Christian Haring

Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age

Drug monitoring in psychiatry is of increasing interest due to compliance problems, side effects of psychoactive drugs and thesearch for adequate dosage. In the present study, plasma levels of clozapine, as determined by high performance liquid chromatography, were investigated in 148 patients receiving a daily dose between 12.5 and 700 mg clozapine. Regression analysis revealed a linear relationship between dose and plasma concentrations. Plasma concentrations at a given dose (level divided by dose and body weight) in male patients reached only 69.3% of the concentrations in female patients (Mann-Whitney U Test P<0.001). When the patients were divided into smokers and non-smokers, the corresponding plasma levels were also found to be linearly dose dependent in each of the two groups. However, the average plasma concentration at a given dose was only 81.8% in smokers, compared to non-smokers. This difference was statistically significant (variance analysis P=0.022). Dividing female patients into smokers and non-smokers, the smokers reached nearly the same plasma levels as the non-smokers. Male smoking patients reached average plasma concentrations which were only 67.9% of those of non-smokers. This difference was statisticallysignificant (Mann-Whitney U Test P-0.0083). The plasma levels of the different age groups at a given dose per kg body weight were compared using the Mann-Whitney U Test. Significant differences were found between group 1 (18–26) and group 4 (45–54), (P<0.01) and group 2 (27–35) and group 4 (P<0.01) showing higher plasma levels in the older age group. The present results indicate a considerable variation of clozapine plasma levels at a given dose depending on a number of factors. These factors should be taken into consideration for efficient therapy with the lowest possible dose.

Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests.

Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug’s effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug’s reinforcing effect, (3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1–3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent ‘reinforcement’ (in its original meaning, like ‘tolerance’ or ‘sensitization’, a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals self-administering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches.

Do vertical shifts in dose-response rate-relationships in operant conditioning procedures indicate “sensitization” to “drug wanting”?

Escalation of drug use by addicts has traditionally been interpreted as tolerance to the drug’s effects. Among these effects, drug reinforcement, roughly corresponding to “drug wanting”, is thought to be a major determinant of a drug’s abuse liability. The reinforcing effect of a drug can be investigated and quantified under controlled laboratory conditions. In correspondence to the clinical impression, a development of tolerance to the reinforcing effect of the psychostimulant cocaine (Fig. 1A) or opioids (Fig. 1B) has been demonstrated by three independent groups (Emmett-Oglesby et al 1993, Negus and Mello 2003; Winger and Woods 2001) in the animal laboratory. Over the last few years, alternative explanations for an escalating drug use by addicts have been proposed by Robinson and Berridge (1993, 2001) and Koob, Le Moal and coworkers (Koob and Le Moal 2001). These two groups, for different theoretical reasons, propose that increased drug consumption is not due to tolerance but to sensitization to the drug’s reinforcing effect or, to put it in Kent Berridge’s and Terry Robinson’s terms, an “increase in drug wanting” or “incentive sensitization”. What is the experimental basis for the tolerance-tosensitization paradigm change? Certainly not human behavioral studies. Not even the originators of the “incentive sensitization” theory could provide a single controlled human laboratory study that demonstrates an increase in “drug wanting”, either directly expressed by the subject or indirectly assessed by the amount of money a subject would be willing to pay for the drug. Rather than at the clinical or human behavioral laboratory level, “sensitization” to “drug wanting” was demonstrated in rats in a study by Ahmed and Koob (1998), who used a lever-press-based self-administration operant conditioning paradigm. Prolonged self-administration of cocaine resulted in a vertical upward shift of a biphasic (inverted U-shaped) cocaine dose-response ratecurve (Fig. 1C). In a similar vein, LeMoal’s group (Koob and Le Moal 2001) demonstrated an upward shift of the descending part of a cocaine dose-response rate curve (Fig. 1D). Unfortunately, these authors failed to determine the ascending part of the cocaine dose-response relationship and the nature of the shift of this part of the dose-response curve. However, vertical shifts of complete cocaine dose-response rate-curves could be induced by other experimental manipulations in this laboratory and were explained by an increase in the reinforcing effect of cocaine (Piazza et al. 2000). To summarize, prolonged exposure to a drug of abuse has been shown to produce either parallel rightward (Fig. 1A, B) or vertical upward (Fig. 1C, D) shifts in doseresponse rate-curves. The parallel rightward shifts of dose-reinforcement curves can be easily explained by drug tolerance, a well-known pharmacological phenomenon that has already been demonstrated exhaustively for the analgesic effects of opioids. Could we explain upward vertical shifts of dose-reinforcement-curves also by tolerance rather than sensitization? Pharmacological interpretation of the findings shown in Fig. 1 is complicated by the fact that the experimental paradigm used to determine the reinforcing effects of the drugs, i.e. a multiple-injection and lever-press-based selfadministration operant conditioning paradigm, typically produces dose-effect-curves that are biphasic. These doseresponse rate-curves look like an inverted U, as opposed to monophasic S-shaped dose-response-curves favored for pharmacological analysis. Other experimental paradigms used to determine the reinforcing effects of drugs, such as Replies to this letter are available at http://dx.doi.org/10.1007/s00213-003-1602-z, http://dx.doi.org/10.1007/s00213-003-1603-y, http://dx.doi.org/10.1007/s00213-003-1604-x, http://dx.doi.org/10.1007/s00213-003-1605-9 and http://dx.doi.org/10.1007/s00213-003-1606-8

Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction

Plasma concentrations of calcitonin gene-related peptide (CGRP), a potent regulator of vascular tone, creatine kinase, myoglobin, and cardiac troponin T were assessed in 31 patients with acute myocardial infarction. In patients who had sustained acute myocardial infarctions, maximum CGRP concentrations (median, 3.2 pmol/L; interquartile range, 1.5 to 4.8 pmol/L) were markedly elevated as compared with healthy control subjects (n = 23; median, 1.02 pmol/L; p = 0.02). However, no marked differences in CGRP levels were observed between patients with early reperfusion (n = 19; median, 3.5 pmol/L) and patients without early reperfusion (n = 12; median, 2.6 pmol/L; p = 0.96), as well as between those with congestive heart failure (n = 8; median, 3.9 pmol/L) and those without congestive heart failure (n = 23; median, 3.2 pmol/L; p = 0.62). CGRP did not correlate closely with myocardial protein release or hemodynamic parameters (heart rate and blood pressure) or the occurrence of arrhythmias. Therefore we conclude that elevated peripheral venous CGRP concentrations in patients who have sustained an acute myocardial infarction are independent of successful reperfusion and hemodynamic state. Although the cause of CGRP increase is not yet identified, CGRP may play a role in the regulation of coronary vascular tone in patients after acute myocardial infarction.

Uneventful self poisoning with a very high dose of captopril

A 43-year-old patient with mild heart failure attempted suicide by ingesting between 5000 and 7500 mg of captopril. Blood pressure oscillated around 100-120/50-75 mmHg and pulse rate showed no tendency to accelerate (75-100/min). The psychiatric examination showed no drug induced psychopathological symptoms. The calculated half-life of captopril was 4.4 h. Seven hours after ingestion of approximately 50 times the maximal therapeutic daily dose of captopril the serum concentration reached 20 micrograms/ml. The calculated amount of absorbed captopril was approximately 5400 mg. Atrial natriuretic factor (ANF) plasma levels were slightly elevated and showed no tendency to increase or to fall.

Methadone Doses upon Multiple Readmissions to Inpatient Detoxification: Clinical Evidence for Very Moderate Opioid Tolerance

Escalation of drug use by addicts has traditionally been interpreted as tolerance to the drug’s effects. On the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e., that such an escalation of drug dose might not be based on tolerance but rather be indicative of (i) sensitization to the reinforcing effect or the incentive salience of the drug of abuse or (ii) shifts in baseline mood, i.e., allostasis. In the present study, the emergence of opioid tolerance or sensitization during the progression of opioid dependence was assessed by comparing the methadone doses that were initially required to alleviate the opioid withdrawal symptoms of intravenous opioid users who presented for detoxification upon 3–7 consecutive admissions over the course of up to 84 months. Upon the second admission, the 48 surveyed male patients needed 115 ± 6% (p = 0.012) and the 32 female patients needed 121 ± 12% (p = 0.01) of the methadone dose required upon the first admission. Upon the third admission, the respective values were 121 ± 8% (males; p = 0.013) and 111 ± 12% (females; n.s.), and upon the fourth admission, 125 ± 14% (males; p = 0.026) and 131 ± 14 (females; p = 0.01). Inter-admission intervals averaged 14 ± 1 months (n = 135) for males and 13 ± 1 months (n = 91) for females and were not significantly different across consecutive admissions, suggesting that tolerance did not develop faster upon repetition of abuse-withdrawal cycles. In conclusion, the intravenous opioid users surveyed in the present study developed only very moderate tolerance during the repeated abuse-detoxification cycles that were typical for their disease progression. The present data do not support the notion that sensitization to the opioids’ reinforcing effects occurred in this naturalistic clinical sample.