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SSRI stands for Selective Serotonin Reuptake Inhibitor. There are five available in the U.S. When the patents on tricyclic medications were running out, the pharmaceutical industry and their psychiatrists suddenly discovered that increasing serotonin was the secret in treating depression. The tricyclics had been increasing both serotonin and norepinepherine to varying degrees. Thus, the SSRIs were more selective, focusing only on serotonin. Now that the patents on the SSRIs are expiring, the industry is finding that medicines that work on both serotonin and norepinepherine work better. The SSRIs are still good anti-depressants. They did represent a definite advance for patient treatment. SSRIs are the best treatment for obsessive-compulsive symptoms and they don't cause weight gain. They are fairly safe in overdose situations. Unfortunately, SSRIs do have their own share of side-effects. These side-effects do tend to diminish and often disappear with time. The least expensive SSRI is fluoxetine, which is the least expensive of all anti-depressants at only $3.30 per month at the wholesale rate and standard dose. Prozac Increases Norepinephrine, Epinephrine, and Dopamine: In a study of 12 patients treated with fluoxetine for 40 days compared to 40 healthy controls, plasma norepinephrine, epinephrine and dopamine levels significantly increased after acute and chronic treatment (p < 0.001), reaching the highest concentrations on the last day. Blardi et al. University of Siena. Neuropsychobiology. 2005;51(2):72-6. British Say Fluoxetine (Prozac) Only Acceptable SSRI for Children: British drug regulators have asked doctors not to prescribe Paxil, Zoloft, Effexor, Celexa, or Luvox to children after reviewing 11 studies using these medicines for depression in children and teens due to fears of increasing suicial thoughts and behaviors and hostility. According to the British, children already doing well on these medicines to continue them. Fluoxetine, the longest acting anti-depressant, was given a nod of approval. (New York Times 12/16/03). The FDA will hold hearing on February 3rd. Ed: Older tricyclics tend not to help depressed children. Fortunately, there are other medications and non-medication strategies, the later of which may have been underutilized up to the present time. SSRIs Increase Suicide Attempts Initially: In a review of all Medline and the Cochrane Collaboration's registered controlled trials through November 2004, 702 trials involving 87,650 patients met the inclusion criteria. A significant increase in the odds of suicide attempts (odds ratio 2.28, number needed to treat to harm 684) was observed for patients receiving SSRIs compared with placebo. An increase in the odds ratio of suicide attempts was also observed in comparing SSRIs with therapeutic interventions other than tricyclic antidepressants (1.94, 239). In the pooled analysis of SSRIs versus tricyclic antidepressants, no significant difference was found (0.88). Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. Fergusson D, Doucette S, et al. Ottawa Health Research Institute, Canada. BMJ. 2005 Feb 19;330(7488):396. SSRIs Better Than Tricyclics for Diabetes: In comorbid diabetes mellitus and depression, most evidence supports the use of fluoxetine in control of glucose handling. six studies of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), at a dose of 60 mg/day pursued up to 12 months that have demonstrated that medication's usefulness in diabetic patients, with reductions in weight (to 9.3 kg), in FPG (to 45 mg%), and in HbA1c (to 2.5%). In studies in comorbid diabetes mellitus and depression, nortriptyline, a norepinephrine reuptake inhibitor that produces increased synaptic catechols, has led to worsening of indices of glucose control. Other characteristics in terms dosing, drug interactions, cognition, and sleep make sertraline an attractive alternative agent. In diabetic neuropathy without depression, the best choices among non-TCAs may include sertraline, citalopram, and perhaps, venlafaxine, since the TCAs appear to increase cravings and increase FBG levels. Goodnick, U Miami, Ann Clin Psychiatry 2001 Mar;13(1):31-41 SSRI Helped Alzheimer’s Depression: A PC DB 12 week study of 44 Major Depressive Disorder Alzheimer’s patients found those given sertraline up to 150 mg/d did much better than those on placebo. Patients all had MMSEs over 9. 20 vs. 7 had at least partial responses. Cognitive function did not improve. Those not improving in six weeks did not improve with additional treatment. Johns Hopkins. Lydetsos C, DelCampo L, et al: Treating depression in Alzheimer disease. Efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry 2003;60:737-46. Serotonergic Meds (SSRI, Clomipramine) Better for Young Adults: An analysis of the results of two randomized New Zealand studies without placebo controls (one was an open trial) found that young adults 18-24 responded much better to serotonergic medications than to noradrenergic ones (desipramine 200 mg/d or nortriptyline 100 mg/d) (72% vs. 38%). By contrast, there was no significant difference in response rate for older adults (65% noradrenergic vs. 57% serotonergic). Age may affect response to antidepressants with serotonergic and noradrenergic actions. Mulder RT, Watkins WG, Joyce PR, Luty SE. J Affect Disord. 2003 Sep;76(1-3):143-9. Children and teens tend respond to serotonergic medicines much better as well. SSRIs Did Better for Young Women: In a small prospective study of venlafaxine, an SSRI, or nefazodone for 115 female patients with major depression for 8 weeks, younger women responded faster and better and were helped more by the SSRI. The same pattern was not found for men. A comparison of antidepressant response in younger and older women. Grigoriadis S, Kennedy SH, Bagby RM. J Clin Psychopharmacol. 