Anti-depressants may not work as well as we think & result in adverse drug interactions.

This is from our friends at LexiComp.

Two reports on antidepressants: They are the top drug group for drug-related hospital admissions; they have questionable efficacy against mild to moderate forms of mental depression.

Antidepressants are some of the most widely prescribed drugs in the world. Two reports concerning the use of these drugs are the subject of this month’s article. First, they are reported to be the top drug group involved in adverse drug reaction-related hospital admissions; secondly, they have questionable efficacy against mild to moderate forms of mental depression.

Antidepressants showed the highest probability of adverse drug reaction-related hospitalization out of all drug groups, so says a report from investigators at the University of Medicine and Dentistry of New Jersey. The researchers studied the likelihood of hospitalization caused by adverse drug reactions (ADRs) from commonly implicated therapeutic groups. The method involved an analysis of records of exposure cases involving drugs reported to the New Jersey Poison Information and Education System (NJPIES), reported through the National Poisoning Data System (NPDS) and conducted from year 2000 to year 2007. Reports of ADRs with the most frequently implicated therapeutic groups were analyzed based on whether the patients were managed onsite, referred to a health care facility, or managed at a health care facility. The investigators then established an Adverse Drug Reaction Hospitalization (ADRH) index and calculated the index for all therapeutic drug groups.

Only reports involving a single drug were selected for inclusion in the analysis. The ADRH index was calculated from the ratio of the number of ADRs in patients admitted to a health care facility divided by the total number of reported ADRs within the same therapeutic drug group.

Results

A total of 454,520 cases of human poisoning exposure were reported to NJPIES from 2000 to 2007. Of these cases, 162,105 were exposures implicating a single drug, of which 5,461 were classified as an ADR based on the definition from the NPDS. Among all the therapeutic groups of drugs implicated in 5% or more of all ADRs, the antidepressant family of drugs represented the therapeutic group with the highest hospitalization index of 20.4%. This top group was followed by dietary supplements, herbals, and homeopathics (9.8%), followed by sedatives, hypnotics, and antipsychotics at 8.1%. Analgesics and cough preparations had essentially the same ADRH index among the remaining groups, while antimicrobials had the lowest at 2.2%.

In their discussion of the study, the authors stated that the antidepressant group of drugs had the highest probability for an ADR-related hospital admission. Analgesics and antimicrobials were most commonly implicated in ADRs, but were not tops in hospital admissions due to those ADRs. The study, in the authors’ opinion, provides essential information about the likelihood of therapeutic group-specific ADRs resulting in hospital admission with the antidepressants leading the list. The reference to the study is Vassilev ZP, Chu AF, Ruck B, et al “Evaluation of Adverse Drug Reactions Reported to a Poison Control Center Between 2000 and 2007,Am J Health Syst Pharm, 2009, 66(5):481-7.

The second report described here questions the efficacy of antidepressant medications against mild to moderate forms of mental depression.

The Hamilton Depression Rating Scale (HDRS) is used to measure the severity of mental depression. A description of the HDRS can be found below. The American Psychiatric Association’s Handbook of Psychiatric Measures defines mild depression as HDRS scores from 8-13, moderate depression from 14-18, severe depression from 19-22, and very severe depression as >23. Many depressed individuals start antidepressant medication having a score well below 20. This study, reported in the Journal of the American Medical Association (JAMA) in January 2010, was done to estimate the benefit of antidepressant medication compared to placebos in patients having baseline HRDS scores ranging from mild to very severe depression. There is little evidence that the medications have a specific pharmacological effect relative to a placebo for patients with less severe baseline depression.

Methods

This was a retrospective study which searched the literature using three databases, including the National Library of Medicine’s PubMed from January 1980 through March 2009. Randomized placebo-controlled trials of antidepressants approved by the FDA in the treatment of major or minor depressive disorders were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication versus placebo comparison for at least 6 weeks, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies encompassing 718 patients were included. The mean change in depression symptoms with treatment for at least 6 weeks was the end-point measure. Three of the studies used the antidepressant, imipramine, and three used paroxetine. Imipramine (Tofranil®) is one of the original tricyclic antidepressant medications that increase the synaptic concentrations of norepinephrine and serotonin. Paroxetine, also known as Paxil CR® is a selective serotonin reuptake inhibitor.

