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I have received a number of questions during the past few months regarding the sexual side effects of psychotropic medications. I thought it would make sense to address these questions together and discuss more broadly the sexual side effects of psychotropics. Side effects of psychotropics affecting appetite, metabolism, and weight will be discussed in a future column.
Not only psychotropics, but a large number of medications, can cause sexual side effects. These side effects include decreased desire, diminished capacity for erection in men, diminished capacity for arousal and lubrication in women, and/or decreased or absent ability to achieve orgasm for both men and women.
It is also important to note, in this context, that the illnesses for which psychotropics are prescribed can have negative effects on a person’s sexuality. For example, loss of desire is often a prominent symptom of depression. Post-traumatic stress disorder (and other post traumatic disorders), in which a person has been traumatized by sexual or other physical contact, may result in flashbacks related to any physical contact and/or hyperarousal of the autonomic nervous system (not the sexual kind of arousal). These symptoms and hypervigilance, in which a person cannot relax enough to become sexually aroused, can impair sexual functioning in PTSD patients. Other anxiety disorders in which somatic (body feeling) anxiety is prominent may also include feeling increased anxiety when there is any change in the body’s feeling state and a constant “scanning” of the body for sensations, so that the person becomes alarmed by any change in how their body feels, before they can decide whether the feeling might become pleasurable. Nevertheless, a lot of people, even if their sexual functioning is impaired by their illnesses, suffer a (further) decrease in their sexual sensation and impairment of some or all phases of their sexual responses after they have taken some psychotropic medications.
Among psychotropic medications, selective serotonin reuptake inhibitor antidepressants (SSRIs), including fluoxetine (Prozac), paroxetine (Paxil, Pexeva), citalopram (Celexa), escitalopram (Lexapro), sertraline (Zoloft), fluvoxamine (Luvox), and the combined sertonin-norepinephrine reuptake inhibitor venlafaxine (Effexor) are the most notorious for sexual side effects. Studies show up to a 30% incidence these side effects among people who take these medications, or possibly even higher, depending on how the study is done, because these side effects are not always volunteered by patients to their doctors. Sexual side effect rates in the drugs’ prescribing information, such as in the package insert or PDR are generally lower than this, because the initial studies to get drugs marketed were of short duration and relied on self-report of sexual side effects in most cases. Post-marketing surveillance and follow up studies using interviews and questionnaires have found the higher rates.
The medications mentioned in the foregoing paragraph all have a potent effect to increase serotonin availability between cells by blocking serotonin reuptake back into the cells, which is the mechanism by which serotonin is cleared from the synapses between cells. It is for this reason that these drugs are called serotonin reuptake inhibitors (or serotonin-norepinephrine reuptake inhibitors, in the case of Effexor), and this effect is not limited to the brain but occurs throughout the body. Thus, there is increased serotonin available also in the spinal nerves and ganglia, where serotonin functions to inhibit sexual arousal and the responses involved in orgasm. In fact, this side effect is even utilized by doctors sometimes in treating men who experience premature ejaculation, where slowing down the sexual response cycle is the goal of treatment! Statistically, there is not a great deal of difference in the rates at which these drugs cause sexual side effects. Manufacturers often claim lower rates of side effects for newer drugs, because they are looking at their short term trial data, rather than post marketing surveillance. One meta-analysis of these drugs’s side effects suggested that sertraline might not be as bad as the others, presumably because of a secondary effect to increase dopamine availability (dopamine is a pro-sexual neurtotransmitter), and that paroxetine might be a little worse, due to its secondary effects on other transmitters. Other data and patient reports suggest that Lexapro might not be as bad as other SSRI’s, too.
Cymbalta is a newer serotonin-norepinephrine reuptake inhibitor that may have a lower frequency of sexual side effects than the previously mentioned group – at least in women. Reasons for this difference are not known, but I have treated women who described restoration of their sexual sensation and functioning when changed from an SSRI to Cymbalta, while maintaining their benefits for depression and/or anxiety symptoms, making this also a worthwhile lead to pursue, for patients whose illnesses respond to the mechanism of serotonin reuptake inhibition.
