coordination between clinics and primary care psychiatrists. Many, especially older psychotropic drugs are approved for psychopathologic phenomena rather than on ICD-10 categories. According to current judication of the German supreme court for social issues, specific criteria for Off-Label Use have been defined. Now, in social legislation, under particular circumstances Off-Label Use is feasible. Recommendations of expert groups for psychiatry are currently lacking, but are expected in next future for Methylphenidate in treatment of adult attention-deficit-hyperactive disorder (ADHS). Especially important for all psychiatrists is to receive informed consent of the patient before initiation of a drug therapy Off-Label.

Choreoathetosis related to lithium intoxication.

A 76-year old woman was admitted because of severe gait ataxia and dysarthric speech that had worsened over the last 24 h. The patient was initially suspected of having repeated transitory ischemic attacks (TIAs) as her daughter reported a similar episode that had happened 3 weeks prior to admission. The onset of spontaneous twisting, choreoathetotic movements of both hands and arms and worsening of symptoms one hour after admission together with a history of lithium therapy lead to the correct diagnosis and appropriate treatment.

The effects of exogenous analgesia in a patient with borderline personality disorder (BPD) and severe self-injurious behaviour.

In order to analyse the effects of potent exogenous analgesia with opioids in borderline personality disorder (BPD), we present a case report in which the application of morphine abolished the perception of pain during self-injury and intensified self-injurious activities. On the basis of our observations, we concluded that the use of potent analgesics might aggravate psychopathology in BPD.

Acute detoxification of opioid-addicted patients with naloxone during propofol or methohexital anesthesia: a comparison of withdrawal symptoms, neuroendocrine, metabolic, and cardiovascular patterns.

OBJECTIVE: Mu-Opioid receptor blockade during general anesthesia is a new treatment for detoxification of opioid addicted patients. We assessed catecholamine plasma concentrations, oxygen consumption, cardiovascular variables, and withdrawal symptoms after naloxone and tested the hypothesis that variables are influenced by the anesthetic administered during detoxification. DESIGN: Prospective randomized clinical study. SETTING: Intensive care unit of a university hospital and psychiatric ward. PATIENTS: Twenty-five mono-opioid addicted patients with mild to moderate systemic disease (ASA II classification) in a methadone substitution program. INTERVENTION: General anesthesia with either propofol (129+/-7 microg x kg(-1) x min(-1), mean +/- SEM) or methohexital (74+/-14 microg x kg(-1). min(-1)), mu-opioid receptor blockade by naloxone in a stepwise fashion (increasing doses of 0.4 mg, 0.8 mg, 1.6 mg, 3.2 mg, and 6.4 mg at 15 min intervals followed by 0.8 mg x hr(-1) for 24 hrs) and naltrexone 50 mg x day(-1) orally for > or =4 wks. Clonidine was started 180 mins after the first naloxone dose and its infusion rate was individually adjusted to mitigate withdrawal symptoms during weaning and after extubation. MEASUREMENTS AND MAIN RESULTS: During propofol and methohexital anesthesia, naloxone induced a 30-fold increase in epinephrine and a significant three-fold increase in norepinephrine plasma concentrations without a significant difference between groups. This increase in catecholamine plasma concentrations was associated with increased oxygen consumption and marked cardiovascular stimulation with both anesthetics, as shown by increased cardiac index, heart rate, and systolic atrial pressure whereas diastolic pressure remained unchanged. Patients receiving propofol could be extubated significantly earlier after discontinuation of the anesthetics. Although the maximum degree of withdrawal symptoms (Short Opioid Withdrawal Scale) on the day after detoxification was similar with both anesthetics, subsequent withdrawal symptoms decreased significantly more rapidly after propofol anesthesia. CONCLUSIONS: Naloxone treatment, in opioid-addicted patients, induced a marked increase in catecholamine plasma concentrations, metabolism, and cardiovascular stimulation during anesthesia with both propofol and methohexital. Although both anesthetics appear suitable for detoxification treatment, the use of propofol is associated with earlier extubation and, surprisingly, a shortened period of long-term withdrawal symptoms during detoxification.

Perforation of the posterior tracheal wall during percutaneous dilatational tracheotomy.

Dilatative percutaneous tracheotomy is more and more indicated in intensive-care medicine. We report on the perforation of the posterior tracheal wall observed in 3 patients after this procedure. In 2 patients the tracheo-oesophageal fistula was closed by the use of a pediculated flap from the infrahyoideal muscle. The third patient died due to the underlying disease. As demonstrated by the 3 cases reported here, this complication cannot be avoided in every case neither by the use of an endoscope nor by extensive personal experience of the physician. The possibility of this complication should be known, because it seems to be typical of this procedure. In the case of perforation of the posterior tracheal wall, active surgical treatment seems to be a successful method to deal with this complication.

