Overarousal Sertraline

a ► meta-analysis. This methodology provides a large enough sample to detect differences between active agents.

Escitalopram has demonstrated modest but consistent advantages over other SSRIs, but these differences were most significant in the comparisons with citalopram. Using a ''multiple-treatments meta-analysis'' method, which includes both direct and indirect comparisons of drugs, the efficacy and acceptability of 12 new-generation antidepressants (including the 6 SSRIs) were compared across 117 randomized control trials (Cipriani et al. 2009). Two SSRIs, escitalopram and sertraline, were among the four drugs with significant advantages over the other antidepressants in terms of efficacy. These two agents also had the best tolerability profiles, making them the most favorably ranked overall.

Tolerability

Even though the tolerability and safety profile of SSRIs is superior to the previous generation of TCAs, lack of compliance due to treatment-emergent side-effects remains a significant issue. There are both early transient adverse effects and persistent effects, which frequently result in drug discontinuation. Acute effects most often involve the central nervous system (CNS) and the gastrointestinal (GI) system, while later sustained effects are more likely to influence metabolism and sexual dysfunction (Table 3) (Kennedy et al. 2007).

Central Nervous System

Headache, sleep disturbance, sedation, and paraesethesia are commonly reported in the acute phase of treatment with any SSRI. Although some aspects of sleep are improved with SSRIs, there are reports that SSRIs disrupt sleep continuity and may exacerbate ► bruxism and restless leg syndrome. Additionally, while SSRIs generally improve cognitive dysfunction associated with depression, there is evidence, specifically with paroxetine, of drug-related cognitive side effects, likely due to its additional anticho-linergic effects.

Gastrointestinal and Metabolic Effects

Nausea is a common gastrointestinal side-effect during the first 2 weeks of treatment with an SSRI, and is most pronounced for fluvoxamine and sertraline. This is generally a transient effect.

Weight gain is a factor that can severely decrease drug compliance. Although initial treatment with SSRIs can result in weight loss, mainly due to nausea and an enhanced feeling of early ► satiety, long-term use of SSRIs

SSRIs and Related Compounds. Table 3. Common side effect profile of SSRIs across average dose range.

Drug

Averagedose range

IQ-30%1

30%1

Citalopram

20-60mg

CNS over arousal

Nausea

Escitalopram

10-20mg

Headaches and nausea

None

Fluoxetine

20-60mg

CNS over arousal

Nausea and headaches

Fluvoxamine

100-300mg

CNS over arousal, dizziness and constipation

Drowsiness, headaches, nausea, nervousness

Paroxetine

20-60mg

CNS over arousal, constipation and dizziness

Drowsiness, nausea, sexual dysfunction

Sertraline

50-200mg

CNS over arousal, dizziness, sexual dysfunction

Headaches and nausea

1Drug-placebo differences modified from product monographs CNS = central nervous system

1Drug-placebo differences modified from product monographs CNS = central nervous system has been associated with weight gain, particularly with paroxetine (Fava et al. 2000; Kennedy et al. 2007).

Recent studies have suggested that SSRIs may result in the loss of bone mineral density during long-term use. This appears to reflect inhibitory actions of serotonin on osteogenesis. Whether this might contribute to the development of clinical osteopenia or osteoporosis is still unclear.

Sexual Dysfunction

The consensus from a series of well designed comparative studies is that up to 60% of patients receiving SSRIs report some form of treatment emergent sexual dysfunction, with paroxetine and sertraline exerting the greatest burden of sexual side effects (Kennedy and Rizvi 2009). All of the SSRIs have been associated with delayed or absent orgasm/ejaculation and, in some instances, a reduction in libido and arousal. These effects appear to be related to the stimulation of serotonin, particularly its ► agonist effects on 5HT2 receptors. However, other mechanisms that block cholinergic receptors and inhibit nitric oxide synthase are also likely to be involved as well. This may explain why patients receiving paroxetine compared with other SSRIs had a significantly greater incidence of erectile dysfunction or reduced vaginal lubrication.

Safety

► History of Psychopharmacology

► Randomized Controlled Trials

► SNRI Antidepressants

► Tryptophan Depletion

Suicidality

Depressed patients are at greatest risk for ► suicide attempts during the month before and the first month after starting medication, and the risk progressively declines with treatment. Although most population studies have shown a reduction in rates of completed suicide associated with increased use of modern antidepressants, the issue of suicidality with SSRIs has attracted considerable media attention and appears to be most pronounced in adolescents. The "► black-box'' warning for SSRIs in the U.S., Canada and elsewhere, due to findings of increased suicidal ideation, has likely contributed to a decrease in antidepressant prescriptions for children and adolescents. Since the 2003-2004 warning, studies indicate that U.S. and Canadian rates of completed suicide hasve increased for the first time in a decade for adolescents. In adults, meta-analyses of ► randomized controlled trials (RCTs), or analyses of research databases, have found no support for increased suicides with antide-pressant use (Moller 2006).

Serotonin syndrome

Excessive serotonin release may result in a clinically significant "► serotonin syndrome'', characterized by diarrhea, delirium, tremor, muscle rigidity and hypothermia. This may occur when patients are taking two SSRIs or taking an SSRI with another serotonin-enhancing agent. Therefore, caution must be applied when combining treatments and during dose increases.

Conclusions

Since the launch of fluoxetine, SSRI use has increased to the extent that this is now the most widely prescribed antidepressant class, reflecting a favorable balance between efficacy and tolerability. The ► pharmacokinetic profile of SSRIs allows for easy dosing and long-term use. Future research should be directed to increasing the specificity of agents at the serotonin receptor and transporter sites.

References

Chen Y, Kelton CM, Jing Y, Guo JJ, Li X, Patel NC (2008) Utilization, price, and spending trends for antidepressants in the US Medicaid Program. Res Social Adm Pharm 4:244-257 Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JPT, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet (Published online). doi:10.1016/S0140-6736(09)60046-5 Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC (2000) Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 61:863-867

Healy D (1999) The antidepressant era. Harvard University Press, London

Kennedy SH, Rizvi S (2009) Sexual dysfunction, depression and the impact of antidepressants. J Clin Psychopharmacoll 29:157-164 Kennedy SH, Lam RW, Nutt DJ, Thase ME (2007) Treating Depression Effectively: applying Clinical Guidelines, 2nd edn. Informa, London Kramer PD (1999) Listening to Prozac. Viking, New York McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepress-ant treatment. Am J Hum Genet 78:804-814 Meyer JH (2007) Imagining the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32:86-102 Moller HJ (2006) Is there evidence for negative effects of antidepressants on suicidality in depressive patients? A systematic review. Eur Arch Psychiatry Clin Neurosci 256:476-496 Sanchez C (2006) The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol 99:91-95 Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18: 391-418

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

Get My Free Ebook


Post a comment