Baclofen in the treatment of alcohol use disorder: tailored doses matter.

AIMS: To address the question of tailored baclofen prescribing in alcohol use disorder (AUD) in relation to dose-dependent efficacy and the potential danger of high doses and to provide suggestions for the use of high doses of baclofen in the treatment of AUD. The context is the approvement in France of baclofen in the treatment of AUD without dose limitation, making French physicians, who usually prescribe baclofen in a tailored manner, often use high or very high doses. METHODS: A narrative review of the results of randomized controlled trials (RCTs) and observational studies that used tailored baclofen prescribing and of the severe adverse effects of baclofen that have been reported in the literature. RESULTS: The results show that RCTs using tailored doses of baclofen in AUD are not completely demonstrative, though they are encouraging according to certain meta-analyses, while observational studies that used tailored doses constantly show a good effectiveness of baclofen treatment. The results suggest that many severe adverse effects of baclofen could be related to a nonrespect by physicians of prescription rules and appropriate treatment monitoring. CONCLUSIONS: The use of tailored doses shows that the dose required to suppress cravings is highly variable, low or high, depending on each case. Analysis of the circumstances in which severe adverse effects occur suggest that a careful monitoring of baclofen prescribing might prevent a large majority of severe adverse effects. We propose that the education of the patients and the prescription skills, seriousness, and availability of the prescribing physicians are of major importance in the managing of tailored baclofen treatment of AUD.

Baclofen in alcohol use disorder: An analysis of the data provided by the French "Temporary Recommendation for Use" 2014-2017 cohort.

Alcohol use disorder (AUD) is a devastating illness for which effective treatments are lacking. Studies over the last two decades have shown that baclofen, a GABA-B agonist, could be a promising treatment for AUD. However, the efficacy of baclofen is still controversial, and studies have shown that it may be associated with an excess of hospitalizations and deaths. In March 2014, the French Health Safety Agency granted a "Temporary Recommendation for Use" (TRU) regulating the prescription of baclofen in subjects with AUD. The TRU allowed physicians to prescribe high-dose baclofen (up to 300 mg/d). The doses were adjusted, and tailored to the needs of each patient. Between March 2014 and March 2017, TRU clinical data were collected for a total of 6,939 subjects. The recorded data included information on alcohol consumption, the intensity of alcohol cravings, and adverse events. The present article proposes an analysis of the data provided by the TRU. Subjects for which data were missing regarding baclofen daily dosage, alcohol consumption or craving scores were discarded from the analyses. A cohort of two groups of subjects was analyzed. The first group included all TRU subjects suitable for analyses (5,550 subjects), and the second group included subjects followed for at least 365 days (169 subjects). Comparisons were made between baseline and endpoint of the follow-up period. The results show that a majority of subjects in the whole cohort had received doses of over 80 mg/d. The mean dose of baclofen at the endpoint was >110 mg/d in the second group of subjects. Doses of >80 mg/d were not associated with an increase in adverse events after adjustment for the follow-up duration. In terms of efficacy, comparisons between baseline and endpoint show that baclofen treatment significantly decreased alcohol consumption and alcohol cravings, and significantly increased the number of subjects with null or low-risk alcohol consumption according to WHO criteria.

Binge Eating Disorders in Antipsychotic-Treated Patients With Schizophrenia: Prevalence, Antipsychotic Specificities, and Changes Over Time.

BACKGROUND: Excessive energy intake likely favors metabolic dysfunction in patients with schizophrenia and may be, in part, the consequence of antipsychotic treatments. However, previous studies on the prevalence of bulimia and binge eating symptoms in antipsychotic-treated patients are contradictory and not sufficiently informative. METHODS: The prevalence of bulimia nervosa, binge eating disorder, and subsyndromal binge eating disorder was studied using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria in 156 patients with schizophrenia or schizoaffective disorder treated with antipsychotic monotherapy. The effects of different antipsychotics were compared. RESULTS: The prevalence of full syndromal binge eating disorder was 4.4% and that of subsyndromal binge eating disorder was 18.7% in patients (23.1% for binge eating spectrum disorder), and there were no cases of bulimia nervosa. Compared with the whole sample, binge eating spectrum disorders were significantly more prevalent in clozapine- and olanzapine-treated patients. Comparisons of patients having undergone treatment for 2 years or less with patients treated for more than 2 years showed that binge eating spectrum disorders decrease significantly over time, the difference being significant in clozapine- and olanzapine-treated patients. Night eating, simply assessed by a single question, showed a prevalence of 30% and was more prevalent in women treated with clozapine and olanzapine, with no significant change over time. CONCLUSIONS: Binge eating disorders should be considered as important factors involved in the development of weight gain and metabolic syndrome in antipsychotic-treated patients with schizophrenia. The difficulty to reliably assess binge eating spectrum disorders in patients with psychosis is highlighted.

