Sexual side-effects – let’s talk!

Sexual side-effects, sometimes experienced by patients during treatment, are not only debilitating but may lead to poor treatment compliance and possible treatment discontinuation. Here we see that much can be done to prevent and overcome sexual side-effects.

“If sex is good for you, why not for your patients?” asked Angel Luis Montejo Gonzalez, Salamanca, Spain. His question was provoked by the finding that 85% of psychiatrists think that sex is important to their patients, yet 73% never ask their patients about it despite 35% of patients experiencing sexual dysfunction, due in part, to side-effects from their medications.

The implications are immense, not least when considering compliance with treatment. Therefore, psychiatrists need to treat patients’ sex lives with the same respect they treat their own, he suggested. “If you don’t ask,” he said, “they won’t tell.”

A neuroendocrine balancing act

So how does it all work and where best to intervene pharmacologically?

Sexual responsiveness requires the integration of sensory, motor, attentional and motivational aspects of sexual function balancing excitation (norepinephrine and oxytocin stimulating peripheral arousal, and dopamine (DA) and melanocortins impacting attention and desire) and inhibition (serotonin driving satiety, opioids mediating sexual reward, endocannabinoids inducing sedation, and prolactin reducing DA effects) in neuroendocrine pathways.

 

Balancing excitation/inhibition in treatment

Antidepressants and antipsychotics can have effects on sexual function and satisfaction by upsetting this precarious excitation/inhibition balance, Anita Clayton, Virginia, USA, explained.

A review of the available literature suggests that: antidepressants with positive effects on DA and melanocortin receptors and that are not broad 5-HTA1 agonists or 5-HT2 antagonists appear to have less impact on sexual functioning. Antipsychotics with D2 antagonist-partial agonistic effects or that act as 5-HT1A agonists or as 5-HT2 antagonists are also appear to be associated with lower rates of sexual dysfunction.

Sexual problems can be alleviated, if not avoided, through appropriate treatment

 

Putative prolactin control pathways

Raised serum levels of prolactin are often associated with sexual side-effects.

Dr Christian Broberger described some interesting electrophysiological studies on dopamine’s role in neuroendocrine tuberoinfundibular dopamine (TIDA) neuron feedback control.  TIDA neurons inhibit prolactin release from the pituitary and it is thought that D2 receptor antagonists’ action in blocking pituitary D2 receptors causes hyperprolactinaemia. However, other systems may also be at play. These include D2 antagonist-induced TIDA neuronal depolarization blockade which likely removes the dopamine ‘brake’ for prolactin release.

Hyperpolarization of TIDA neurons is thought responsible for the adverse reproductive effects in patients with depression. SSRIs decrease TIDA neurons intrinsic excitability but in ways that are both 5HT-dependent and independent. Clearly, further work has to be done but as Dr Broberger said, “This is in vitro lab work and we don’t know if it applies to humans – but it does generate ideas for pharmacologists!”

References
  1. Clayton AH, El Haddad S, Iluonakhamhe JP, Ponce Martinez C, Schuck AE. Sexual dysfunction associated with major depressive disorder and antidepressant treatment. Expert Opin Drug Saf. 2014 Oct;13(10):1361-74.
  2. Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015 May 15;95(2):81-97.
  3. Druyts E, Eapen S, Wu P, Thorlund K. The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis. Syst Rev. 2014 Oct 13;3:116.
  4. Kingsberg SA, Clayton AH, Pfaus JG. The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder. CNS Drugs. 2015 Nov;29(11):915-33.
  5. Lyons DJ, Ammari R, Hellysaz A, Broberger C. Serotonin and Antidepressant SSRIs Inhibit Rat Neuroendocrine Dopamine Neurons: Parallel Actions in the Lactotrophic Axis. J Neurosci. 2016 Jul 13;36(28):7392-406.
  6. Montejo ÁL1, Arango C2, Bernardo M3, Carrasco JL4, Crespo-Facorro B5, Cruz JJ et al. Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia. [Article in English, Spanish]. Rev Psiquiatr Salud Ment. 2016 Jul-Sep;9(3):158-73.
  7. Montejo ÁL1, Arango C2, Bernardo M3, Carrasco JL4, Crespo-Facorro B5, Cruz JJ et al. Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics. Front Neuroendocrinol. 2017 Apr;45:25-34.
  8. Park YW, Kim Y, Lee JH. Antipsychotic-induced sexual dysfunction and its management. World J Mens Health. 2012 Dec;30(3):153-9.
  9. Pfaus JG. Pathways of sexual desire. J Sex Med. 2009 Jun;6(6):1506-33.
  10. Stagkourakis S, Kim H, Lyons DJ, Broberger C. Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network. Cell Rep. 2016 Apr 14. pii: S2211-1247(16)30333-3.
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