The unsexy side of antidepressants

Do you suffer from sadness, loss of interest or anxiety? Talk to your doctor about NeuWriteSD.org. Ninety-five percent of depressed individuals report a more positive outlook and greater contentment after reading NeuWriteSD 1. Please, always consult your doctor before reading this or any other blog, as side effects may include decreased libido, impaired sexual function, or reduced sexual sensation.

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AntidepressantsTo the dismay of thousands of individuals taking antidepressants, escape from depression all too often demands a heavy sacrifice: a healthy sex life. An estimated 26-80% of patients on antidepressants report experiencing sexual side effects 2, demonstrating the high variability across drug effects and individuals. I’ll spare you the (not-so-juicy) details of these physical and psychological consequences, but let’s just say they take the fun out of date night. While the prospect of taking currently available antidepressants might be … well, depressing … not all hope is lost. Drug developers have become increasingly sensitive to patients’ escalating complaints and have devoted greater efforts to developing antidepressants that are gentler on users’ intimate lives. While some of these treatments show promise, others have flopped. Central to this ongoing challenge is an inadequate understanding of how antidepressants mechanistically alter the neurobiological systems supporting normal sexual drive and function.

In their paper recently published in the journal Pharmacology Biochemistry and Behavior 3, a team of scientists made a significant step towards solving this puzzle by characterizing how six distinct classes of antidepressants alter sexual activity. The researchers administered rats a given drug for two weeks and measured their sexual performance before treatment, half-way through, immediately after, or following a week-long washout. They quantified sexual performance as the number of ejaculations per half-hour, relative to a normal reference of two to three (stop comparing yourselves, boys … these are rats).

Before we can interpret their findings, we need to understand the purported mechanism of typical antidepressants. But before we delve into the many implicated neurotransmitters and receptors, let’s brush up on some basic neuroscience. Neurons can communicate by releasing chemicals – or neurotransmitters – across inter-neuron gaps called synapses. Neurotransmitters from the pre-synaptic (releasing) neuron bind to receptors on the post-synaptic (receiving) neuron to activate a signaling cascade that may induce a host of downstream effects. The pre-synaptic neuron also performs some housekeeping, taking up excess neurotransmitters from the synaptic space via transporter proteins. A prevailing theory holds that depression is mediated by deficient serotonin transmission. The most prevalent type of antidepressants – selective serotonin reuptake inhibitors (SSRIs) – functions by blocking the normal pre-synaptic reuptake of serotonin, making the neurotransmitter more available at the synapse and thus restoring it to healthy levels.

Blame serotonin for your inadequacies

At all doses, chronic paroxetine (PAR) reduces ejaculation frequency in rats. subchronic = 8 days; chronic = 15 days. From Bijlsma et al., 2013.

At all doses, chronic paroxetine (PAR) reduces ejaculation frequency in rats. subchronic = 8 days; chronic = 15 days. From Bijlsma et al., 2013.

The researchers began by examining this commonly prescribed antidepressant class, SSRIs. Think Prozac, Paxil or Lexapro. Confirming what we already know from humans, in this study chronic use of the SSRI paroxetine impaired rats’ sexual performance, which returned to normal after a week off the drug (See Figure). Although many patients on SSRIs report sexual dysfunction, it’s unclear how these side effects result from increased serotonergic transmission.

Serotonin binds to various receptor types, each of which could influence sexual activity in a radically different way. To explore which particular receptors might be the culprits behind the rats’ poor performance in bed, the researchers tested two drugs that selectively act on distinct serotonin (5-HT) receptors. Busipirone, a 5-HT1A receptor agonist, did not affect rats’ ejaculation frequency. However, probing deeper, additional tests suggested that this may have arisen from a coincident increased physical sexual function and reduced ratty libido. Similarly, rats taking a 5-HT2C receptor antagonist showed normal sexual function. These findings were consistent with earlier studies showing that serotonin receptor agonists differentially alter the motor and motivational components of sexual function 4,5, which may depend on whether they’re administered systemically or targeted to specific brain regions. So while disrupting serotonergic transmission can clearly mess up one’s sex life, we can’t simply place blame on a single serotonin receptor.