A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder.

Baclofen, a GABA-B receptor agonist, is a promising treatment for alcohol use disorder (AUD). Its mechanism of action in this condition is unknown. GABA-B receptors interact with many biological systems potentially involved in AUD, including transduction pathways and neurotransmitter systems. Preclinical studies have shown that GABA-B receptors are involved in memory storage and retrieval, reward, motivation, mood and anxiety; neuroimaging studies in humans show that baclofen produces region-specific alterations in cerebral activity; GABA-B receptor activation may have neuroprotective effects; baclofen also has anti-inflammatory properties that may be of interest in the context of addiction. However, none of these biological effects fully explain the mechanism of action of baclofen in AUD. Data from clinical studies have provided a certain number of elements which may be useful for the comprehension of its mechanism of action: baclofen typically induces a state of indifference toward alcohol; the effective dose of baclofen in AUD is extremely variable from one patient to another; higher treatment doses correlate with the severity of the addiction; many of the side effects of baclofen resemble those of alcohol, raising the possibility that baclofen acts as a substitution drug; usually, however, there is no tolerance to the effects of baclofen during long-term AUD treatment. In the present article, the biological effects of baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. In conclusion, it is proposed that baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. It is also proposed that this action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems in certain regions of the brain.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Nicotine enhances alcohol intake and dopaminergic responses through ß2* and ß4* nicotinic acetylcholine receptors.

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of ß4 * nAChRs, but not ß2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (ß2-/- and ß4-/- mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in ß2-/- and ß4-/- mice, suggesting that nicotine triggers ß2* and ß4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.

Striatal and Extrastriatal Dopamine Transporter Availability in Schizophrenia and Its Clinical Correlates: A Voxel-Based and High-Resolution PET Study.

Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia.

Colitis possibly induced by quetiapine.

A 39-year-old man with bipolar disorder was hospitalised for depression. He was started on quetiapine (titrated up to 300 mg), lactulose (a laxative) and tropatepine (an anticholinergic). Valpromide (a mood stabiliser) and prazepam were later added and rapidly withdrawn. Seven days after quetiapine initiation, the patient reported abdominal pain and constipation; 2 days later, CT revealed an important distention of the colon including the caecum and a pre-perforation. A subtotal colectomy was performed and histology confirmed necrotising ischaemic colitis. The patient survived. This is the first case reported so far of ischaemic colitis related to quetiapine, in the absence of other antipsychotics simultaneously prescribed. Tropatepine likely acted as a cofactor to determine colitis. Clinicians need to be aware of the potential danger of the co-prescription of quetiapine with tropatepine (and possibly other anticholinergics).

The use of very high-doses of baclofen for the treatment of alcohol-dependence: a case series.

Baclofen, particularly high-dose baclofen, has recently emerged as a treatment of major interest for alcohol-dependence. However, baclofen has many potentially dangerous side effects, and the maximal dose of baclofen that may be used is a matter of discussion. Here, the author analyses the medical charts of the last 100 patients seen in his clinic, 17 of whom have been taking a very high dose of baclofen, which is to say, more than 300 mg/day. The analysis of the charts shows that the very high-doses baclofen were justified in almost all the cases. Side effects are analyzed.

[Off-label prescriptions in public psychiatric hospital practice]. / Prescriptions hors autorisation de mise sur le marché en psychiatrie publique hospitalière.

AIM: Analyze prescriptions in public hospital psychiatric practice. METHODS: Psychiatric and somatic prescriptions were analyzed a given day regarding their indication, dosage, treatment duration, and prescription scheme. Consultants were individually asked for the reasons of off-label prescriptions. RESULTS: Five thousand eighty-six lines of prescription were recorded for 495 patients, showing a total of 34% off-label prescriptions, including 43.5% for psychiatric medications and 22.7% for somatic medications. Psychiatric medications: 22.3% were off-label for indication, 13.1% for dosage, 4.5% for treatment duration, and 6.2% for prescription scheme. (off-label prescriptions for indication: 12.1% without clonazepam - which delivery have been restricted by the end of 2011). Somatic medications: respectively 4.5%, 14.9%, 4.8% and 12.5%. CONCLUSIONS: Percentage of off-label prescriptions for indication of psychiatric medications was clearly less than percentages published in the literature (other percentages are new). While most of off-label prescriptions were made in accordance with clinical reports in the literature, some others were not.

