Anti-depressant update Dr David Straton

SSRIs Brands Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Cipramil, Celapram, Talam, Talohexal Lexapro, Esipram Prozac, Auscap, Fluohexal, Lovan, Zactin Luvox, Faverin, Movox Aropax, Oxetine, Paxtine Zoloft, Concorz, Eleva, Setrona, Xydep

SNRIs Brands Others Desvenlafaxine Duloxetine Venlafaxine Pristiq Cymbalta Efexor Others Bupropion (NDRI) Buspirone (Piperazine) Mianserin (Tetracyclic) Mirtazapine (NaSSA) Moclobemide (RIMA) Reboxetine (NRI) Tranylcypromine (MAOI) Zyban Buspar Tolvon, Lumin Avanza, Axit 30, Mirtazon, Remeron Aurorix, Arima, Clobemix, Maosig, Mohexal Edronax Parnate

Normal Synapse

Serotonin

Synapse in depression

SSRI increases serotonin 5HT1a

Some receptors may upregulate

SSRI effects 5HT1a Anxiety down, mood up 5HT2a Insomnia, sex problems 5HT2c Agitation 5HT3 Nausea

Major studies and meta-analyses 2008-9 STAR*D (Sequenced Treatment Alternatives to Relieve Depression). 26th Feb 2008, PLoS Medicine published the Hull meta-analysis of anti-depressant trials from the FDA. 18th Nov 2008, the American College of Physicians published two background papers on anti-depressants. 28th Jan 2009, the Lancet published online a major meta-analysis of antidepressants. 3rd Feb 2009, the Canadian Medical Association Journal published a review of studies about whether SSRIs increase the risk of suicide. June 2009, the Journal of Clinical Psychopharmacology published a meta-analysis of anti-depressant related sexual dysfunction. In August 2009, the BMJ published a meta-analysis on suicidality.

STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

Remission was defined as an exit score of ≤7 on the Hamilton Depression Rating Scale (HAM-D). Response was defined as a reduction of ≥50% in baseline Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR).

After a mean of 9. 6 weeks of treatment, remission rates were 15 After a mean of 9.6 weeks of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T3 augmentation Second, we did not systematically assess laboratory indices, including pretreatment assessment of thyroid function and serial monitoring of lithium levels.

The Hull meta-analysis Attempt to avoid publication bias. FOI on FDA, all clinical trials, both published and unpublished. Trials with no benefit + no data left out. (Citalopram and sertraline). Most trials only 6 weeks duration. Conclusion, drug only beat placebo in most severe depressions. Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration Kirsch I, et al. PLoS Med February 26, 2008, 5(2): e45 Full text pdf

Hull

The American College of Physicians Reviews ‘Overall, no substantial differences in efficacy’ Fluvoxamine lost every comparison test for efficacy Venlafaxine prone to nausea Sertraline prone to diarrhoea Mirtazapine prone to weight gain Venlafaxine and paroxetine prone to discontinuation syndrome Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians. Amir Qaseem, et al. Ann Intern Med. 2008 Nov 18;149(10):725-733. Full text pdf. Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians. Gerald Gartlehner, et al. Ann Intern Med. 2008 Nov 18;149(10):734-750. Full text pdf.

Fluvoxamine compared to other anti-depressants ACP

Fluvoxamine compared to other anti-depressants ACP

Fluvoxamine compared to other anti-depressants I.e Fluvoxamine lost every drug-to-drug contest ACP

Lancet meta-analysis Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Andrea Cipriani, et al. Published online 29 January 2009. Full-text here.

Odds of being most effective 1) Mirtazapine 24.4% 2) Escitalopram 23.7% 3) Venlafaxine 22.3% 4) Sertraline 20.3% 5) Citalopram 3.4% 6) Milnacipran 2.7% 7) Bupropion 2.0% 8) Duloxetine 0.9% 9) Fluvoxamine 0.7% 10) Paroxetine 0.1% 11) Fluoxetine 0.0% 12) Reboxetine The cumulative probabilities of being among the four most effective treatments were: Lancet

Odds of being most acceptable 1) Escitalopram 27.6% 2) Sertraline 21.3% 3) Bupropion 19.3% 4) Citalopram 18.7% 5) Milnacipran 7.1% 6) Mirtazapine 4.4% 7) Fluoxetine 3.4% 8) Venlafaxine 0.9% 9) Duloxetine 0.7% 10) Fluvoxamine 0.4% 11) Paroxetine 0.2% 12) Reboxetine 0.1% The cumulative probabilities of being among the four most acceptable treatments were: Lancet

Lancet

Suicide Risk (CMAJ) CMAJ Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies Corrado Barbui, MD, Eleonora Esposito, MD and Andrea Cipriani, MD CMAJ • February 3, 2009; 180 (3) 291-297. Full-text. CMAJ

CMAJ

Odds of suicidality (ideation or worse) for active drug relative to placebo by age in adults Stone, M. et al. BMJ 2009 Copyright ©2009 BMJ Publishing Group Ltd.

