Antidepressant update Dr David Straton SSRIs Citalopram Escitalopram

Anti-depressant update Dr David Straton

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

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

Serotonin – Noradrenalin Ratio

Normal Synapse

Synapse in depression

SSRI increases serotonin 5 HT 1 a

Some receptors may upregulate

SSRI effects 5 HT 1 a Anxiety down, mood up 5 HT 2 a Insomnia, sex problems 5 HT 2 c Agitation 5 HT 3 Nausea

Major studies and meta-analyses 2008 -9 � STAR*D (Sequenced Treatment Alternatives to Relieve Depression). � 26 th Feb 2008, PLo. S Medicine published the Hull meta-analysis of anti- depressant trials from the FDA. � 18 th Nov 2008, the American College of Physicians published two background papers on anti-depressants. � 28 th Jan 2009, the Lancet published online a major meta-analysis of antidepressants. � 3 rd 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)

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 �FOI on FDA, all clinical trials, both published and unpublished.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.

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

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 Lancet 2009

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 0. 0% Lancet 2009

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% Lancet 2009

Lancet 2009

Lancet 2018

Lancet 2018

All patients Placebo Escitalopram

Patients with less severe depression Placebo Escitalopram

Patients with more severe depression Placebo Escitalopram ‘Our findings indicate that what appears to be a modest effect in the grouped data is actually a very large effect for a subset of patients who benefited more from escitalopram than from placebo treatment. ’

Suicide Risk (CMAJ) 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.

Suicide risk (BMJ) Suicidality risk vs placebo (ideation or worse) in adults Drug n % Placebo n % 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 29 5593 0. 52% 30 3904 0. 77% 0. 71 Fluoxetine 81 7180 1. 13% 67 4814 1. 39% 0. 71 Sertraline 18 6363 0. 28% 28 5081 0. 55% 0. 51 All drugs 314 50043 0. 63% 197 27164 0. 73% 0. 83 BMJ

Sexual Side-effects Total Desire Arousal Orgasm Severe Sertraline 27 Citalopram 55 Citalopram 82 Clomipramine 42 Venlafaxine 25 Paroxetine 47 Venlafaxine 54 Paroxetine 18 Citalopram 20 Fluoxetine 46 Paroxetine 44 Venlafaxine 16 Paroxetine 17 Sertraline 43 Sertraline 39 Sertraline 15 Fluoxetine 16 Venlafaxine 23 Fluoxetine 31 Citalopram 14 Mild Duloxetine 4 Fluvoxamine 6 Duloxetine 11 Fluoxetine 12 Escitalopram 3 Mirtazapine 6 Fluvoxamine 7 Mirtazapine 4 Fluvoxamine 3 Duloxetine 5 Mirtazapine 4 Escitalopram 4 Mirtazapine 2 Moclobemide 4 Moclobemide 2 Fluvoxamine 3 Nil Placebo 1 Escitalopram 1 Placebo 1 Moclobemide 0. 2 Placebo 1 Escitalopram 0. 7 Moclobemide 0. 4 Serretti

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

Treatment algorithm: plan A �Escitalopram. 2. 5 mg rising to 20 mg. � Similar to Level 1 in STAR*D � 2 nd for efficacy in Lancet meta-analysis � 1 st 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 T 4 <14 mmol/L �Add mianserin, esp if 5 HT-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)

Treatment algorithm: plan C �California rocket-fuel �Combination of: � Venlafaxine 75 – 300 mg � Mirtazapine 30 – 60 mg

Mirtazapine

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