[The development of a rational national MDMA policy and its relevance for psychiatry]. / Voorstel voor rationeel MDMA-beleid.

BACKGROUND: MDMA (ecstasy) is a relatively safe drug and induces little dependence, but is nevertheless scheduled as a hard drug (Dutch Opium Act, List 1). Concerns about MDMA-related crime, health incidents and possible inappropriate listing of MDMA on List I have led to an ongoing debate about current Dutch ecstasy policy. AIM: To develop a rational MDMA policy that takes into account all aspects related to production, sale and use of MDMA. METHOD: An interdisciplinary group of 18 experts formulates a science-based MDMA policy by assessing the expected effects of 95 policy options on 25 outcomes, including health, crime, law enforcement and finance. The optimal policy model consists of the combination of the 22 policy options with the highest total score on all 25 outcomes. RESULTS: The optimal policy model consisted of a form of regulated production and sale of MDMA, better quality management of ecstasy tablets and more intensive fight against MDMA-related organized crime. Such a policy would lead to a small increase in the prevalence of ecstasy use, but with less health damage, less MDMA-related crime, and less environmental damage. To increase practicality and political feasibility, the optimal model was slightly modified. CONCLUSION: The developed optimal model offers a politically and socially feasible set of policy instrument options, with which the placement of MDMA on List I can be revised, thereby reducing the damage of MDMA to users and society. For psychiatry, it means promoting therapeutic research and less nuisance from unnecessary stigmatization in the treatment of patients.

[Recreative ecstasy use in the Netherlands: use characteristics, health risks and criminality]. / Recreatief ecstasygebruik in Nederland: gebruikskenmerken, gezondheidsschade en criminaliteit.

BACKGROUND: Ecstasy (MDMA) is used by approximately 370,000 Dutch people yearly, mainly young adults with a good education.
AIM: To describe ecstasy-related negative health effects, health risks, use profiles and crime based on data from scientific literature and other publicly available sources.
RESULTS: Ecstasy appears to cause little health damage during recreational use. Adverse health incidents, particularly hyperthermia, are observed, but are probably partly due to the use of ecstasy under (a combination of) unfavourable circumstances, such as: a warm environment, too little drinking, and considerable physical exertion (dancing). The estimated risk of serious ecstasy-related non-fatal accidents was 1 in 3,400 pills and 1 per 700 users. The number of fatal ecstasy-related incidents is estimated to be a maximum of 35 per year. Crime associated with the production and trade of ecstasy is worrying and, according to some authors, disruptive to society.
CONCLUSION: On the basis of these results, we conclude that the use of ecstasy does involve health risks, but given the widespread use of ecstasy, the number of (fatal) incidents is relatively low. Better information about the conditions under which ecstasy can be used more safely will contribute to fewer incidents.

Rapid versus non-rapid cycling bipolar II depression: response to venlafaxine and lithium and hypomanic risk.

OBJECTIVE: To examine the safety and effectiveness of antidepressant versus mood stabilizer monotherapy in rapid versus non-rapid cycling bipolar II disorder. METHOD: Subjects ≥18 years old with bipolar II depression (n = 129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n = 59) received continuation monotherapy for six additional months. RESULTS: Rapid cycling did not affect frequency of response or change over time in depressive symptoms. Rapid cycling status did not affect frequency of depressive relapse or sustained treatment response. Rapid cyclers were more likely to experience hypomanic symptoms (P = 0.005) during continuation monotherapy; however, rates were similar in venlafaxine (17.6%) and lithium (42.9%) (P = 0.31). CONCLUSION: Rapid cycling status may not be associated with an increased risk of diminished response or greater depressive relapse during venlafaxine, relative to lithium monotherapy, in bipolar II subjects. Additional randomized studies are needed to confirm these findings.

[Cognitive impairment due to intensive use and overdoses of gammahydroxybutyric acid (GHB)]. / Cognitieve schade door intensief gebruik en overdoses van GHB.

