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Tuesday, November 18, 2008

No Difference in Psych Drugs for Depression

SSRI group of anti-depressant pharmaceuticals have been problematic ever since Prozac was introduced some decades ago. The list of side effects and untoward behavior related to fluoride containing drugs also creates other concerns.

If it all boils down to looking at the issues of side effects, cost and response then I would suggest that better evaluation of the person's state of general health, especially endocrine health, and nutritional status be addressed before prescribing any of these drugs.

For example, I learned that a friend was taking Chantix in an effort to stop smoking. My knowledge of this person's situation is that he was smoking to cover up a deep seated emotionally painful life event.

After he started on Chantix, and while he was taking endocrine system altering drugs for prostate cancer, he became depressed.

He was just written an Rx for Lexapro, however, no effort was taken to evaluate his history and symptoms or look at drug side effects and related issues.

I can't quite get the current ethic to overlook this basic health care function, but perhaps it is why I gave up on my work in mainstream medicine 15 years ago after I was attacked by a young girl taking Zoloft, and seriously injured.
Internist Group Finds No Efficacy Difference Among Modern Antidepressants
By John Gever, Senior Editor, MedPage Today
Published: November 17, 2008

Practice Guidelines

PHILADELPHIA, Nov. 17 -- Second-generation antidepressants all have similar efficacy, so physicians should base their medication choices for depressed patients on side effects, cost, and patient response, according to a new practice guideline from the American College of Physicians.

Clinicians should also begin monitoring patients for adverse effects and clinical response within one to two weeks of starting antidepressant therapy, recommended Amir Qaseem, M.D., Ph.D., M.H.A., of the American College of Physicians, and the other authors of the guideline, published in the Nov. 18 issue of Annals of Internal Medicine.

"The current evidence did not show any clinically significant differences between efficacy, effectiveness, or quality of life between various second-generation antidepressants," said Dr. Qaseem.
Action Points

* Explain to interested patients that a treatment guideline from the American College of Physicians recommends that second-generation antidepressant choices be made on the basis of side effects, cost, and patient preference, since efficacy of these drugs is equivalent.

* Explain that individual patient factors should always guide treatment decisions.

* Note that the guidelines do not address use of older medications that are still available and may be appropriate for some patients.

The findings do not differ markedly from the American Psychiatric Association's current practice guideline on major depressive disorder, last updated in 2005.

"The effectiveness of antidepressant medications is generally comparable between classes and within classes of medications," according to the APA guideline. "Therefore, the initial selection of an antidepressant medication will largely be based on the anticipated side effects, the safety or tolerability of these side effects for individual patients, patient preference, quantity and quality of clinical trial data regarding the medication, and its cost."

The ACP's recommendations were based on a review of more than 200 published studies of a dozen antidepressants, conducted by a separate group of researchers led by Gerald Gartlehner, M.D., of Danube University in Krems, Austria.

Drugs covered in the review included:

* Fluoxetine (Prozac)
* Sertraline (Zoloft)
* Paroxetine (Paxil)
* Bupropion (Wellbutrin)
* Citolapram (Celexa)
* Escitolapram (Lexapro)
* Duloxetine (Cymbalta)
* Fluvoxamine (Luvox)
* Mirtazapine (Remeron)
* Trazodone (Desyrel)
* Nefazodone (Serzone)
* Venlafaxine (Effexor)

The guideline also calls for physicians to modify treatment if patients fail to respond adequately within six to eight weeks.

Drugs that show adequate symptom relief should be maintained for four to nine months after a major depressive episode, or longer in the case of recurrent episodes.

The review and guidelines do not address more traditional medications such as tricyclic antidepressants and monoamine oxidase inhibitors.

Dr. Qaseem and colleagues said these agents are no longer in common use because newer drugs have similar effectiveness with less toxicity.

Among the newer drugs, the review disclosed no efficacy differences among patient subgroups defined by age, sex, race-ethnicity, or comorbid conditions.

A few studies identified certain agents as better than others in patients with other neuropsychiatric symptoms besides depression, such as insomnia or anxiety. But these studies were mostly not of the highest quality, and others found little or no difference.

Those findings stand in contrast to the APA's depression guideline, which suggests that some subgroups may benefit more than others from particular agents, although with no specifics.