Results

Medication versus placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, the differences in improvement of mood appeared to be very small, and perhaps insignificant, between medication and dummy pill. Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined for clinically significant difference between the two treatments at a baseline depression score of 25. The magnitude of difference between the two treatments was very apparent at baseline scores from 28 to 40, with the medication groups showing much greater levels of improvement compared to the placebo groups. Both the imipramine medication group and the paroxetine medication group showed the same increases over placebo groups as the baseline depression scale increased.

Discussion of the Results

Efficacy of antidepressant medication (ADM) treatment for depression varied considerably as a function of baseline symptom severity. This study defined “true drug effects” as an apparent advantage of ADM over placebo. A true drug effect was nonexistent or negligible among the depressed patients with mild, moderate, and severe baseline symptoms. However, a true drug effect appeared to be very evident in patients with very severe baseline symptoms of depression.

For baseline severity scores on the HDRS of <25, estimates of the magnitude of drug/placebo differences did not meet a threshold for clinical significance proposed by the National Institute for Clinical Excellence (NICE) of the National Health Service in England. They define a threshold of clinical significance as an effect size of 0.50, or a drug/placebo difference of 3 points on the Hamilton Depression Rating Scale (HDRS). For patients with the highest levels of baseline depression severity, ADM treatment was markedly superior to placebo.

Study authors went on to comment that several studies have demonstrated that ADM is consistently superior to placebo for patients diagnosed with a form of mental depression known as dysthymia. Dysthymia is a chronic low grade depression that occurs on most days and lasts for 2 years or longer. The studies indicated that ADM can produce a true drug effect in patients with mild to moderate depressive symptoms. But dysthymia is, by definition, a chronic condition and that chronicity is known to be associated with a poor response to placebo.

Early studies in the 1950s have shown that researchers conducting controlled investigations of treatments for a wide variety of psychiatric conditions described a phenomenon whereby patients with higher levels of severity showed greater differential benefit from active treatments compared to placebo. The recent JAMA study was the first to show the very high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge. This is an important finding because the majority of patients receiving ADM in clinical practice present with scores way below these levels.

Efficacy of medications is usually established from studies that have included only those individuals with more severe forms of depression. The authors of the JAMA study editorialized that messages in marketing of drugs to clinicians and the consumer omit information on drug effects, or lack of, in the less severe forms of depression. There is little mention of the fact that efficacy data often come from studies that exclude these major depressive disorder patients who derive little pharmacological benefit from taking medications.

In summary, this study showed that antidepressant medication can have substantial effect with more severe depressions, and there is little evidence to suggest that these drugs produce specific pharmacological benefit for the majority of patients with less severe depression. Reference for the abstract is Fournier JC, DeRubeis RJ, Hollon SD, et al, “Antidepressant Drug Effects and Depression Severity. A Patient-Level Meta-analysis,JAMA, 2010, 303(1):47-53.

Hamilton Depression Rating Scale

The Hamilton Depression Rating Scale (HRSD) is a multiple choice questionnaire that physicians may use to rate the severity of a patient’s major mental depression. This rating scale has been used since 1960 and modified slightly over the ensuing years. It was originally considered the “Gold Standard” of methods to rate the severity of mental depression.

The questionnaire rates the severity of symptoms observed in depression such as low mood, insomnia, agitation, anxiety, and weight loss. The questionnaire is presently one of the most commonly used scales for rating depression in medical research.

The physician must choose the possible responses to each question by interviewing the patient and by observing the patient’s symptoms. Each question has between 3-5 possible responses which increase in severity. In the original scale established in 1960, the first 17 questions contribute to the total score (HRSD-17). Questions 18-21 are recorded to give further information about the depression (such as whether diurnal variation or paranoid symptoms are present), but are not part of the scale. The original 17-question scale is also known as HDRS-17.

Popularity of Antidepressant Drugs

Seven antidepressant drugs are within the top 50 most widely prescribed drugs in the US. These include, in rank order, (1) sertraline (Zoloft®), (2) escitalopram (Lexapro®), (3) fluvoxetine (Prozac®), (4) citalopram (Cymbalta®), (5) venlafaxine (Effexor ER®), (6) trazodone (Desyrel®), and (7) paroxetine (Paxil CR®). Collectively,these seven agents accounted for over 150 million written prescriptions by health care providers in 2008 according to SDI/Verispan, VONA at http://drugtopics.modernmedicine.com/top200gen and at http://formularyjournal.modernmedicine.com/formulary/data/articlestandard//formulary/202009/598275/article.pdf.