Depression paroxetine

SCHEME 25 Parallel detoxication pathways that compete with the P450-catalyzed bioactivation pathway of the anti-depressant paroxetine as explanation for its wide safety margin. 

SSRIs are widely used for treatment of depression, as well as, for example, panic disorders and obsessive—compulsive disorder. These dmgs are well recognized as clinically effective antidepressants having an improved side-effect profile as compared to the TCAs and irreversible MAO inhibitors. Indeed, these dmgs lack the anticholinergic, cardiovascular, and sedative effects characteristic of TCAs. Their main adverse effects include nervousness /anxiety, nausea, diarrhea or constipation, insomnia, tremor, dizziness, headache, and sexual dysfunction. The most commonly prescribed SSRIs for depression are fluoxetine (31), fluvoxamine (32), sertraline (52), citalopram (53), and paroxetine (54). SSRIs together represent about one-fifth of total worldwide antidepressant unit sales. 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

Lapierre Y, Bentkover J, Schainbaum S, Manners S (1995). Direct cost of depression analysis of treatment costs of paroxetine versus imipramine in Canada. Can J Psychiatry 40, 370-7. 

Melton ST, Kirkwood CK, Farrar TW, et al (1997). Economic evaluation of paroxetine and imipramine in depressed outpatient. PsychopharmacolBull t >y 93-100. 

Venlafaxine extended release, in doses of 75 to 225 mg/day, improves social anxiety, performance, and avoidance behavior with a reduction in disability.61 Treatment with venlafaxine results in response rates similar to those seen with paroxetine.60 Venlafaxine may be effective in SSRI non-responders.62 As with SSRIs, doses should be tapered slowly when discontinuing therapy. Tolerability is similar to that observed in depression trials with venlafaxine extended release. Common side effects are anorexia, dry mouth, nausea, insomnia, and sexual dysfunction. 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Pollock, B. G., Ferrell, R. E. et al. (2000). Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology, 23(5), 587-90. 

Zanardi, R. et al. (2000). Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. /. Clin. Psychopharmacol., 20(1), 105-7. 

During acute treatment with paroxetine, Late life depression Caucasian... 

Paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. Major depression Caucasian... 

Maprotiline, Moclobemide, Mianserin, Fluoxetine (Prozac), Paroxetine, Sertraline, Fluvoxamine, Citalopram, Venlafaxin (generic IR formulation and the brand Venlafaxine XR), Mirtazapine, Flupentixol-melitracen (Deanxit), Tianeptine, Extract of St. John s Wort, Buspirone Depression and anxiety... 

An open-label study of paroxetine and fluoxetine (Alonso et al, 1997) in depressed Hispanic (Mexican descent, n = 13) and non-Hispanic females (n = 13) showed no differences in response rates. At variance with the tricyclic data, Hispanic subjects complained of fewer side effects (2.2 2.0 vs. 5.1 2.5 p < 0.005), but twice as many terminated participation prior to study completion due to non-compliance, intolerable side effects or pregnancy. 

Marshall, R. D., Lewis-Fernandez, R., Blanco, C., Simpson, H. B. et al. (2007). A controlled trial of paroxetine for chronic PTSD, dissociation, and interpersonal problems in mostly minority adults. Depress. Anxiety, 24, 77-84. 

Babyak, Michael A., James A. Blumenthal, Steve Herman, Parinda Khatri, P. Murali Doraiswamy, Kathleen A. Moore, W. Edward Craighead, Teri T. Baldewicz and K. Ranga Krishnan, Exercise Treatment for Major Depression Maintenance of Therapeutic Benefit at 10 Months , Psychosomatic Medicine 62 (2000) 633-38 Barbui, Corrado, Andrea Cipriani and Irving Kirsch, Is the Paroxetine-Placebo Efficacy Separation Mediated by Adverse Events A Systematic Re-Examination of Randomised Double-Blind Studies , submitted for publication (2009)... 

Paroxetine in the Treatment of Acute Major Depression in Adults A Systematic Re-Examination of Published and Unpublished Data from Randomized Trials , Canadian Medical Association Journal 178, no. 3 (2008) 296-305... 

Seroxat (Paroxetine) Depression Obsessive-compulsive disorders Panic Post-traumatic stress disorder 2.1 0.7 1991 - UK 1993 - US Once daily... 

Treatment with a selective serotonin reuptake inhibitor is usually initiated in depressed patients with AD. Paroxetine causes more anticholinergic side effects than the other selective serotonin reuptake inhibitors. Ven-lafaxine may also be used. 

Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or an atypical antipsychotic (e.g., risperidone). Risperidone has been shown to be effective in combination with fluvoxamine, paroxetine, or citalopram in treatment-resistant depression. Olanzapine and fluoxetine have been found to be safe and effective in treatment-resistant depression. 

Since the introduction of the first approved SSRI, fluoxetine (1) in 1987 [9], a number of SSRIs have been developed for the treatment of depression [2], Currently, the five most commonly prescribed SSRIs are fluoxetine, escitalopram (2, S-enantiomer of citalopram), sertraline (3), paroxetine (4) and fluvoxamine (5). Recent effort in the clinical development of new SSRIs has focused on the treatment of premature ejaculation (PE) by taking advantage of the ejaculation-delaying side effects of SSRIs [10]. Although SSRIs have been prescribed off-label to treat this condition, an SSRI with rapid onset of action and rapid clearance could be preferred for on-demand treatment of PE [11,12]. Dapoxetine (LY210448, 6), an... 

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