Abstinence and 'low-risk' consumption 1 year after the initiation of high-dose baclofen: a retrospective study among 'high-risk' drinkers.

AIMS: The aim of the study was to assess the proportions of 'high-risk' drinkers' abstinent or with 'low-risk' consumption levels 1 year after the initiation of high-dose baclofen. METHODS: This is a retrospective 'open' study; the outcome of this study was to assess the level of alcohol consumption in the 12th month of treatment. RESULTS: Of the 181 patients included, a follow-up evaluation was possible in 132 patients. The initial alcohol consumption of the 132 patients analysed averaged 182 ± 92 g/day. After 1 year, 80% of the 132 (i.e. 58% of 181) were either abstinent (n = 78) or drinking at low-risk levels (n = 28) in their 12th month of treatment. The mean baclofen dose at 1 year was 129 ± 71 mg/day. CONCLUSION: High-dose baclofen should be tested in randomized placebo-controlled trials among high-risk drinkers.

Is smoking linked to positive symptoms in acutely ill psychiatric patients?

BACKGROUND: The self-medication hypothesis is commonly put forward to explain the high prevalence of smoking in psychiatric patients. However, studies supporting the self-medication hypothesis have most often been carried out on chronic patients stabilized by antipsychotics. AIM: Given that antipsychotics tend to erase psychiatric symptoms, the present study was undertaken on acutely ill patients usually receiving no medications, or on whom medications are ineffective. METHODS: Participants were 492 consecutively hospitalized patients. They were evaluated the day of their hospitalization with the Brief Psychiatric Rating Scale (BPRS, 18 items). Urinary cotinine and creatinine were measured the morning following their hospitalization. The urinary cotinine/creatinine ratio and the cotinine/creatinine/number of cigarettes smoked per day ratio (nicotine extraction index) were calculated for each patient. RESULTS: The positive symptoms subscale of the BPRS significantly correlated with smoking, whereas other BPRS subscales did not. In patients with mood disorder, the nicotine extraction index correlated with the positive symptoms, activation and hostility subscales, but not with the negative symptoms subscale. Analyses of individual BPRS items using the cotinine/creatinine ratio measure showed that smoking is positively associated with "unusual thought content" and "grandiosity" items and negatively associated with "guilt feeling", "depressed mood" and "motor retardation". Analyses of individual BPRS items using the nicotine extraction index showed a positive association only with "unusual thought content" and "grandiosity" items. Patients with schizophrenia extract more nicotine from cigarettes than other patients. CONCLUSION: In acutely ill psychiatric patients, smoking is linked with positive symptoms and not with negative symptoms.

Suppression of alcohol dependence using baclofen: a 2-year observational study of 100 patients.

AIMS: The purpose of this study was to examine the long-term effects of baclofen in a large cohort of alcohol-dependent patients compliant to baclofen treatment. METHODS: A hundred patients with alcohol dependence, resistant to usual treatments, were treated with escalating doses of baclofen (no superior limit). Alcohol consumption (in grams) and craving for alcohol were assessed before treatment and at 3, 6, 12, and 24 months. Assessments were simply based on patients' statements. The outcome measure was the consumption of alcohol, rated according to the World Health Organization criteria for risk of chronic harm. RESULTS: While all patients were rated "at high risk" at baseline, approximately half of them were rated "at low risk" at 3, 6, 12, and 24 months. The sum of patients who were at "low risk" and at "moderate risk" (improved patients) was 84% at 3 months, 70% at 6 months, 63% at 1 year, and 62% at 2 years. The constancy of improvement over the 2-years was remarkable. The average maximal dose of baclofen taken was 147 mg/day. Ninety-two percentage of patients reported that they experienced the craving-suppressing effect of baclofen. Significant relationships were found between the amount in grams of alcohol taken before treatment and the maximal dose of baclofen required, and between the existence of a mental disorder and a lesser effect of baclofen. CONCLUSION: Baclofen produces an effortless decrease or suppression of alcohol craving when it is prescribed with no superior limit of dose. Potential limitations in the effectiveness of baclofen include the coexistence of a mental disorder, the concomitant use of other psychotropic drugs, a lack of real motivation in patients to stop drinking, and the impossibility to reach the optimal dose of baclofen because of unbearable side-effects (sometimes possibly related to too sharp a protocol of dose escalation).

Smoke extracts and nicotine, but not tobacco extracts, potentiate firing and burst activity of ventral tegmental area dopaminergic neurons in mice.

