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Long-Term Treatment With Antidepressant Drugs Can Worsen the Course of Depression

April 5th, 2012

Gary G. Kohls, MD

Very unfavorable long-term outcomes often occur in patients with major depression treated by pharmacologic means, including: paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances; antidepressant-induced switching and cycle acceleration in bipolar disorder; development of tolerance to the effects of antidepressants during long-term treatment; onset of resistance upon re-challenge with the same antidepressant drug; and withdrawal syndromes following discontinuation.

Major depression has been ranked as the fourth most disabling medical disorder by disability-adjusted life-years, a measure of burden. By 2010 major depression is predicted to be ranked second unless meaningful improvements occur in prevention, diagnosis, and treatment.

The poor outcome among depression patients may reflect the inadequate treatment that patients tend to receive in general practice, in terms of dose or length of treatment, their poor compliance and the complications of medical co-morbidity, including drug-induced worsening.

Antidepressant drugs may be depressogenic in some cases, similar to the reality that early treatment of Parkinson’s disease with levodopa may worsen its progression, or inhaled bronchodilators may worsen the long-term course of asthma.

Long-term use of antidepressant drugs may increase biochemical vulnerability to depression and worsen the long-term outcome and symptomatic expression of the illness, decreasing both the likelihood of subsequent response to pharmacologic treatment and the duration of symptom-free periods.

The findings of this article call for a more cautious attitude among clinicians in prescribing antidepressant drugs, because these drugs may worsen the course of depression.

Whether one treats a depressed patient for 3 months or 3 years, it does not matter when one stops the drugs. A statistical trend suggested that the longer the drug treatment, the higher the likelihood of relapse.

Systematic treatment with tricyclic antidepressants has proved to be associated with an increase in the total number of recurrences.

In a recently randomized, double-blind crossover study comparing the effects of Remeron and Zoloft in 20 healthy, non-depressed volunteers, 2 subjects reported becoming depressed and 2 others reported becoming suicidal, a dramatic incidence of 20% serious depression, obviously caused by the drugs.

Another trial for panic disorder comparing an antidepressant, (imipramine) cognitive-behavioral therapy (CBT) or a combination of the two modalities resulted in much higher 6 month response rates with the CBT plus placebo (41%) than CBT plus drug (26%).

The occurrence of mania in depressed patients upon treatment with antidepressant drugs is a relatively old clinical observation, even with the use of “mood stabilizers.” Antidepressants may double the incidence of a switch into mania (50% in some cases) compared with placebo (25% of cases).

Antidepressant-induced mania is not simply a temporary and reversible phenomenon, but a complex biochemical mechanism of illness deterioration.

The return of depressive symptoms during maintenance antidepressant treatment was found to occur in 9% to 57% of patients in published trials. Possibilities include pharmacologic tolerance, loss of placebo effect, increase in disease severity, change in disease pathogenesis, accumulation of a detrimental metabolite, unrecognized drug-induced mania and prophylactic inefficacy.

Discontinuation of antidepressant drugs may trigger hypomania or mania despite adequate concomitant mood-stabilizing treatment. Mood elevation may also occur by decreasing the antidepressant dose.

Processes that change the number or properties of drug-sensitive receptor populations, have very limited explanatory power in terms of the clinical phenomena previously described.

A therapeutic action of antidepressant drugs (e.g., “down-regulation” {a pharmaceutical industry euphemism for decreased sensitivity or actual disappearance of synaptic organelles or neurotransmitters - Ed} of postsynaptic 5-HT2 receptors) may, under certain conditions, trigger changes in post-receptor signal transduction, in intraneuronal signaling pathways, or in neuronal architecture that are likely to affect the balance of serotonin receptors.

Impairment in neurogenesis may be the key pathophysiologic event in depression.

Antidepressant drugs may yield changes in connections or sensitivity to neurotransmitters indirectly related to the specific actions.

Both sensitization to stressors and episode sensitization may occur in mood disorders and become encoded at the level of gene expression. Stressors and the biochemical concomitants of the episode can themselves induce the proto-oncogene c-fos and related trancription factors, which then affect the expression of neurotransmitters, receptors, and neuropeptides that alter responsiveness in a long-lasting way.

The use of antidepressant drugs is so prevalent that it is difficult to recruit clinical populations who have never been exposed to them!

CBT appears to reduce the risk of depressive relapse and may have a more durable effect than pharmacotherapy alone.

Researchers thus should demonstrate that the combination of psychotherapy and pharmacotherapy is inferior in terms of relapse prevention to psychotherapy alone.

Patients with past antidepressant treatment had more episodes of depression and a longer duration of illness.

We strongly suspect that many patients who are simply unhappy receive these drugs, with predictable consequences in terms of morbidity from side effects, mortality from overdose, economic waste, and irrational, unproductive clinical management.

A treatment that is helpful on average may be harmful for some patients, as shown by a re-analysis of the Beta-Blocker Heart Attack Trial.

Certainly, researchers working along these lines are likely to encounter tremendous difficulties in disclosing their results in journals and symposia or in getting their studies started and funded, in view of the current ideological and pharmaceutically driven climate.

We should be aware that we are stretching the original indications (major depressive episodes) of drugs of modest efficacy to include prevention of relapse, anxiety disorders and demoralization. Antidepressant drugs may speed improvement and change the boundary between “responders” and “non-responders.” However, when we prolong treatment to more than 6 to 9 months, we may recruit different phenomena, such as tolerance, episode acceleration, and paradoxical effects (not to mention prescription drug addictions! - Ed).


Preventive Psychiatry E-Newsletter # 56

Excerpts and Paraphrasing (by Gary G. Kohls, MD) from an article by Giovanni A. Fava, MD, in the Journal of Clinical Psychiatry 64:2, February 2003 page 123ff

The mission of the Preventive Psychiatry E-Newsletter (PPEN) is to disseminate important information relating to issues of mental wellness, especially that which pertains to the many root causes of mental ill health (and therefore reveals potential strategies that can lead to the prevention of what are commonly mis-labeled "mental illnesses"). The information in PPENs is usually not readily available in the mainstream psychiatric and medical industry's professional journals. Most of the items passed on are derived from other sources, which PPEN believes to be accurate, but cannot guarantee. The editor of the PPEN (Gary G. Kohls, MD, Duluth, MN) does not accept responsibility for any errors or omissions. PPEN strives to provide references so that the reader can independently evaluate the validity of the information.

Mental health-related essays: http://www.ihealthtube.com/aspx/search.aspx?sp=GARY+G.+KOHLS&displayType=articles
Mental health-related videointerviews of Dr. Kohls available
and http://www.youtube.com/results?search_query=gary+kohls&aq=f

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