Percutaneous dilatational tracheostomy--early results and long-term outcome of 326 critically ill patients.

OBJECTIVE: To analyze perioperative and postoperative complications and long-term sequelae following percutaneous dilatational tracheostomy (PDT). DESIGN: A prospective clinical study of patients undergoing PDT. SETTING: Seven intensive care units at a University hospital PATIENTS: 326 intensive care patients (202 male, 124 female; age: 11-95 years) with indications for tracheostomy. INTERVENTIONS: Using tracheoscopic guidance, 337 PDTs were performed according to Ciaglias' method. In 106 decannulated patients, tracheal narrowing was assessed by plain tracheal radiography. RESULTS: Two procedure-related deaths were seen (0.6%). Perioperative and postoperative complications occurred with 9.5% of the PDTs. One of 106 patients, who were followed-up for at least 6 months, showed a clinically relevant tracheal stenosis. Subclinical tracheal stenosis of at least 10% of the cross-sectioned area was recognized in 46 of 106 patients (43.4%). In the univariate analysis, the degree of stenosis was influenced by the age of the patient (p = 0.044), the duration of intubation prior to PDT (p = 0.042) and by the duration of cannulation (p = 0.006). These parameters had no statistical significance in a multiple regression model. CONCLUSION: When performed by experienced physicians, percutaneous dilatational tracheostomy under fiberoptic guidance is a safe method. The risks of early complications and of clinically relevant tracheal stenoses are low. Subclinical tracheal stenoses are found in about 40% of patients following PDT.

Profound increase in epinephrine concentration in plasma and cardiovascular stimulation after mu-opioid receptor blockade in opioid-addicted patients during barbiturate-induced anesthesia for acute detoxification.

BACKGROUND: Acute displacement of opioids from their receptors by administration of large doses of opioid antagonists during general anesthesia is a new approach for detoxification of patients addicted to opioids. The authors tested the hypothesis that mu-opioid receptor blockade by naloxone induces cardiovascular stimulation mediated by the sympathoadrenal system. METHODS: Heart rate, cardiac index, and intravascular pressures were measured in 10 patients addicted to opioids (drug history; mean +/- SD, 71 +/- 51 months) during a program of methadone substitution (96 +/- 57 mg/day). Cardiovascular variables and concentrations of catecholamine in plasma were measured in the awake state, during methohexital-induced anesthesia (dose, 74 +/- 44 microg x kg(-1) x min(-1)) before administration of naloxone, and repeatedly during the first 3 h of mu-opioid receptor blockade. Naloxone was administered initially in an intravenous dose of 0.4 mg, followed by incremental bolus doses (0.8, 1.6, 3.2, and 6.4 mg) at 15-min intervals until a total dose of 12.4 mg had been administered within 60 min; administration was then continued by infusion (0.8 mg/h). RESULTS: Concentration of epinephrine in plasma increased 30-fold (15 +/- 9 to 458 +/- 304 pg/ml), whereas concentration of norepinephrine in plasma only increased to a minor extent (76 +/- 44 to 226 +/- 58 pg/ml, P < 0.05). Cardiac index increased by 74% (2.7 +/- 0.41 to 4.7 +/- 1.7 min(-1) x m(-2)), because of increases in heart rate (89 +/- 16 to 108 +/- 17 beats/min) and stroke volume (+44%), reaching maximum 45 min after the initial injection of naloxone. In parallel, systemic vascular resistance index decreased (-40%). Systolic arterial pressure significantly increased (113 +/- 16 to 138 +/- 16 mmHg), whereas diastolic arterial pressure did not change. CONCLUSIONS: Despite barbiturate-induced anesthesia, acute mu-opioid receptor blockade in patients addicted to opioids induces profound epinephrine release and cardiovascular stimulation. These data suggest that long-term opioid receptor stimulation changes sympathoadrenal and cardiovascular function, which is acutely unmasked by mu-opioid receptor blockade. Because of the attendant cardiovascular stimulation, acute detoxification using naloxone should be performed by trained anesthesiologists or intensivists.

Cyclic nucleotide-gated channels in identified human olfactory receptor neurons.

Patch-clamp recordings revealed the presence of a non-desensitizing cyclic nucleotide-gated channel on human olfactory receptor neurons and a fast-desensitizing non-specific cation channel activated by nucleotides on human supporting cells. Cyclic nucleotide-gated channels on olfactory receptor neurons showed selective channel activation by cAMP (K1/2 = 5 microM) and cGMP (K1/2 = 2 microM), a unitary conductance of approximately 20 pS, a reversal potential of single-channel currents close to 0 mV, a linear current-voltage relationship over the range of -80 to 80 mV and a strong extracellular but a weaker intracellular blocking effect of Ca2+. The channel activity outlasted the cyclic nucleotide pulses for hundreds of milliseconds when higher agonist concentrations (> 50 microM cAMP) were applied. The duration of the response was longer than in cyclic nucleotide-gated channels from other species studied so far. The plateau duration and the decay remained constant for pulses with a length of 50-150 ms, whereas pulses shorter than 50 ms successively reduced the time required by shortening the plateau phase. A larger difference for the K1/2 values of cAMP (K1/2 = 22 microM) and cGMP (K1/2 = 2.5 microM) were found for a small group (n = 3) of cyclic nucleotide-gated channels, pointing to the selective expression of the alpha-subunit in a small subgroup of olfactory receptor neurons.