Nicotine prominently mediates the behavioral effects of tobacco consumption, either through smoking or when taking tobacco by snuff or chew. However, many studies question the exclusive role of nicotine in these effects. The use of preparations containing all the components of tobacco, such as tobacco and smoke extracts, may be more suitable than nicotine alone to investigate the behavioral effects of smoking and tobacco intake. In the present study, the electrophysiological effects of tobacco and smoke on ventral tegmental area dopaminergic (DA) neurons were examined in vivo in anesthetized wild-type (WT), ß2-nicotinic acetylcholine receptor (nAChR) knockout (ß2-/-), α4-/-, and α6-/- mice and compared with those of nicotine alone. In WT mice, smoke and nicotine had similar potentiating effects on DA cell activity, but the action of tobacco on neuronal firing was weak and often inhibitory. In particular, nicotine triggered strong bursting activity, whereas no bursting activity was observed after tobacco extract (ToE) administration. In ß2-/- mice, nicotine or extract elicited no modification of the firing patterns of DA cells, indicating that extract acts predominantly through nAChRs. The differences between DA cell activation profiles induced by tobacco and nicotine alone observed in WT persisted in α6-/- mice but not in α4-/- mice. These results would suggest that tobacco has lower addiction-generating properties compared with either nicotine alone or smoke. The weak activation and prominent inhibition obtained with ToEs suggest that tobacco contains compounds that counteract some of the activating effects of nicotine and promote inhibition on DA cell acting through α4ß2*-nAChRs. The nature of these compounds remains to be elucidated. It nevertheless confirms that nicotine is the main substance involved in the tobacco addiction-related activation of mesolimbic DA neurons.

"Where do auditory hallucinations come from?"--a brain morphometry study of schizophrenia patients with inner or outer space hallucinations.

Auditory verbal hallucinations are a cardinal symptom of schizophrenia. Bleuler and Kraepelin distinguished 2 main classes of hallucinations: hallucinations heard outside the head (outer space, or external, hallucinations) and hallucinations heard inside the head (inner space, or internal, hallucinations). This distinction has been confirmed by recent phenomenological studies that identified 3 independent dimensions in auditory hallucinations: language complexity, self-other misattribution, and spatial location. Brain imaging studies in schizophrenia patients with auditory hallucinations have already investigated language complexity and self-other misattribution, but the neural substrate of hallucination spatial location remains unknown. Magnetic resonance images of 45 right-handed patients with schizophrenia and persistent auditory hallucinations and 20 healthy right-handed subjects were acquired. Two homogeneous subgroups of patients were defined based on the hallucination spatial location: patients with only outer space hallucinations (N=12) and patients with only inner space hallucinations (N=15). Between-group differences were then assessed using 2 complementary brain morphometry approaches: voxel-based morphometry and sulcus-based morphometry. Convergent anatomical differences were detected between the patient subgroups in the right temporoparietal junction (rTPJ). In comparison to healthy subjects, opposite deviations in white matter volumes and sulcus displacements were found in patients with inner space hallucination and patients with outer space hallucination. The current results indicate that spatial location of auditory hallucinations is associated with the rTPJ anatomy, a key region of the "where" auditory pathway. The detected tilt in the sulcal junction suggests deviations during early brain maturation, when the superior temporal sulcus and its anterior terminal branch appear and merge.

Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state.

Second-generation antipsychotics are widely used in the treatment of all forms of psychoses, but they often produce undesirable side effects, among which are weight gain and other elements of metabolic syndrome. The mechanisms of these adverse effects are not known. The liver and adipose tissue are the principal candidate organs implicated in the development of antipsychotic-induced metabolic adverse effects. The present study investigated in the rat the effects on liver and white adipose tissue of a chronic treatment (46 days) with olanzapine 2 mg/kg or haloperidol 1 mg/kg, as compared with a control solution. In the liver, the expression of key genes involved in glucose transport and lipid metabolism and of regulatory transcription factors, as well as the TNFalpha gene, was not altered in response to either antipsychotic. Similarly, key genes involved in glucose transport and lipid metabolism were not changed in adipose tissue. However, the white adipose tissue was inflammatory in olanzapine-treated rats, with extensive macrophage infiltration and a significant increase in TNFalpha expression. In the plasma, TNFalpha and IL-1beta concentrations were slightly elevated. Chronic olanzapine treatment therefore produces a low-grade inflammatory state, likely initiated in the adipose tissue. Such an inflammatory state is known to be associated with an increased risk of insulin-resistance and cardiovascular diseases. This antipsychotic-induced inflammatory syndrome may participate in the inflammatory syndrome often observed in patients with schizophrenia. The strong and rather selective effect of olanzapine on TNFalpha expression may open new therapeutic opportunities for the prevention of olanzapine-induced metabolic abnormalities.