The ACP review found relatively few clear differences between second-generation drugs in side effects.

"Most of the second-generation antidepressants had similar adverse events, with some differences in the incidence of specific adverse events," according to the guideline authors.

Nausea and vomiting were more common with venlafaxine than with other agents, they noted, whereas sertraline appeared especially prone to cause diarrhea.

Weight gain was more frequent with mirtazapine and paroxetine, and drowsiness was relatively common with trazodone compared with several other drugs.

Sexual adverse effects were another area where drugs have different profiles.

For example, bupropion was less likely to have sexual adverse effects than fluoxetine and sertraline, whereas paroxetine had relatively high rates.

The ACP review found little difference between agents in suicidality, although non-fatal suicide attempts appeared to be more common with SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine) than with other drug classes.

Few data were available on other severe adverse effects such as seizures, cardiovascular problems, liver toxicity, hyponatremia, or serotonergic abnormalities, the researchers said.

The guideline graded the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system.

All four recommendations were considered to be strong with moderate quality evidence.

The American College of Physicians funded the review underlying the recommendations.

Authors of the guideline reported relationships with Atlantic Philanthropies, Novo Nordisk, Boehringer Ingelheim, Sanofi Pasteur, and Endo.

Authors of the literature review reported relationships with GlaxoSmithKline, Pfizer, Wyeth-Ayerst, Shire Pharmaceutical, Phillips Lytle, Bristol-Myers Squibb, Novartis, Robert Wood Johnson Foundation, and M-3 Corporation.

Primary source: Annals of Internal Medicine
Source reference: Qaseem A, et al "Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians" Ann Intern Med 2008; 149: 725-33.

Additional source: Annals of Internal Medicine
Source reference: Gartlehner G, et al "Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians" Ann Intern Med 2008; 149: 734-50.

And as an additional consideration, it has been suggested that more than 85% of physicians are unaware that Serotonin Syndrome even exists.
How Common or Significant Is Serotonin Syndrome?

Joel Lamoure, RPh, BSP, FASCP
Medscape Pharmacists. 11/10/2008 ©2008 Medscape

We are seeing more patients who are taking multiple antidepressants of different classes. All drug interaction programs cite drug-drug interactions leading to the potentially severe toxicity known as serotonin syndrome. Just how common and clinically significant is serotonin syndrome?

Response from Joel Lamoure, RPh, BSP, FASCP
Assistant Professor, Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Mental Health Pharmacist, London Health Sciences Centre, London, Ontario, Canada

The Toxic Exposure Surveillance System reviewed cases from office-based practices, inpatient settings, and emergency departments and found that during 2004, selective serotonin reuptake inhibitors (SSRIs) caused significant toxic effects in 8187 persons, leading to 103 deaths.[1] The true incidence of serotonin syndrome and associated morbidity are likely to be much greater. This syndrome may be underdiagnosed given the fact that SSRIs are not the only contributing class of agents. Moreover, it has been suggested that more than 85% of physicians are unaware that the syndrome even exists.[2]

Serotonin syndrome is a condition caused most often by the concurrent use of 2 or more agents that enhance synaptic serotonin levels.[3] A triad of clinical changes -- cognitive, neuromuscular, and autonomic -- characterizes this syndrome. Specific changes may include confusion, delirium, agitation, restlessness, muscular spasms, hyperpyrexia, diaphoresis, tachycardia, blood pressure fluctuations, mydriasis, nausea, or diarrhea.[4,5] Symptoms often develop within 2 hours of the increase in the synaptic level of serotonin.[6] The clinician must be proactive to identify the early symptoms, such as cognitive changes, when they occur.

Confusion about symptoms may be responsible for the difficulty in assessing the actual incidence of serotonin syndrome.[2] Agitation, a cardinal symptom of serotonin syndrome, is clinically similar to activation, an adverse effect associated with SSRI use.[7]

Polypharmacy is pandemic, and the incidence of serotonin syndrome may be on the rise. Both drug factors and patient factors can contribute to the toxicity of SSRIs in some individuals. A wide range of medications can increase serotonin levels in the body. When these agents are combined, the risk of serotonin syndrome increases. Drug classes implicated include anti-migraine agents (eg, triptans); antidepressants (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors, buspirone, tricyclic antidepressants, monoamine oxidase inhibitors); antipsychotics; anticonvulsants; anti-Parkinsonian agents; analgesics (eg, meperidine, tramadol); over-the-counter products (eg, medications containing dextromethorphan); herbal products (eg, St. John's Wort); and antibiotics (eg, linezolid).[6,8-14]

