Wednesday, 26 June 2013

Fluvoxamine

Fluvoxamine (brand name: LUVOX) is a most fascinating drug. It belongs to the selective serotonin reuptake inhibitor (SSRI) class of drugs, which includes the antidepressants and anxiolytics (anti-anxiety drugs) sertraline (ZOLOFT), fluoxetine (PROZAC), citalopram (CELEXA), escitalopram (LEXAPRO) and paroxetine (PAXIL). It is the only such drug that's approved by the US Government’s Food and Drug Administration (FDA) solely for obsessive compulsive disorder (OCD) (the others are approved for depression and, depending on the drug, usually, for numerous anxiety disorders and, in the case of fluoxetine, sertraline and paroxetine premenstrual dysphoric disorder, which is basically like PMS but with the associated emotional/psychiatric problems (e.g. depression) more severe).1 SSRIs work, or so we believe, by interfering with the removal of serotonin from the synaptic cleft, which is where serotonin and other neurotransmitters are used as chemical messengers between two neurons (the electrically-signalling cells of the brain, spinal cord and nerves). This in turn increases chemical signalling via the neurotransmitter, serotonin, which we believe leads to the therapeutic effects of SSRIs.

Despite this well-designed clinical trials have repeatedly demonstrated that fluvoxamine is superior to placebo in the treatment of major depressive disorder2-5 (MDD; also known as clinical or unipolar depression) and at least one less well-designed clinical trial demonstrated some benefit in dysthymia6 (a chronic [long-term] mild depression). There is some reason why some people might be a little sceptical of fluvoxamine’s use in the treatment of depression: one of the two shooters involved in the Columbine High School massacre, Eric Harris, was on it after switching from sertraline. I personally see this as bad luck seeing how he was on it as part of a court-mandated anger management treatment and if enough people with pre-existing anger management issues are given antidepressants the odds are high that one of them is going to act out violently.

Despite clinical trials demonstrating that fluvoxamine has superior efficacy to placebo in the treatment of MDD compared to many other antidepressants fluvoxamine appears relatively weak in the treatment of MDD, and according to one meta-analysis7 (which is a statistical analysis of a large amount of available clinical trial data comparing the different antidepressants and their efficacy) of twelve second-generation (newer) antidepressants it is outperformed by (bracketed is the percentage more patients that responded to the listed drug compared to those that responded to fluvoxamine):
  • Bupropion (10%; WELLBUTRIN, ZYBAN)
  • Citalopram (13%)
  • Duloxetine (1%; CYMBALTA)
  • Escitalopram (35%)
  • Fluoxetine (2%)
  • Milnacipran (3%; SAVELLA)
  • Mirtazapine (36%; AVANZA, REMERON)
  • Paroxetine (4%)
  • Sertraline (27%)
  • Venlafaxine (30%; EFFEXOR)
in the treatment of MDD. In this study it outperformed just one drug (the percentage is the percentage more patients that responded to fluvoxamine compared to the drug listed):
  • Reboxetine (45%; EDRONAX)

What makes fluvoxamine so special, however, is that it displays the highest known affinity for the σ1 receptor of all commercially available antidepressants, that is, it activates the σ1 receptor more potently than any other antidepressant that has been tested for this ability.8 The σ1 receptor is a receptor primarily found in the central nervous system (CNS; a structure composed of the brain and spinal cord) that appears to regulate a number of functions in the body including:
  • Cognition (memory, learning, problem solving, etc.)
  • Coughing (codeine seems to suppress coughing by activating these receptors)
  • Mood (σ1 receptor agonism appears to contribute to the antidepressant activity of some antidepressants and drugs that solely act at the σ1 receptor are believed to possess antidepressant activity too)
  • Pain (σ1 receptor antagonists have been found to possess analgesic (painkilling) effects against certain types of pain)

Fluvoxamine has been tried as an adjunct (add-on) treatment to antipsychotics (the standard treatment for schizophrenia) in schizophrenia based on the theory that it might help with some of the more difficult-to-treat negative (emotional and social) symptoms of schizophrenia such as blunted affect (ability to express and feel emotions), inability to express oneself verbally and inability to experience pleasure in everyday activities and life in general and was found effective in this capacity. It was likely theorised to work in this application due to the fact that the negative symptoms of schizophrenia resemble many of the symptoms of depression.8-9 Another thing that might be advantageous about fluvoxamine in the treatment of schizophrenia is that it inhibits the metabolism of some antipsychotic drugs including clozapine thus requiring a lower dosage of such drugs to elicit the same effects and thus also avoiding some of the side effects the metabolites of these drugs can cause. A good example of such an interaction is with clozapine (CLOZARIL) which is a last-resort treatment for schizophrenia because it has the rare, potentially-fatal side effect of agranulocytosis (a potentially fatal drop in white blood cell count that leaves people wide open to life-threatening infections) despite displaying superior efficacy in the treatment of schizophrenia, especially treatment-resistant schizophrenia. Clozapine is a rather expensive drug too with a month’s supply costing, usually, a matter of hundreds of dollars and hence reducing the amount needed to treat patients can be advantageous in itself.9-10

Reference List:

  1. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 27]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. Dominguez RA, Goldstein BJ, Jacobson AF, Steinbook RM. A double-blind placebo-controlled study of fluvoxamine and imipramine in depression. J Clin Psychiatry. 1985 Mar;46(3):84–7.
  3. Claghorn JL, Earl CQ, Walczak DD, Stoner KA, Wong LF, Kanter D, et al. Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients. J Clin Psychopharmacol. 1996 Apr;16(2):113–20.
  4. Hashimoto K. Sigma-1 Receptors and Selective Serotonin Reuptake Inhibitors: Clinical Implications of their Relationship. Central Nervous System Agents in Medicinal Chemistry [Internet]. 2009 Sep 1 [cited 2013 Jun 27];9(3):197–204. Available from: http://www.eurekaselect.com/84835/article.
  5. Ottevanger EA. The efficacy of fluvoxamine in patients with severe depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry [Internet]. 1994 Jul [cited 2013 Jun 27];18(4):731–40. Available from: http://www.sciencedirect.com/science/article/pii/0278584694900809.
  6. Rabe-Jablonska J. Therapeutic effects and tolerability of fluvoxamine treatment in adolescents with dysthymia. J Child Adolesc Psychopharmacol. 2000;10(1):9–18.
  7. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The Lancet [Internet]. 2009 Feb [cited 2013 Jun 27];373(9665):746–58. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60046-5/fulltext.
  8. Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of σ receptors in rat brain. European Journal of Pharmacology [Internet]. 1996 Jun 20 [cited 2013 Jun 27];307(1):117–9. Available from: http://www.sciencedirect.com/science/article/pii/0014299996002543.
  9. Silver H, Kaplan A, Kushnir M. Fluvoxamine augmentation in chronic schizophrenia: An open exploratory study. Human Psychopharmacology: Clinical and Experimental [Internet]. 1995 [cited 2013 Jun 27];10(1):59–63. Available from: http://onlinelibrary.wiley.com/doi/10.1002/hup.470100110/abstract.
  10. Silver H. Selective serotonin re-uptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Expert Opinion on Pharmacotherapy [Internet]. 2004 Oct [cited 2013 Jun 27];5(10):2053–8. Available from: http://informahealthcare.com/doi/abs/10.1517/14656566.5.10.2053.

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