BACKGROUND: In several countries, including the Netherlands, the use of GHB seems to be increasing. Many recreational users of GHB consider the drug to be harmless and to have no serious side effects. In recent years the number of patients with GHB addition has been increasing steadily. AIM: To draw attention to the possible development of neurotoxicity due to chronic and intensive use of GBH. METHOD: We reviewed the literature using PubMed. RESULTS: Several studies point to an increase in the number of incidents arising from the risky use of GHB or from a GHB overdose. Other drugs, such as ketamine and alcohol, are known to cause neurotoxicity, leading to cognitive impairment. As outlined in this review article, GHB , alcohol and ketamine show clear similarities in their mechanism of action. This suggests that GHB might have almost the same neurotoxic effects as ketamine and alcohol. An overdose of GHB, just like binge-drinking and a high dose of ketamine, may lead to a coma that probably harms the brain, particularly if comas occur repeatedly. CONCLUSION: The risk of neurotoxicity is likely to increase with chronic, intensive use of GHB, which is a feature of GHB-addition. We therefore advocate research into the possible toxic effects of GHB in the long term, involving, for instance, the study of lasting effects on the cognitive functions of GHB users and former users.

Can pharmacotherapists be too supportive? A process study of active medication and placebo in the treatment of depression.

BACKGROUND: This study examined therapist-patient interactions during clinical management with antidepressant medication and pill-placebo. METHOD: The sample consisted of 80 patients on active medication and 40 patients in a pill-placebo condition from a randomized controlled trial for moderate to severe depression. Pharmacotherapist-patient interactions were characterized using observer ratings of the therapeutic alliance, pharmacotherapist-offered facilitative conditions, pharmacotherapist adherence to clinical management treatment guidelines and pharmacotherapist competence. Patients, therapists and raters were blind to treatment condition and outcome. RESULTS: Provision of greater non-specific support (facilitative conditions) in early sessions predicted less subsequent improvement in depressive symptoms for patients receiving pill-placebo but not those receiving active medications, for which none of the process ratings predicted subsequent change. Early symptom change predicted later alliance and adherence in both conditions and therapist competence in the active condition. CONCLUSIONS: Higher levels of support in early sessions predict poorer subsequent response among placebo patients. It remains unclear whether patients who are likely to be refractory elicit greater non-specific support or whether the provision of such support has a deleterious effect in unmedicated patients. Differences in treatment process variables between conditions late in treatment are likely to be largely a consequence of symptom relief produced by active medications.

Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy.

OBJECTIVE: We examine the safety and efficacy of venlafaxine monotherapy in bipolar type II (BP II) patients with major depressive episode (MDE) who were unresponsive to prior lithium monotherapy. We hypothesized that venlafaxine would be superior to lithium with a low hypomanic conversion rate. METHOD: Seventeen patients who were unresponsive to prior lithium monotherapy were crossed to venlafaxine monotherapy for 12 weeks. The primary outcome was within-subject change in total Hamilton Depression Rating (HAM-D) score over time. Secondary outcomes included the change in Young Mania Rating (YMRS) and clinical global impressions severity (CGI/S) and change (CGI/C) scores. RESULTS: Venlafaxine produced significantly greater reductions in HAM-D (P < 0.0005), CGI/S (P < 0.0005), and CGI/C (P < 0.0005) scores vs. prior lithium. There was no difference in mean YMRS scores between treatment conditions (P = 0.179). CONCLUSION: Venlafaxine monotherapy may be a safe and effective monotherapy of BP II MDE with a low hypomanic conversion rate in lithium non-responders.

The effect of post-injury depression on return to pre-injury function: a prospective cohort study.

BACKGROUND: Millions of people seek emergency department (ED) care for injuries each year, the majority for minor injuries. Little is known about the effect of psychiatric co-morbid disorders that emerge after minor injury on functional recovery. This study examined the effect of post-injury depression on return to pre-injury levels of function. METHOD: This was a longitudinal cohort study with follow-up at 3, 6 and 12 months post-injury: 275 adults were randomly selected from those presenting to the ED with minor injury; 248 were retained over the post-injury year. Function was measured with the Functional Status Questionnaire (FSQ). Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV-TR disorders (SCID). RESULTS: During the post-injury year, 18.1% [95% confidence interval (CI) 13.3-22.9] were diagnosed with depression. Adjusting for clinical and demographic covariates, the depressed group was less likely to return to pre-injury levels of activities of daily living [odds ratio (OR) 8.37, 95% CI 3.78-18.53] and instrumental activities of daily living (OR 3.25, 95% CI 1.44-7.31), less likely to return to pre-injury work status (OR 2.37, 95% CI 1.04-5.38), and more likely to spend days in bed because of health (OR 2.41, 95% CI 1.15-5.07). CONCLUSIONS: Depression was the most frequent psychiatric diagnosis in the year after minor injury requiring emergency care. Individuals with depression did not return to pre-injury levels of function during the post-injury year.

Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders.

Borna disease virus causes a rare meningoencephalitis in horses and sheep and has been shown to produce behavioral effects in some species. The possibility that the Borna virus is associated with mental disorders in humans was evaluated by examining serum samples from 979 psychiatric patients and 200 normal volunteers for the presence of Borna virus-specific antibodies. Antibodies were detected by the indirect immunofluorescence focus assay. Antibodies to the virus were demonstrated in 16 of the patients but none of the normal volunteers. The patients with the positive serum samples were characterized by having histories of affective disorders, particularly of a cyclic nature. Further studies are needed to define the possible involvement of Borna virus in human psychiatric disturbances.

Differences in serotonin transporter binding affinity in patients with major depressive disorder and night eating syndrome.

OBJECTIVE: We examined serotonin transporter (SERT) binding affinity using single photon emission computed tomography (SPECT) in patients with major depressive disorder (MDD) and night eating syndrome (NES). There are similarities between MDD and NES in affective symptoms, appetite disturbance, nighttime awakenings, and, particularly, response to selective serotonin reuptake inhibitors (SSRIs). METHODS: Six non-depressed patients with NES and seven patients with MDD underwent SPECT brain imaging with 123I-ADAM, a radiopharmaceutical agent selective for SERT sites. Uptake ratios of 123I-ADAM SERT binding were obtained for the midbrain, basal ganglia, and temporal lobe regions compared to the cerebellum reference region. RESULTS: Patients with NES had significantly greater SERT uptake ratios (effect size range 0.64-0.84) in the midbrain, right temporal lobe, and left temporal lobe regions than those with MDD whom we had previously studied. CONCLUSIONS: Pathophysiological differences in SERT uptake between patients with NES and MDD suggest these are distinct clinical syndromes.

Subchronic inhalation of mixtures of cigarette smoke constituents in Xpa-/-p53+/- knock-out mice: a comparison of intermittent with semi-continuous exposure to acetaldehyde, formaldehyde, and acrolein.

We investigated whether inhaling peak concentrations of aldehydes several times daily is more damaging than semi-continuously inhaling low-dose aldehydes. We exposed Xpa-/-p53+/- knock-out mice either intermittently or semi-continuously to mixed acetaldehyde, formaldehyde, and acrolein. The intermittent regimen entailed exposure to the aldehydes 7 min every 45 min, 12 times/day, 5 days/week, corresponding to concentrations inhaled by smokers. Semi-continuously exposed animals received half the dose of aldehydes in 8h/day, 5 days/week. Some mice in each group were sacrificed after 13 weeks of exposure; the rest breathed clean air until the end of 1 year. Mice injected intratracheally with benzo[a]pyrene formed a positive control group. The nasal cavity, lungs, and any macroscopically abnormal organs of all mice were analysed histopathologically. After 13 weeks of exposure, the subacute, overall, histopathological changes induced by the inhalation differed noticeably between the intermittently and semi-continuously treated Xpa-/-p53+/- knock-out mice. After 13 weeks of mixed aldehyde exposure, atrophy of the olfactory epithelium generally appeared, but disappeared after 1 year (adaptation and/or recovery). Respiratory epithelial metaplasia of the olfactory epithelium occurred at a higher incidence at 1 year. Except for a significantly greater number of tumours observed in knock-out mice compared to wild mice (semi-continuous aldehyde exposure and controls), no differences between the semi-continuous and intermittent exposure groups were observed.

Risk assessment of khat use in the Netherlands: a review based on adverse health effects, prevalence, criminal involvement and public order.

In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance.

Significance of ammonium compounds on nicotine exposure to cigarette smokers.

