SSRI INDUCED ALCOHOLISM, VIOLENCE AND BEHAVIOURS WITHIN THE CRIMINAL JUSTICE SYSTEM

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001875

https://www.ncbi.nlm.nih.gov/pubmed/16624467

Mirtazapine for patients with alcohol dependence and comorbid depressive disorders: a multicentre, open label study.

Yoon SJ1, Pae CU, Kim DJ, Namkoong K, Lee E, Oh DY, Lee YS, Shin DH, Jeong YC, Kim JH, Choi SB, Hwang IB, Shin YC, Cho SN, Lee HK, Lee CT.
Author information
Abstract
Major depressive disorder and alcohol dependence are common and serious mental illnesses. There is a great interest in discovering useful treatments for both mood symptoms and alcohol abuse in those patients with depressive disorders and comorbid alcohol dependence. The primary purpose of this study was to evaluate the effectiveness and tolerability of mirtazapine for the treatment of patients with alcohol dependence comorbid with a depressive disorder in an open label, naturalistic multicentre treatment setting. The 17-item Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS) and the Clinical Global Impression-Severity (CGI-S) scale were measured at baseline and at weeks 4 and 8 for the assessment of treatment effectiveness. Alcohol craving was measured using the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analog Scale for Craving (VAS). This study showed a statistically significant reduction of the scores on the HDRS (13.9+/-7.3, p<0.0001), HARS (10.8+/-7.2, p<0.0001) and the CGI-S (1.7+/-1.0, p<0.0001) from baseline to the endpoint (week . The OCDS and VAS scores were also decreased significantly by 42.3% and 53.2% (9.0+/-10.0, p<0.0001; 2.5+/-2.4, p<0.0001, respectively). The number of patients with a 50% reduction or more in the HDRS and HARS scores was 103 (72.0%) and 106 (74.1%) at the endpoint, respectively. Adverse events related to mirtazapine were observed in 10% or more of the patients in this study. In conclusion, the results from this naturalistic study suggest that the use of mirtazapine for the patients with alcohol dependence comorbid with depressive disorder is accompanied by clinical improvement in their mood and alcohol craving.

.https://www.ncbi.nlm.nih.gov/pubmed/21247998

Am J Psychiatry. 2011 Mar;168(3):265-75. doi: 10.1176/appi.ajp.2010.10050755. Epub 2011 Jan 19.
Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking.

Johnson BA1, Ait-Daoud N, Seneviratne C, Roache JD, Javors MA, Wang XQ, Liu L, Penberthy JK, DiClemente CC, Li MD.
Author information
Erratum in
Am J Psychiatry. 2011 Jul;168(7):756.
Abstract
OBJECTIVE:
Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT(3) receptor antagonist, ondansetron.
METHOD:
The authors randomized 283 alcoholics by genotype in the 5'-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3'-untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy.
RESULTS:
Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5'-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined.
CONCLUSIONS:
The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics.
Comment in
Betting on biomarkers. [Am J Psychiatry. 2011]
PMID: 21247998 PMCID: PMC3063997 DOI: 10.1176/appi.ajp.2010.10050755
[Indexed for MEDLINE] Free PMC Article
Share on FacebookShare on TwitterShare on Google+
Images from this publication.See all images (3)Free text
Figure 1Figure 2Figure 3
Publication types, MeSH terms, Substances, Grant support

https://pdfs.semanticscholar.org/d99c/5c3ffba5c0a3ef5a34b2a0a520e201d750ee.pdf

https://www.ncbi.nlm.nih.gov/pubmed/15252293

Format: AbstractSend to
Alcohol Clin Exp Res. 2004 Jul;28(7):1065-73.
Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy.