Suicidality risk vs placebo (ideation or worse) in adults Suicide risk (BMJ) Suicidality risk vs placebo (ideation or worse) in adults Drug n % Placebo Odds ratio Escitalopram 10 3130 0.32% 5 2604 0.19% 2.44 Citalopram 24 2661 0.90% 7 1371 0.51% 2.11 Fluvoxamine 22 2187 1.01% 13 1828 0.71% 1.25 Mirtazapine 8 1016 0.79% 6 644 0.93% 0.97 Paroxetine 50 9919 0.50% 29 6972 0.42% 0.93 Duloxetine 25 2327 1.07% 18 1460 1.23% 0.88 Venlafaxine 5593 0.52% 30 3904 0.77% 0.71 Fluoxetine 81 7180 1.13% 67 4814 1.39% Sertraline 6363 0.28% 28 5081 0.55% 0.51 All drugs 314 50043 0.63% 197 27164 0.73% 0.83 One might expect suicide risk rates on placebos to be the same. BMJ

Sexual Side-effects Serretti Total Desire Arousal Orgasm Severe Sertraline 27 Citalopram 55 82 Clomipramine 42   Venlafaxine 25 Paroxetine 47 54 18 20 Fluoxetine 46 44 16 17 43 39 15 23 31 14 Mild Duloxetine 4 Fluvoxamine 6 11 12 Escitalopram 3 Mirtazapine 7 5 2 Moclobemide Nil Placebo 1 0.2 0.7 0.4 Treatment-Emergent Sexual Dysfunction Related to Antidepressants: A Meta-Analysis Serretti, Alessandro MD, PhD; Chiesa, Alberto MD. Journal of Clinical Psychopharmacology: June 2009 - Volume 29 - Issue 3 - pp 259-266 Abstract This table shows the relative size of sexual side-effects of many antidepressants. The number is the Odds Ratio (OR) compared to placebo, such that placebo is defined as 1. The numbers are rounded to a whole number. Data from the Supplementary Table from the paper above. http://links.lww.com/a1028 Serretti

S-(+)-citalopram (Escitalopram) R-(-)-citalopram 50/50 mixture of both = Citalopram

Treatment algorithm: plan A Escitalopram. 2.5mg rising to 20 mg. Similar to Level 1 in STAR*D 2nd for efficacy in Lancet meta-analysis 1st for acceptability in Lancet meta-analysis Mild sex side-effects Trial should last at least 2 months. Possible disadvantage if suicide risk high (BMJ)

Treatment algorithm: plan B (in no particular order) Add thyroxine, esp if T4 <14 mmol/L Add mianserin, esp if 5HT-2 related side-effects Change to mirtazapine 30 – 60 mg. Advantage with panic and insomnia. (Beware weight) Change to sertraline 50 – 100 mg. Possible advantage with suicide risk. (Beware diarrhoea and sex problems). Change to venlafaxine (Beware nausea, sex problems, discontinuation symptoms, and risk of suicide in adolescents) a) Augment with thyroxine (T4). Especially if the measured T4 level is below average, eg <14 mmol/L. (Level 3, STAR*D 1, 4) b) If failure of Plan A is related to 5HT-2 related side-effects (eg insomnia, agitation, anxiety, panic, sexual dysfunction) there is a logical case for augmenting with a drug with 5HT-2 blocking properties, such as mianserin. 11 c) Change to mirtazapine (Beware of weight gain). (Most efficacious, Lancet meta-analysis 7) d) Change to sertraline. (Beware of diarrhoea and sexual problems). (Level 2, STAR*D 14, and Lancet 7) e) Change to venlafaxine (Beware of nausea, sexual problems, discontinuation symptoms, and risk of suicide in adolescents) (Level 2, STAR*D 14, and Lancet 7).

Treatment algorithm: plan C California rocket-fuel Combination of: Venlafaxine 75 – 300 mg Mirtazapine 30 – 60 mg (Level 4, STAR*D 15)

Treatments to abandon Fluvoxamine Reboxetine Augmentation with lithium for unipolar depression

Treatments to downplay Paroxetine Antidepressants in adolescents, especially venlafaxine and paroxetine

Treatments in danger of being abandoned prematurely Tranylcypromine. 'Approximately 30% of participants in the tranylcypromine group had less than 2 weeks of treatment, and nearly half had less than 6 weeks of treatment‘ (STAR*D)

Papers mentioned available here: psyberspace.com.au/depression