Dose dependent time course of the analgesic effect of a sustained-release preparation of tramadol on experimental phasic and tonic pain.

1. The aim of this study was to investigate the analgesic effect and its duration of a new sustained-release preparation of tramadol in an experimental pain model based on pain-related chemosomatosensory evoked potentials (CSSEPs) and subjective intensity estimates of painful phasic and tonic stimuli. 2. Twenty volunteers participated in a randomised, double-blind, three-fold cross-over study. Measurements were obtained before and 0.5, 1, 4, 6, and 12 h after administration of the drug (100 mg, 200 mg and placebo orally). CSSEPs were recorded after stimulation of one nostril with phasic, painful CO2 pulses. The other nostril was stimulated with a constant stream of dry air, which produced a tonic painful sensation. Subjects rated the perceived intensity of phasic and tonic stimuli via visual analogue scales. In order to test for nonspecific effects, acoustic evoked potentials (AEPs) were recorded, the spontaneous EEG was analysed in the frequency domain, the subject's vigilance was assessed in a tracking task, and the side effects of the drug were monitored. 3. The sustained-release preparation of tramadol produced a significant dose-related decrease in CSSEP amplitudes when compared with placebo. The reduction in amplitudes outlasted the observation period of 12 h, demonstrating the prolonged duration of the analgesic effect. 4. A dose-related significant decrease could be observed for the estimates of tonic pain. Similar to the decrease of amplitudes of the CSSEP, the reduction of the ratings of tonic pain outlasted the observation period of 12 h. The observed slight decrease in the estimates of phasic pain under medication did not reach a statistically significant level when compared with placebo. No significant effect could be demonstrated for the perception of the phasic and the tonic pain as determined by the McGill-Questionnaire. 5. A significant dose-related increase in the estimates of the side effects 'drowsiness', 'vertigo' and 'sickness' but not for 'tiredness' could be demonstrated.

Responses recorded from the frog olfactory epithelium after stimulation with R(+)- and S(-)-nicotine.

The aim of this study was to determine whether the olfactory system is responsible for the discriminability of the stereoisomers of nicotine. The EOG was recorded after stimulation with different concentrations of undistilled S(-)-, distilled S(-)- and distilled R(-)-nicotine separately in three groups of frogs (Xenopus laevis). The responses to all types of nicotine used in the experiments increased with increasing stimulus concentration. The responses to undistilled S(-)-nicotine were significantly lower compared to responses to distilled S(-)- and R(+)-nicotine, whereas no significant differences could be found when the purified stereoisomers of nicotine [distilled S(-)-nicotine, distilled R(+)-nicotine] were compared. Control measurements of time course and peak concentration employing a UV-detection method demonstrated that the differences between distilled and undistilled S(-)-nicotine could not be explained by different nicotine concentrations. The fact that no differences between the pure nicotine stereoisomers could be found for all concentrations used in our experiments and that experiments in humans revealed similar detection thresholds for both stereoisomers points to a similar receptor affinity of R(+)- and S(-)-nicotine within the olfactory system. At this point, it cannot be determined whether the observed differences in the perception of nicotine enantiomers in humans are due to differences in quality coding by stereospecific receptors on the olfactory sensory cells or by specific receptors on the trigeminal nerve endings.

Different sensitivity of pain-related chemosensory potentials evoked by stimulation with CO2, tooth pulp event-related potentials, and acoustic event-related potentials to the tranquilizer diazepam.