2003 Aug;23(4):405-7. Univ. Toronto Hypomania Sometimes Dose-Dependent: Two cases with no family history of hypomania on paroxetine and sertraline both resolving with decreased dose. Ramasubbu, U Ottawa, Acta Psychiatr Scand 2001 Sep;104(3):236-8; discussion 238-9 SSRIs for Alpha Interferon Depression: Common s-e is depression. Two cases reported where fluoxetine 20 QD successfully Rx the depression. M. Gulati, Balt. VA, APA 5/17/99 SSRI Helps Depressed Alzheimer’s: Random assignment 50 68-74yos given donepezil with or without citalopram. SSRI group less depressed and did better over the next year. Trieste, Depression and Alzheimer's disease: symptom or comorbidity? Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Am J Alzheimers Dis Other Demen 2002 Nov-Dec;17(6):338-44 SSRI Overdose, Self Harm Higher than TCA: 2800 consecutive ER visits for deliberate self-harm (80% were by overdose). Acetaminophen (Tylenol) used in 40% of ODs, painkillers in 27%, anti-depressants in 17%. Twelve died in hospital. 307 overdosed within 30 days of new prescription for depression (102 TCA, 180 SSRI, 25 other e.g lithium, trazodone). Self harm with SSRI 12-20/10,000 vs. 4.1/10,000 for TCAs amitriptyline, imipramine, dothiepin. SSRIs were prescribed more often in younger and those with history of self-harm. Psych Drug Alerts says, "prescribing SSRIs in patients at risk for self-harm may reduce morbidity associated with antidepressant overdose, it is unclear whether this is offset by the increased risk of self-harm by other methods." Brit J Psychiatry 00;177:551. Genetic Variant Found More Sensitive to SSRI Side-Effects: The short (S) allele of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been associated with poorer antidepressant response in major depressive disorder (MDD) and with antidepressant-induced mania. A Harvard-MGH study of 36 Major Depressive Disorder patients given fluoxetine found that the nine with the short allele were much more likely to develop insomnia (78% vs. 22%) and agitation (67% vs. 7%) due to the medication. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Perlis RH, Mischoulon D, Smoller JW, Wan YJ, Lamon-Fava S, Lin KM, Rosenbaum JF, Fava M. Biol Psychiatry. 2003 Nov 1;54(9):879-83. Those without the short allele responded more quickly to sertraline. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB Psychopharmacology (Berl). 2003 Sep 4 SSRI Increase Brain GABA by Direct Effects: In a DB PC crossover study of 10 healthy adults given citalopram 10 mg. IV, the occipital GABA/creatine ratio was measured with a proton MR spectral editing technique. The SSRI increased the brain GABA concentration in the occipital cortex by 35%. It appears this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement. Increased Brain GABA Concentrations Following Acute Administration of a Selective Serotonin Reuptake Inhibitor. Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ. Am J Psychiatry. 2004 Feb;161(2):368-7 SSRIs: Four in US citalopram, fluoxetine, paroxetine, sertraline. Citalopram inhibits serotonin reuptake with little dopamine or NE effect or muscarinic, histaminergic, adrenergic or serotonergic receptor affinity. Half-life 35 hr steady state 1 wk. Less inhibition effect on P450 CYP3A, 2C19, and 2D6. Cimetidine increased citalopram concentration by inhibition CYP2D6 and 3A4. Citalopram increased metoprolol and imipramine. No effect on lithium, warfarin, digoxin, carbamazepine. Erythromycin, ketoconazole and omeprazole may incr. Sertonin syndrome with MAOI. Citalopram used at 20-80mg. Two of five studies on package insert found citalopram better than placebo. In two studies, citalopram was equal to fluoxetine and sertraline for depression but no placebo (Int Clin Psychopharm 11:129, ’96; Int Clin Psychopharm 12:323, ’97). One study 300 patients better on citalopram than placebo although sertraline was not better than placebo (S Stahl, APA 6/98). Published SSRI Research Biased: Five SSRIs were approved in Sweden between 1989 and 1994 for treating major depression. Forty two short term (4-8 weeks) placebo controlled clinical trials with the approved doses were submitted to the Swedish drug regulatory authority and formed the basis for the approvals. When applying for marketing authorization, the applicants are obliged to submit full reports of all studies performed by the applicants as well as all available information on any study not performed by the applicants. Studies showing significant differences between efficacy of drug and placebo were three times more likely to appear as stand alone publications than were studies with non-significant results. Although both intention to treat analyses and per protocol analyses were available in the submissions to the regulatory agency, only 24% of the stand alone publications reported the usually less favorable intention to treat results. "For anyone who relies on published data alone to choose a specific drug, our results should be a cause for concern. Without access to all studies (positive as well as negative, published as well as unpublished) and without access to alternative analyses (intention to treat as well as per protocol), any attempt to recommend a specific drug is likely to be based on biased evidence. "Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications Hans Melander, Jane Ahlqvist-Rastad, Gertie Meijer, Björn Beermann. BMJ 2003;326:1171-1173 (31 May), Uppsala Thomas E. Radecki, M.D., J.D.
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