Norepinephrine just can’t perform

Notably, other neurotransmitters, including norepinephrine and dopamine, have been found to promote sexual function, and antidepressants that stimulate their activity are associated with fewer sexual side effects. The researchers next tested whether increasing the availability of these neurotransmitters counteracts some of ugly side effects of SSRIs. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (i.e. it increases synaptic levels of serotonin and norepinephrine), impaired rats’ ejaculation frequency, reminiscent of the SSRI-induced dysfunction. This came as no surprise, since humans on vanlafaxine also report an elevated prevalence of sexual side effects 6. Evidently, norepinephrine is ineffective at overcoming the sexual inadequacies of SSRIs.

Dopamine to the rescue

The researchers next supercharged their efforts to overcome SSRIs’ side effects by adding dopamine to the mix. They tried a triple monoamine reuptake inhibitor, which prevents the reuptake of serotonin, norepinephrine and dopamine. Rats on this sexed-up antidepressant performed equally as well in ratty-bed as their drug-free counterparts. Shoot and score! What set this drug apart from the other failures? Dopamine.

If dopamine can counteract SSRI-induced dysfunction, could it – in the absence of an SSRI – turn your average Joe rat into the Energizer Playboy Bunny? Rats taking bupropion, a combined norepinephrine-dopamine reuptake inhibitor showed no signs of sexual superpowers (or impairments). So while neither dopamine nor norepinephrine enhances normal sexual function, dopamine may override some of the impairments in a dysfunctional sexual system.

What have we learned about sex and drugs?

By manipulating distinct neurotransmitter systems, the researchers hoped to unravel the mechanisms by which different antidepressants can induce or prevent sexual dysfunction. While many mysteries still remain, this study adds a layer of clarity to our understanding. Together, their review confirmed that altered serotonergic transmission indeed underlies antidepressant-related sexual dysfunction, which can be overcome by manipulating dopaminergic signaling. Based on this pattern, they conjecture that elevated serotonin may tonically suppress dopamine release in projection areas that mediate psychological and physical sexual functions, including the hypothalamus, limbic regions or spinal neurons. However, these findings leave unanswered 1) how downstream dopamine signaling modulates sexual function, 2) how distinct neurotransmitter systems interactively alter particular aspects of sexual function, and 3) to what extent the sexual circuitry and drug effects in rats translate to humans.

So maybe this post didn’t make you any happier. But hopefully it’s taught you how not to sabotage your sex life. Just remember to plan ahead and lay off the serotonin – or go heavy on the dopamine – if you want to stay frisky come date night.

References

1. Reas et al. (2013). Deceptive stats to lure readers to your blog. J Sci Blogging Propoganda.

2. Serretti A. & Chiesa A. (2009). Treatment-Emergent Sexual Dysfunction Related to Antidepressants: A Meta-Analysis. J Clin Psychopharm. 29(3):259-66.

3. Bijlsma EY, Chan JSW, Olivier B, Veening JG, Millan MJ, Waldinger MD & Oosting RS. (2013). Sexual side effects of serotonergic antidepressants: Mediated by inhibition of serotonin on central dopamine release? Pharm Biochem & Behav.

4. de Castilhos J, Marcuzzo S, Forti CD, Frey RM, Stein D, Achaval M & Rasia-Filho AA. (2005). Further studies on the rat posterodorsal medial amygdala: dendritic spine density and effect of 8-OH-DPAT microinjection on male sexual behavior. Brain Res Bull. 69(2):131-9.

5. Popova NK & Amstislavskaya TG. (2002). Involvement of the 5-HT(1A) and 5-HT(1B) serotonergic receptor subtypes in sexual arousal in male mice. Psychoneuroendocrinology. 27(5):609-18.

6. Lee KU, Lee YM, Nam JM, Lee HK, Kweon YS, Lee CT & Jun TY. (2010). Antidepressant-Induced Sexual Dysfunction among Newer Antidepressants in a Naturalistic Setting. Psychiatry Investig. 7(1):55-9.

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