Psychotropic Drug-Induced Sexual Dysfunction

Management of and Counseling for Psychotropic Drug-Induced Sexual Dysfunction


from Pharmacotherapy
Mary A. Gutierrez, Pharm.D.,Glen L. Stimmel, Pharm.D.



Abstract and Introduction
Abstract
Clinicians are increasingly faced with the need to identify, treat, and counsel patients regarding psychotropic drug-induced sexual dysfunction. Antipsychotic and antidepressant drugs have both rational mechanisms to explain their effects on sexual function and established literature documenting these effects. The agents have potential for causing decreased libido, delayed ejaculation, and anorgasmia. Management and counseling can be highly effective for patients taking these agents.

Introduction
Sexual response consists of three primary phases: desire, arousal, and orgasm (Table 1).[1] Normal sexual response depends on the interplay of many hormones and neurotransmitters. Altogether, it is a delicate chain of events that is easily broken. Key hormones and neuro-transmitters are dehydroepiandrosterone (DHEA), oxytocin, phenylethylamine (PEA), estrogen, testosterone, progesterone, prolactin, vasopressin, dopamine, serotonin, and acetylcholine. In addition to well-known effects of psychotropic drugs on various neurotransmitters, their effects on hormones and peptides may contribute to disruption of sexual function. The androgen DHEA, which is a precursor to testosterone, estrogen, and pheromones, has an excitatory role in limbic arousal in men and women. Drugs known to decrease DHEA include carbamazepine, phenytoin, cytochrome P450 (CYP) 3A4 inhibitors, and alcohol. Increases in DHEA may be caused by bupropion, digoxin, diltiazem, and cigarette smoking.[2]
Oxytocin's role in sexual response is primarily to facilitate attraction and touch sensation, with levels increasing secondary to touch and spiking during orgasm. Oxytocin is also responsible for postorgasm inertia and refractory period, greater in men than in women. Drug effects on oxytocin are not well established, but estrogen and yohimbine increase its levels and alcohol decreases them. Amphetamine-like PEA is a stimulant whose levels spike at orgasm and ovulation and is believed to mediate feelings of romance and love. Its levels are increased by monoamine oxidase inhibitors. Prolactin directly inhibits sexual desire, arousal, and orgasm as well as erectile function in men. Its levels are increased by dopamine-blocking drugs (most antipsychotic drugs) and opiates and decreased by bromocriptine, testosterone, dopamine, and bupropion.

Understanding the mechanisms and neuro-transmitters responsible for each phase of sexual function allows clinicians to predict how psychotropic drugs may affect sexual response and provides the basis for developing pharmaco-logic treatments to manage drug-induced sexual dysfunction.


Sexual Desire
Sexual desire (libido) is dependent on both psychogenic stimuli, involving all five senses, and hormonal factors. In men, androgens are an essential determinant of sexual desire. Evidence shows that the threshold testosterone level required for sexual desire is lower than the normal circulating range, and levels beyond this range do not directly increase sexual desire. In both men and women, increased estrogen or an increased estrogen:testosterone ratio decreases libido. High prolactin levels decrease libido directly. Antipsychotic drugs with dopamine-blocking activity increase prolactin levels and are a common cause of reduced libido.

Sexual Arousal
Arousal in men and women requires vascular and neurologic components. Adequate arterial inflow is necessary for penile erection and, in women, pelvic vasocongestion. Penile erection requires at least a 6-fold increase in arterial inflow into the cavernosa. Changes in arteries seen with atherosclerosis, smoking, diabetes, and hypertension may lead directly to erectile dysfunction. In addition to the necessity for adequate arterial inflow, several neurophysiologic pathways mediate sexual arousal.
Penile erection results from relaxation of the arterial smooth muscle within the corpus cavernosa, allowing increased blood inflow and mechanical occlusion of venous outflow. Arteries dilate in response to peripheral cholinergic activity and release of nitric oxide from parasympathetic nerve endings onto vascular smooth muscle. Parasympathetic stimulation in women causes similar erectile tissue vasocongestion and also causes vaginal lubrication by secretion of mucus from Bartholin's glands.

As antihypertensive drugs lower blood pressure, the resulting decreased arterial inflow explains the primary mechanism of their poten-tial to cause erectile dysfunction. Drugs with sig-nificant anticholinergic effect also may negatively influence sexual arousal, and selective serotonin reuptake inhibitors (SSRIs) reduce nitric oxide synthesis, explaining their potential to impede arousal. These early findings are being investi-gated in clinical trials to determine the role of treatments such as sildenafil. Dopamine-blocking antipsychotic drugs also decrease nitric oxide synthesis, and dopamine agonists enhance it.[3]

Detumescence requires both sympathetic and a-adrenergic activity to contract arterial smooth muscle, whereas b-adrenergic activity increases venous outflow. Trazodone, the agent most com-monly associated with drug-induced priapism, is a potent a-adrenergic-blocking agent without significant anticholinergic effect.


Orgasm
Orgasm in both men and women is primarily under adrenergic control. In men, released norepinephrine acts on a-adrenergic receptors of smooth muscle of the vas deferens, prostate, and seminal vessels to contract and propel seminal fluid into the bulbar urethra (emission). Ejaculation, as well as orgasm in women, is a sacral spinal reflex mediated primarily by adrenergic activity. Oxytocin plasma levels are increased during orgasm in men and women, and oxytocin levels correlate with orgasmic intensity.

Neurotransmitters and Sexual Function
Although the effect of psychotropic drugs on various hormones is not certain, their effect on several neurotransmitters influencing sexual function is well established. Dopamine is the neurotransmitter in the mesolimbic "pleasure center." Increasing dopaminergic activity may enhance sexual response, and blocking it may compromise response. Among psychotropic drugs, many antipsychotic agents are dopamine blockers, whereas the antidepressant bupropion has mild dopamine-agonist activity. A reciprocal relationship exists between serotonin and dopamine, in that serotonin can diminish the release of dopamine in the mesolimbic area, thus decreasing sexual response. Drugs that increase serotonergic activity are most commonly associated with delayed ejaculation in men and anorgasmia in men and women. In addition, the serotonin 5-HT2 receptor may block descending pathways from the brain stem to spinal neurons and interfere with spinal reflex centers necessary for ejaculation and orgasm. This mechanism underlies the delayed ejaculation and anorgasmia seen so commonly with serotonin agonists and explains why some antidepressants with 5-HT2-blocking effects (nefazodone, mirtazapine) do not cause anorgasmia.[4]