1. The aim of this study was to investigate the sensitivity of pain-related potentials used in experimental pain models to the non-specific effects of the tranquilizer diazepam. Pain-related potentials were recorded after painful stimulation of the nasal mucosa with CO2 and after painful stimulation of the tooth pulp. Acoustically evoked potentials were measured in order to compare their sensitivity to the tranquilizer diazepam with the sensitivity of the pain-related potentials. 2. Twenty volunteers participated in this randomised, double-blind, three-fold crossover study. Measurements were obtained before and 20 min after the administration of the drug. Event-related potentials were recorded after painful stimulation of the nasal mucosa with CO2 (two stimulus intensities: 60% v/v and 70% v/v CO2), after painful stimulation of the tooth pulp (two stimulus intensities: 2.2 x and 3.3 x detection threshold), and after non-painful acoustical stimulation of the right ear. The subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale. In addition the spontaneous EEG was analysed in the frequency domain and the vigilance of the subjects was assessed in a tracking task. 3. Diazepam reduced significantly the amplitudes of the event-related potentials after painful stimulation of the tooth pulp and after acoustical stimulation. In contrast only a small, statistically non-significant reduction could be found after painful stimulation with CO2. The pain ratings of the painful stimuli were not affected by diazepam. Diazepam reduced the performance of the tracking task. A decrease of arousal could be found in the alpha 2-range, whereas in the beta 2 and the theta-range the power density increased under diazepam. 4. We demonstrated that event-related potentials after painful stimulation of the nasal mucosa with CO2 are less affected by the nonspecific effects of the tranquilizer diazepam than event-related potentials after painful stimulation of the tooth pulp. The effects of diazepam on the tracking task, the spontaneous EEG and the event-related potentials clearly confirm its sedative properties. Diazepam had no analgesic effect measurable by pain intensity estimates.

Nociceptive and reflexive responses recorded from the human nasal mucosa.

Slow electrical responses after painful stimulation with carbon dioxide, which is known to specifically activate nociceptors, were recorded from the nasal respiratory epithelium in human volunteers. The negative component of these potentials (negative mucosal potential NMP) has been hypothesized to be a summated receptor potential. The aim of the present study was to characterize the stimulus-response relationship and to demonstrate that the NMP is restricted to the site of stimulation, i.e., to the area of activated nociceptors. Eight healthy volunteers participated in the experiments. The NMP was recorded from the nasal septum and intensity ratings were obtained for each of the applied stimuli. To control for autonomic reflexes, blood flow changes were additionally recorded using a laser Doppler flow meter. Both increasing stimulus duration and increasing concentration produced a significant increase in the subjects' intensity estimates, in the NMP's amplitudes and areas under the curve, but did not change the local blood flow in a dose-related manner. The odorant hydrogen sulphide, which was used as a non-painful control stimulus, did not elicit mucosal potentials or produce blood flow changes. By recording both ipsi- and contralaterally it was also demonstrated that the NMP could only be obtained at the stimulated site, thus supporting the hypothesis that the NMP is a specific peripheral nociceptive correlate.

[Puncture tracheostomy in intensive care patients. Technique and results of a minimally invasive method]. / Die Punktionstracheostomie beim Intensivpatienten. Technik und Ergebnisse einer minimal-invasiven Methode.

The so-called percutaneous dilatational tracheostomy-essentially a minimally invasive puncture method-inserting the tracheal cannula by a modified Seldinger-technique is an alternative method to the conventional operative tracheostomy. The percutaneous dilatational tracheostomy was evaluated in a prospective trial (June 92-January 93) on 50 consecutive surgical (n = 36), medical (n = 10), and neurological-neurosurgical (n = 4) critically ill patients (29 m, 21 f; age 14-87 years) with need for prolonged mechanical ventilation. After an average duration of endotracheal intubation of 6 (0-22) days, the procedure was endoscopically guided and controlled via the endotracheal tube. An 8 mm cannula was inserted in each case. Eight patients had severe thrombocytopenia (< or = 50,000 Plt./microL). The percutaneous tracheostomy was always performed with success. The average procedure duration was 8 (5-15) minutes. The perioperative complications were: one patient died of acute cardiac failure independent from the method of tracheostomy, one sustained a temporary subcutaneous emphysema and one a minor bleeding. During a mean duration of cannulation of 21 (0-113) days only one bleeding from the skin margin was observed postoperatively. Infection of stoma site, misplacement of cannula, rupture of the tube cuff, and pneumothorax were not noticed. On 13 decannulated patients stenosis of the trachea was not found in a period of 6-8 weeks following the tracheostomy. As a bedside procedure the percutaneous dilatational tracheostomy is safe and quick and should therefore be the method of choice for critically ill patients who require a tracheostomy.

The mucosal potential elicited by noxious chemical stimuli with CO2 in rats: is it a peripheral nociceptive event?

Negative mucosal potentials (NMPs) were recorded from the nasal respiratory mucosa in rats following retrograde stimulation with CO2 through a tube advanced to the nasopharynx. Local application of capsaicin (3 mg in 0.3 ml solvent, n = 5) and lidocaine (31 mg in 0.3 ml solvent, n = 5) eliminated the NMPs and cortical responses in the EEG. A quantitative reduction in NMPs was found following systemic pretreatment with capsaicin (cumulative dose, 200 mg/kg, n = 4), but not with guanethidine (50 mg/kg s.c., n = 4). Blood flow measurements and NMPs were obtained from the same recording position (n = 4). Onset of blood flow changes (1200-4800 ms) appeared significantly later than the onset of NMPs (120-500 ms). On the basis of these results a sensory neurogenic origin of the NMP is assumed.