After many years of controversy, the overwhelming evidence shows that psychiatrists and general practitioners have been misprescribing antidepressants to treat minor and moderate symptoms of depression for patients for whom the drugs don’t work. Such patients comprise the vast majority for whom these drugs are prescribed-they are, thus placed at greater risk for harmful drug side effects without any offsetting beneficial effect.

The JAMA report is significant in that it is a patient-level meta-analysis of 6 major studies that included a full range of patients diagnosed with major or minor depressive disorder. The analysis examined the effects of the selective serotonin reuptake inhibiter (SSRI), paroxetine (Paxil), and the tricyclic antidepressant, imipramine (Tofranil), compared to an inert placebo. The findings are consistent with earlier antidepressant efficacy analyses (by Kirsch et al; Khan et al) confirming that antidepressant medications (ADM) are ineffective in treating all but low-prevalence "very severe" forms of depression, such as chronic dysthymia.

"What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving ADM in clinical practice present with scores below these levels."

(http://jama.ama-assn.org/cgi/content/full/303/1/47 ).

Depending on data source, between 1.6 percent (US Surgeon General) and 4.01 percent (NIMH) of the US population is estimated to suffer this very serious form of depression (http://www.wrongdiagnosis.com/d/dysthymia/prevalence.htm#about_prevalence_and_incidence). The latest report on the prevalence of depression by the Centers for Disease Control and Prevention estimates 1 in 20 or 5 percent had (2005-2006) had current depression at all levels of severity (mild, moderate, severe, very severe) (http://www.cdc.gov/nchs/data/databriefs/db07.htm).



If only 1.6 percent (US Surgeon General) of Americans have dysthymia and the total prevalence of current depression at all levels of severity is 5 percent, one can conclude that antidepressant medication (ADM) is (at best) more effective than placebo in treating people with very severe depression (32 percent). Noting several subtle differences in response patterns among earlier efficacy reports, the JAMA authors note:

"it would be premature to speculate regarding whether the increasing superiority of ADM relative to placebo as severity increases is due to an increasing efficacy of ADM or a declining efficacy of placebo."

For the remaining 68 percent of consumers of these drugs, ADM is no more effective than an inert placebo.

Given the frequency of adverse side-effects of varying degrees of severity-some life-threatening-logic tells that consumption of ADM poses far greater risk for doing harm without any offsetting beneficial effect among the overwhelming majority (68 percent) of people for whom they are prescribed.

The severe adverse effects of imipramine (Tofranil) include:

severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision or other vision changes; changes in sex drive; chest pain; confusion; constipation; fainting; fast, slow, or irregular heartbeat; fever; frequent or difficult urination; hallucinations; impulsive behavior or other unusual changes in behavior; jaw, neck, or muscle spasms; mental or mood changes (e.g., increased anxiety, mood swings, agitation, irritability, nervousness, restlessness); panic attacks; ringing in the ears; seizures; severe dizziness or drowsiness; sore throat; stomach pain; suicidal thinking or behavior; swelling of the testicles; tremor; trouble sleeping; trouble walking or keeping your balance; twitching of the face or tongue; uncontrolled movements of arms and legs or stiffness; unusual bleeding or bruising; worsening of depression; yellowing of the skin or eyes (http://www.drugs.com/sfx/imipramine-side-effects.html ).

The severe adverse effects of paroxetine (Paxil) include:

loss of appetite, unusual or severe mental/mood changes, increased sweating/flushing, unusual fatigue, uncontrolled movements (tremor), decreased interest in sex, changes in sexual ability, black stools, blurred vision, change in amount of urine, "coffee ground" vomit, easy bruising/bleeding, fainting, irregular heartbeat, muscle pain, trouble swallowing, unusual swelling, seizures, tingling or numbness of the hands/feet, obsessive suicidal thoughts, suicide attempts, violence, painful, prolonged erection, serious allergic reaction, e.g., rash, itching, swelling, severe dizziness, trouble breathing

(http://www.medicinenet.com/paroxetine-oral/article.htm )

VIOLENCE-directed at self or others–is a significant, life-threatening risk linked to SSRI antidepressants.

Manufacturers regularly coded aggression and violence occurring in clinical trials under the rubric of hostility. An analysis in PLoS Medicine , reveals that the coding term, hostility, includes homicide, homicidal acts, and homicidal ideation as well as aggressive events and "conduct disorders", although no homicides were reported from these trials. GlaxoSmithKline’s Website shows that when hostile events occurring in both adult and pediatric trials are summed, both on therapy and during the 30-day drug-free phase after taper had finished, 60 (0.65%) of 9,219 patients overall had hostile events.

A previously court sealed 2007 report by psychiatrist Joseph Glenmullen, MD, analyzing internal GSK documents-including memos and reports uncovered during litigation-leaves little doubt that the company had data from controlled clinical trials demonstrating an increased risk of suicide as early as 1989. Indeed, GSK’s data showed that the risk of suicidal behavior in adults increased eightfold in patients prescribed Paxil.

Dr. Glenmullen’s report is posted on the U.S. Senate Finance Committee



There are 3,500 news reports of violence, murder, suicide, self-mutilation involving SSRI antidepressants posted at: http://www.ssristories.com

Media reports about the recent JAMA report of results from the patient-level meta-analysis fail to indicate the clinical significance and true implications of the study, despite the authors’ forceful statement of implications for physicians, policy makers, and consumers:

"True drug effects (an advantage of ADM over placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms." NYT

Against the blitz of pharmaceutical company advertising and the self-interested arguments of prominent psychiatrists, the AHRP must ask what action will the FDA take to protect the public from dangerous drugs whose mostly illusory benefits are far outweighed by severe risks, thereby undermining public health? Independent analyses have consistently shown that antidepressants offer no clinical benefit for the vast majority of people for whom they are prescribed. Evidence from manufacturers own documents show that antidepressants pose severe risks of harm.

Why then, are federal drug regulators silent? Just as the Surgeon General of the United States forcefully warned against the dangers of smoking, federal drug regulators need to inform the American public about the dangers of antidepressant medications-especially because they are overwhelmingly misprescribed.

References:

1. Jay C. Fournier; Robert J. DeRubeis; Steven D. Hollon; et al.

Patient-Level Meta-analysis. JAMA. 2010;303(1):47-53

(doi:10.1001/jama.2009.1943)

http://jama.ama-assn.org/cgi/content/full/303/1/47

2. Irving Kirsch, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, Blair T. Johnson. Initial Severity and Antidepressant

Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med. 2008; 5(2):e45.

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050045

3. Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol. 2002; 22(1):40-45. http://www.ncbi.nlm.nih.gov/pubmed/11799341

4. Healy D, Herxheimer A, Menkes DB (2006) Antidepressants and Violence:

Problems at the Interface of Medicine and Law. PLoS Med 3(9): e372.

http://www.plosmedicine.org/article/info:doi%2F10.1371%2Fjournal.pmed.0030372

5. Joseph Glenmullen. Expert Report in the case of O’Neal v. SmithKline Beecham d/b/a GlaxoSmithKline. Filed under seal, Nov. 14, 2007. Unsealed January 18, 2008. http://finance.senate.gov/press/Gpress/2008/prg020608b.pdf

John H. Noble, Jr., PhD

AHRP Board member and Emeritus Professor, State University of New York at Buffalo.

jhnoble@verizon.net

Vera Hassner Sharav

AHRP President

veracare@ahrp.org

212-595-8974