Tricyclic antidepressants (TCA’s), some of which have been available since the 1960’s, also cause sexual side effects, but vary in the degree to which they have this effect. The variance among TCA’s is due to the fact that they vary greatly in their ratios of serotonin reuptake inhibition to norepinephrine reuptake inhibition, and also vary in their anticholinergic effects, which most commonly are dry mouth, blurred vision, constipation, urinary hesitancy, dry skin, etc. Strong anticholinergic effects can inhibit orgasm. For example, clomipramine (Anafranil) is strongly serotonergic (which makes it useful for Obsessive Compulsive Disorder) and strongly anticholinergic, and causes severe sexual side effects. Amitryptiline (Elavil), still widely used for insomnia and various chronic pain syndromes, including fibromyalgia, is not quite as serotonergic as clomipramine, but is still anticholinergic, and causes moderate sexual side effects. Imipramine (Tofranil), which is still the gold standard interms of antidepressant efficacy, is slightly less anticholinergic than amitryptiline. Nortryptiline (Pamelor) and desipramine (Norpramin) are primarily norepinephrine reuptake inhibitors with minimal effects on serotonin, are only moderately anticholinergic, and have less pronounced sexual side effects. MAO inhibitors are another group of older antidepressants that also increase serotonin availability and cause sexual side effects, but they are seldom used by most practitioners because of the dietary restrictions required by the MAO inhibitors available in the United States in order to prevent the serious side effect of hypertensive crisis.
Antipsychotic drugs can cause sexual side effects, although not as frequently as the SSRI’s, and do this by different mechanisms. Antipsychotic drugs antagonize the effect of dopamine, which is necessary for sexual arousal and for the experience of behaviors as rewarding or pleasurable. The antagonism of reward is more of an issue for the “typical” antipsychotic drugs than for the newer, “atypical” antipsychotic drugs which have less effect on dopamine in certain brain regions. Risperdal and the older antipsychotic drugs also elevate the hormone prolactin, which the body normally makes during pregnancy, and this can lead to breast swelling and sometimes milk production (galactorrhea) and can stop the menstrual cycle. The elevated prolactin level lowers the level of estrogen and this can lead to reduced desire, as well as other unwanted metabolic effects, such as lower bone density. Also, antipsychotic drugs often effect the tone of blood vessels by blocking what are called alpha a receptors (for norepinephrine), and this can interfere with the changes in genital blood flow patterns that are necessary for physical arousal to occur. Blocking alpha receptors also causes dizziness when a person gets up (postural hypotension). Some of the older antipsychotic drugs, like chlorpromazine (Thorazine) and thioridazine (Mellaril) are also strongly anticholinergic. This combination of effects could strongly interfere with sexual functioning, which some would argue was why so much Mellaril used to be prescribed in state hospitals! Among the newer antipsychotic drugs, Risperdal seems to have the most adverse sexual side effects, and there is some evidence that Seroquel is not so problematic in this regard.
Treatment strategies for psychotropic drug sexual side effects depend on what drug is responsible for the side effects, and by what mechanism it is causing them. Several strategies have been described for addressing this problem, with various degrees of benefit and literature support.
“Watchful waiting” is the strategy of hoping that sexual side effects decrease over time as the body adapts to the higher levels of serotonin available. Unfortunately, this does not seem to happen all that often. If “watchful waiting” for side effects to decrease over a period of weeks fails, the literature and my experience offer the following alternatives:
Dosage reduction: Sometimes people are able to sustain improvement or maintain remission from depression and anxiety disorders on lower doses than needed to reduce symptoms initially, or sometimes the initial dose a doctor selects for a patient may be more than they actually needed. A potential barometer of the latter situation is the presence of other symptoms of serotonin excess, such over activation of the gastrointestinal tract where serotonin is an activating transmitter (such as persistent nausea , vomiting, or diarrhea), jerking movements called myoclonic jerks (arms or legs jerk as if they were given a shock), impaired memory and concentration, and apathy or emotional blunting. In such cases, reducing the dose of the drug may relieve sexual (and other) side effects while retaining the drug’s effectiveness. Such a strategy also needs to take into consideration the condition for which the person is being treated. For example, I would not rush into reducing a medication dose if the medication has just helped a person get over a depression that was catastrophic in terms of causing a suicide attempt, hospitalization, inability to work, or other measure of severe disturbance, because I would not want to risk loss of the drug’s efficacy in those situations.
Drug holidays are seldom a good idea with this group of drugs, in my opinion, due to discontinuation symptoms, as well as risk of relapse. Discontinuation symptoms, such as flu-like symptoms or feelings of electric shocks, are the result of neurons that have adapted to higher levels of serotonin suddenly being deprived of the levels they have adapted to.