Concurrent use of medications that interact with serotonergic drugs through the inhibition of the cytochrome P450 pathway can also contribute to serotonin syndrome.[15] For example, extra caution should be observed if a patient is taking an SSRI in addition to a cytochrome P450 2D6 (CYP2D6) inhibitor because SSRIs are extensively hepatically metabolized by this isozyme.

Susceptibility to the serotonin syndrome can also be conferred by patient factors, such as the capacity to metabolize certain drugs. One of the key enzymes related to adverse drug reactions, the CYP2D6 system, has a high degree of genetic polymorphism.[16] An example of this was reported in a study of 4 elderly patients who ostensibly developed serotonin syndrome as a result of an interaction between tramadol and mirtazapine.[17] The patients had auditory and visual hallucinations, myoclonus, hypertension, and changes in behavior. Tramadol may be subject to genetic polymorphism; about 7% of whites are poor metabolizers of CYP2D6.[18,19] Consequently, these patients would have higher serum levels of tramadol and be at increased risk for serotonin syndrome when a second serotonergic agent is added.[18]

Although rare in monotherapy, serotonin syndrome is more prevalent with polypharmacy, even across medication classes. When a computer flags this interaction, the clinician should consider the whole patient: What medications has the patient taken previously? What adverse reactions have previously been experienced? When making an evidence-based recommendation, it is essential to apply the therapeutic thought process and carry out a sound risk-benefit assessment. Awareness of serotonin syndrome and education about its effects are vital. All of these factors must be considered, lest all the "holes in the Swiss cheese line up" and the patient comes to harm.[20]

The author acknowledges Jessica Stovel, pharmacist, and Katherine Bateman, pharmacy resident at London Health Sciences Centre, for their research and contributions to this article.

Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2005;23:589-666. Abstract
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120. Abstract
Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med. 2003;96:635-642.
Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol. 1997;17:208-221. Abstract
Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-285. Abstract
Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109:325-338. Abstract
Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. (letter) J Am Acad Child Adolesc Psychiatry. 2001; 40:1364-1365.
Mills K. Serotonin syndrome. A clinical update. Crit Care Clin. 1997;13:763-783. Abstract
Mitchell, PB. Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Sa.f 1997;17:390-406.
Egberts AC, ter Borgh J, Brodie-Meijer CC. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol. 1997;12:181-182. Abstract
Manos G. Possible serotonin syndrome associated with buspirone added to fluoxetine. Ann Pharmacother. 2000;34: 871-874. Abstract
Sclar DA , Robison LM , Skaer TL. Concomitant triptan and SSRI or SNRI use: a risk for serotonin syndrome. Headache. 2008;48:126-129. Abstract
Lavery S, Ravi H, McDaniel WW, Pushkin YR. Linezolid and serotonin syndrome. Psychosomatics. 2001;42:432-434. Abstract
Gardner DM, Lynd LD. Sumatriptan contraindications and the serotonin syndrome. Ann Pharmacother. 1998;32:33-38. Abstract
Looper KJ. Potential medical and surgical complications of serotonergic antidepressant medications. Psychosomatics. 2007;48:1-19. Abstract
Ingelman-Sundberg M, Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5: 6–13.
Gnanadesigan N, Espinoza RT, Smith R, Israel M, Reuben DB. Interaction of serotonergic antidepressants and opiod analgesics: Is serotonin syndrome going undetected? J Am Med Dir Assoc. 2005;6:265-269.
Gan SH, Ismail R, Wan Adnan WA, Wan Z. Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects. J Pharm Biomed Anal. 2002;30:189-195. Abstract
Enggaard TP, Poulsen L, Arendt-Nielsen L, Brosen K, Ossig J, Sindrup SH. The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg. 2006;102:146-150. Abstract
Reason J. Human error: models and management. BMJ. 2000;320:768-770. Abstract

Suggested Readings: Evans RW. The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reports. Medscape General Medicine. 2007;9:48. Available at: Accessed October 31, 2008.

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