Dundon W1, Lynch KG, Pettinati HM, Lipkin C.
Author information
Abstract
BACKGROUND:
Evidence supporting the use of serotonergic medications for the treatment of alcohol dependence is available from studies where pharmacotherapy targeted specific alcoholic subtypes. We previously established with Babor's alcohol typology that type A "lower risk/severity" alcoholics (n = 55) had better treatment response to 14 weeks of sertraline (200 mg/day) than placebo, and this was not found for type B "higher risk/severity" alcoholics (n = 45). The purpose of this study was to assess in this original study group whether treatment gains in the type A alcoholics were maintained or whether treatment outcomes changed for the type B alcoholics after discontinuing pharmacotherapy.
METHODS:
After the end of a 3-month course of 200 mg/day sertraline, the subjects were interviewed at several time points about their alcohol drinking, if any, using the timeline follow-back method. For 90% of the original study group, mixed effects and generalized estimating equation models were used to compare monthly drinking amounts over a 6-month posttreatment period with drinking amounts in the last month of treatment.
RESULTS:
We found that type A alcoholics who had been treated with sertraline, in contrast to placebo, maintained the good outcomes they had achieved during treatment for at least 6 months after pharmacotherapy. We found that type B alcoholics who had been treated with sertraline, in contrast to placebo, continued to show no advantage for pharmacotherapy in the 6 months after completing treatment. In addition, heavy drinking in type B alcoholics increased over the 6 months postpharmacotherapy in those initially treated with sertraline compared with placebo.
CONCLUSIONS:
These data support the importance of considering alcohol subtype when pharmacologically treating alcohol dependence.
PMID: 15252293 PMCID: PMC1435448
[Indexed for MEDLINE] Free PMC Article
Share on FacebookShare on TwitterShare on Google+
Images from this publication.See all images (3)Free text
Figure 1Figure 2Figure 3
Publication types, MeSH terms, Substances, Grant support

http://survivingantidepressants.org/

http://www.unlock.org.uk/

http://www.pharmaceutical-journal.com/news-and-analysis/drinking-alcohol-during-antidepressant-treatment-a-cause-for-concern/11091677.article

Drinking alcohol during antidepressant treatment — a cause for concern?
The Pharmaceutical Journal20 DEC 2011
Emerging evidence suggests a risk of pathological intoxication when patients taking SSRIs consume alcohol. Andrew Herxheimer and David B. Menkes investigate

By Andrew Herxheimer and David B. Menkes

Emerging evidence suggests a risk of pathological intoxication when patients taking SSRIs consume alcohol. Andrew Herxheimer and David B. Menkes investigate

Preclinical studies of interactions between selective serotonin reuptake inhibitors (SSRIs) and alcohol have mainly been acute experiments in healthy volunteers, using various psychological performance tests. The combination generally fails to impair function or produce other effects beyond those of alcohol alone.1,2 Alcohol use is common in depression,3 but its interaction with antidepressants in patients has been little studied except in problem drinkers. In a subgroup of these, alcohol problems seem to become worse.4,5

In our practices, we have repeatedly noted that some people experience a marked change in alcohol tolerance during treatment with SSRIs and related drugs. The consequences include disinhibition of violence or sexual behaviour, sometimes with profoundly impaired memory of the event.6,7 The same pattern appears across various SSRIs and venlafaxine, and in case reports from different countries,8 but clinicians do not routinely recognise or consider it. The mechanism is not clear, but the disinhibition from alcohol together with the stimulant effect of most SSRI and related antidepressants might lead to effects not seen with either alone. With this problem in mind, we examine the warnings for patients and prescribers in company information about prescribed SSRIs and related drugs.

Pathological intoxication

Pathological intoxication in a given individual refers to usual amounts of alcohol producing either a markedly exaggerated intoxication or qualitatively different intoxication, for example, with highly uncharacteristic disinhibition or violence

Our research

For venlafaxine, mirtazapine, bupropion, duloxetine and each of the SSRIs marketed in the UK, we examined the current summary of product characteristics (SPC) and patient information leaflet (PIL) and extracted all statements about interactions with alcohol, including warnings. We had in 2006–07 asked the UK medical directors of the main companies concerned for any information they had about possible interactions of their drug with alcohol, including experimental studies in volunteers, clinical studies, and case reports of suspected interactions.

Table 1 (PDF) presents the SPC and PIL information. Almost all leaflets for clinicians and for patients stated in some way that alcohol should be avoided (SSRIs and venlafaxine) or used with caution (duloxetine). Most gave no specific reason for the advice. Some made the point generally. For example, the SPC for fluvoxamine states: “As with other psychotropic drugs patients should be advised to avoid alcohol.” But the corresponding PIL is more explicit: “Alcohol may interact and make you feel sleepy and unsteady.” Similarly, GSK’s PIL warned that alcohol use with paroxetine “may make symptoms or side effects worse”. Five of six UK companies marketing branded products (GSK, Lilly, Lundbeck, Pfizer and Wyeth) cited experimental data indicating that their drug(s) did not enhance the effects of alcohol, but still advised against the use of alcohol without explaining why.