The tobacco industry publicly contends that ammonia compounds are solely used as tobacco additive for purposes of tobacco flavoring, process conditioning and reduction of its subjective harshness and irritation. However, neither objective scientific reports, nor the contents of a large number of internal tobacco company documents support this contention. The present review focuses on the hypothesis that addition of ammonium compounds to tobacco enhances global tobacco use due to smoke alkalization and enhanced free-nicotine nicotine exposure. Obviously, ammonia enhances the alkalinity of tobacco smoke. Consequently, the equilibrium shifts from non-volatile nicotine salts to the volatile free base that is more readily absorbed from the airways. The observed change in the kinetics of nicotine (i.e., shorter t(1/2) and higher c(max)) after ammoniation is, however, predominantly due to the higher concentration of nicotine in the smoke, rather than to an increase in the absorption rate of free-base nicotine in the respiratory tract. Although several findings support the hypothesis, additional studies are required and suggested to provide a proper, objective and independent scientific judgment about the effect of tobacco ammoniation on nicotine bioavailability. Scientific and public awareness of the effects of tobacco-specific ammonia compounds may stimulate global control, legislation and restriction of their use in cigarette manufacture.

Elevated expression of the junB proto-oncogene is essential for v-fos induced transformation of Rat-1 cells.

We previously described the isolation of non-tumorigenic revertants from mutagenized populations of v-fos-transformed Rat-1 cells (Zarbl et al., 1987). In the present study we examined the possibility that the revertant phenotype resulted from mutations that altered the expression or activities of the c-jun or junB proto-oncogenes. The results demonstrated that levels of the c-jun mRNA and protein were unchanged in the revertants when compared to the transformed parental cells, and ectopic overexpression of c-jun failed to retransform the revertants. Although one mutant allele was detected in revertant EMS-1-19, overexpression of this mutant allele failed to inhibit v-fos induced cell transformation. Together these results indicated that the revertant phenotype did not result from altered expression or mutations in the c-jun gene. In contrast to the results obtained with c-jun, the levels of junB mRNA and protein were found to be reduced two- or threefold in revertant EMS-1-19. Ectopic overexpression of junB induced transformation of revertant EMS-1-19, but failed to transform Rat-1 cells. Moreover, about 10% of v-fos transformed cells transfected with vectors that express antisense junB mRNA acquired a non-transformed phenotype. Together these results indicate that expression of junB above a threshold level is essential for v-fos-induced transformation of Rat-1 fibroblasts.

Expression of FosB during mouse development: normal development of FosB knockout mice.

FosB, one of the members of the Fos family, is rapidly induced in many cell types upon stimulation and has a stimulatory effect on the proliferation of cultured cells. To understand the tissue distribution of FosB, we have studied its expression pattern by immunohistochemistry in newborn and late embryonic stage mice. These results show that FosB is widely expressed with the highest levels of expression observed in both bony and cartilagenous regions of developing bone. FosB is also detected within whisker follicles, liver, and epidermal tissue. To study the role of FosB in mammalian development we generated embryonic stem (ES) cells, mice and mouse embryo fibroblasts (MEFs) that are deficient for FosB. FosB -/- mice are born at a normal frequency, are fertile and present no obvious phenotypic or histologic abnormalities. FosB-deficient ES cells and MEFs proliferate and enter the S phase normally and we do not find upregulation of other fos family genes to compensate for the lack of FosB. However, we do find that the induction of two AP-1 containing genes is reduced after stimulation of FosB-deficient cells, demonstrating that FosB does indeed play a functional role in transcriptional regulation.

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers.

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.

Enhanced adrenocortical sensitivity to submaximal doses of cosyntropin (alpha1-24-corticotropin) in depressed patients.