Substitution of a different drug that increases serotonin availability: Despite similarities of drugs within a class, people do differ in their response to them, both in terms of therapeutic efficacy and side effects. Switching SRI’s to sertraline (Zoloft) or Lexapro, or switching to the SNRI Cymbalta are helpful strategies on occasion. I would again add a caution about changing a drug that has worked to relieve overwhelming or catastrophic symptoms, because there is no guarantee that the second drug will either work as well, or have less side effects.
Substitution of a different drug that treats the person’s condition, but has less or no sexual side effects: Major depressive disorder responds as frequently to Wellbutrin (bupropion), Remeron (mirtazapine), or norepinephrine reuptake inhibitor TCA’s as it does to SSRI’s. Panic disorder also responds to these TCA’s and probably to Remeron, and responds to high potency benzodiazepines Xanax (alprazolam), Klonopin (clonazepam), and possibly Ativan (lorazepam). Generalized Anxiety Disorder responds also to benzodiazepines, Buspar (busipirone), probably to Remeron, and possibly to a new anticonvulsant called Lyrica. All of these other drugs have their own side effects, of course, including weight gain with Remeron, sedation and abuse potential with benzodiazepines, and dizziness with Buspar. Wellbutrin is often an excellent alternative for major depressive disorder, if the person does not have a history of seizures, but does not have the anti-anxiety or anti-panic properties of some other antidepressants. The same caution stated above, about changing a drug that has helped a catastrophic illness, applies to this strategy.
Adding drugs that increase dopamine availability: This is a popular strategy among psychiatrists, particularly adding Wellbutrin to an SRI or SNRI. In addition, adding Wellbutrin can improve antidepressant efficacy. Wellbutrin needs to be taken every day to have this effect. Less popular, but also reported to be effective is increasing dopamine availability by psychostimulants like methylphenidate or amphetamine preparations. Of course, taking a psychostimulant in the evening may have an adverse effect upon sleep!
Adding a phosphodiesterase-5 (PDE5) inhibitor: The drugs Viagra, Levitra, and Cialis inhibit an enzyme called phoshodiesterase5, which breaks down the chemical called cyclic GMP that allow smooth muscles to relax. Relaxation of smooth muscles in blood vessels and other tissues is necessary for the erectile tissues in the penis and clitoris to become engorged, as part of the sexual response cycle. Drugs that inhibit this enzyme thus allow the c-GMP that facilitates erection and physical arousal to be present longer and accumulate to higher concentrations, and thus improve sexual response. All of these drugs help with drug induced sexual side effects, in both men and women.
Yohimbine is a naturally occurring substance that has been shown to improve erectile dysfunction in men. It facilitates sexual arousal by acting on alpha-2 adrenoceptors (norepinephrine receptors) in the central nervous system and also blocks adrenergic influences in blood vessels, allowing increased blood flow. The effect of yohimbine in the central nervous system also can lead to side effects of headache, sweating, agitation, sleeplessness, and elevated blood pressure, so I have seldom recommended it.
L-arginine is an amino acid that is the precursor of Nitric Oxide (NO). NO is actually a gas, and functions in the body as a chemical messenger that triggers the formation of c-GMP and thus plays a key role in smooth muscle relaxation necessary for sexual arousal. L-arginine can be taken by mouth as a supplement, and high doses of it (several grams per day) have been shown to have a modest benefit in erectile dysfunction, generally, although it has not been studied specifically for antidepressant induced sexual dysfunction. Adding l-arginine to yohimbine may yield a greater effect. I have no personal experience using l-arginine.
Serotonin antagonists and partial agonists, such as buspirone and the antihistamine periactin have shown modest benefit in some studies, meaning that they are not as reliable as Wellbutrin or PDE-5 inhibitors like Viagra. Since buspirone helps with anxiety symptoms and may augment the effect of SSRI’s, it is often worth a try for people with residual anxiety symptoms, and is well tolerated if you don’t get the dizziness side effect that affects about 10% of people.
Herbal supplements have also been studied for sexual dysfunction, including for dysfunction induced by antidepressants. Gingko biloba seemed helpful in an initial study, but subsequent controlled studies have not found a consistent benefit, although some individuals reported that it helped them. High doses of Panax (Red Korean) ginseng have been shown to benefit erectile dysfunction in general, but have not been studied for antidepressant induced sexual dysfunction. These supplements are also worth looking into regarding improvement in memory, especially when used together, but that discussion is beyond the scope of this column.
This has been a lot of material to present, and I appreciate your patience with it. But the more informed you are, and the more you know about alternatives, the more choices you will have for the fullest recovery and healing.
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