Responses from companies to our further request for data on alcohol interactions varied greatly (Table 2, PDF). Some came from a medical director or adviser, others from a pharmacovigilance executive. All were polite, but none had shown interest. Most sent a summary of one or more experimental studies in healthy volunteers, showing that acute doses of their drug and alcohol taken together had caused no greater mental or motor impairment than did alcohol alone. Several sent reports or summaries of published or unpublished clinical trials in alcoholics, testing whether their drug reduced alcohol intake or prevented relapse. None had found a positive benefit.

One company (GSK) sent an extensive literature search, but this was unfiltered and included many animal studies of doubtful relevance. No company sent a specific case report; most referred only to the number of cases in the Medicines and Healthcare products Regulatory Agency Yellow Card register. One claimed that the text of the reports was confidential. None of the international companies referred to cases reported outside the UK.

To drink or not to drink?

We found a general consistency across SPCs and PILs produced by makers of SSRIs and related antidepressants. Almost all discouraged alcohol use and, in something of a mixed message, cited evidence from healthy volunteer studies that their drug did not appear to interact with alcohol.

The warnings to avoid alcohol are thus unsupported by specific evidence. They appear weak and unconvincing for both prescribers and patients. This may explain why many patients do not take the warning seriously.
We have described a syndrome of pathological intoxication, often with serious consequences, in patients prescribed an SSRI or related drug.6–8

It is striking that often only modest or usual amounts of alcohol are involved, and that memory is impaired in roughly half of such cases. The problem is not  rare, but it is often not recognised. That may relate both to the well known under-reporting of adverse events, and the possibility that regulators have not routinely considered such effects by drug class. For example, the MHRA online database includes 129 reports categorised as “interaction with alcohol” of SSRI and related drugs, but these are not considered as a group. The reports are aggregated by individual drug name and relationships between drugs are not visible.9

SPCs and PILs need to be strengthened to warn prescribers and patients clearly about the possibility of pathological alcohol intoxication during treatment with SSRIs and related drugs. This should improve prescribing choices and facilitate detection and study of the problem.

References

1 Allen D, Lader M. Interactions of alcohol with amitriptyline, fluoxetine and placebo in normal subjects. International Clinical Psychopharmacology 1989;4(Suppl 1):7–14.
2 Schaffler K. Study on performance and alcohol interaction with the antidepressant fluoxetine. International Clinical Psychopharmacology 1989;4(Suppl 1):15–20.
3 Davis LL, Rush JA, Wisniewski SR, Rice K, Cassano P, Jewell ME et al. Substance use disorder comorbidity in major depressive disorder: an exploratory analysis of the Sequenced Treatment Alternatives to Relieve Depression cohort. Comprehensive Psychiatry 2005;46:81–9.
4 Chick J, Aschauer H, Hornik K. Efficacy of fluvoxamine in preventing relapse in alcohol dependence: a one-year, double-blind, placebo-controlled multicentre study with analysis by typology. Drug and Alcohol Dependence 2004;74:61–70.
5 Lingford-Hughes AR, Welch S, Nutt DJ. Evidence-based guidelines for the pharmacological management of substance misuse, addiction and comorbidity: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 2004;18:293–335.
6 Chandler P, Herxheimer A. Unexpected aggressive behaviour: interaction of bupropion and alcohol. International Journal of Risk and Safety in Medicine 2011;23:133–7.
7 Herxheimer A. British diplomat cleared of drunk flying charges: paroxetine was involved. International Journal of Risk and Safety in Medicine 2007;19:35–40.
8 Menkes DB, Herxheimer A. Provocation by alcohol of violence as a side-effect of antidepressants. Drug Safety 2009;32:948–9.
9 Download Drug Analysis Prints (DAPs). London: Medicines and Healthcare products Regulatory Agency (MHRA); 2011. Available at: www.mhra.gov.uk (accessed 30 November 2011).


Andrew Herxheimer is emeritus fellow, UK Cochrane Centre, and co-convenor, Cochrane Adverse Effects Methods Group. David B. Menkes is consultant psychiatrist and associate professor of psychiatry at Waikato Clinical School, University of Auckland, New Zealand (email david.menkes@waikatodhb.health.nz)

Citation: The Pharmaceutical Journal, Vol. 287, p732 | URI: 11091677