There is evidence that excessive cortisol secretion in depressed patients might result, in part, from an enhanced adrenocortical sensitivity to corticotropin. This phenomenon has been examined using the cosyntropin (alpha1-24-corticotropin) stimulation test. Most studies have used supramaximal doses of cosyntropin administered in the morning, when adrenal sensitivity to corticotropin is at its maximum. This could partially obscure subtle differences in adrenocortical sensitivity in depression that might otherwise be evident at lower cosyntropin doses given later in the day. To test this hypothesis, we administered two consecutive cosyntropin tests on separate occasions employing a submaximal 0.05-microgram/kg dose and a maximal 0.2-microgram/kg dose. The cortisol centered cumulative response over 240 minutes was measured after each test in 12 depressed patients (7 melancholic, 5 nonmelancholic) and 6 healthy volunteers. When the difference in mean cortisol centered cumulative response values was determined, healthy controls demonstrated a significant increase in cortisol centered cumulative response, while the nonmelancholic patients had a less robust increase in cortisol centered cumulative response. In contrast, the melancholic patients demonstrated cortisol responses similar to those of the healthy subjects after each cosyntropin dose, suggesting an enhanced adrenocortical sensitivity to corticotropin. These data support the hypothesis that increased glucocorticoid secretion in depression may result from abnormalities at several sites within the hypothalamic-pituitary-adrenocortical axis.

A neuroendocrine test battery in bipolar patients and healthy subjects.

Abnormalities of hormonal responses to a number of neuroendocrine challenges have been reported in depressed patients. Most studies have examined responses in a single neuroendocrine axis. We used a series of four neuroendocrine challenges (thyrotropin-releasing hormone test, gonadotropin-releasing hormone test, insulin tolerance test, and dexamethasone suppression test) to examine eight hormonal responses in 22 healthy subjects and 22 patients with bipolar disorder. Variability of hormonal responses in bipolar patients was examined by evaluating the number of abnormal hormonal responses as compared with responses from healthy volunteers. Abnormalities were observed after all four neuroendocrine tests. Nine control subjects (40.9%) and 17 bipolar patients (77.3%) had at least one abnormal response. More strikingly, 12 bipolar patients (54.5%), but no controls, had two or more abnormal responses. These findings suggest that manic-depressive patients show increased variability in hormonal response from multiple neuroendocrine axes.

Desipramine and 2-hydroxydesipramine plasma levels in endogenous depressed patients. Lack of correlation with therapeutic response.

Studies of the relationship between plasma concentrations of desipramine hydrochloride and clinical response have shown contradictory results, and only one prior study examined 2-hydroxydesipramine and its relationship to treatment. We therefore performed a study in a large, carefully diagnosed group of depressed patients taking fixed maintenance doses of desipramine to elucidate a potential relationship between clinical response and plasma concentrations of desipramine and 2-hydroxydesipramine. There was no significant correlation between clinical response and steady-state plasma levels of desipramine, 2-hydroxydesipramine, or the sum of desipramine plus 2-hydroxydesipramine. Although some commercial laboratories suggest a specific therapeutic plasma level "range" for desipramine, our data provide no support for such a range, nor for the routine measurement of plasma desipramine and 2-hydroxydesipramine concentrations in depressed patients.

Borna disease virus. A possible etiologic factor in human affective disorders?

Borna disease virus is a unique neurotropic agent that appears to have a predilection for the limbic area of the brain. In some animal species, it can produce a behavioral syndrome characterized by aggressive and passive phases. This syndrome has suggested an analogy to certain human affective disorders. In this preliminary study, we examined the possible involvement of Borna disease virus in the etiology of human mood disorders by assaying for virus-specific antibodies in 265 patients with unipolar or bipolar depression and 105 normal, healthy volunteers. Twelve patients (4.5%) and none of the healthy controls demonstrated this antibody in their serum samples. It will be necessary to replicate and extend these intriguing preliminary results to determine if Borna disease virus is possibly involved in the pathogenesis of affective disorders in humans.

Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression.

Two hundred forty-one outpatients with a DSM-III diagnosis of major depressive disorder participated in a six-week double-blind therapeutic trial of alprazolam, diazepam, imipramine hydrochloride, and placebo. Side effects were given as a major reason for attrition by patients taking the three active compounds and ineffectiveness was the reason given by patients taking placebo. Imipramine-treated patients reported the most and placebo patients the least number of adverse effects. Imipramine and alprazolam, but not diazepam, produced significantly more improvement in depressed symptomatology than did placebo. Mean diazepam scores frequently assumed an intermediate position between those of imipramine or alprazolam and placebo. These treatment differences were found to be independent of initial severity levels of anxiety and depression.