Answer. There are, to my knowledge, few controlled studies of these agents for the treatment of psychotropic-induced sexual dysfunction; mainly, we are dependent on small uncontrolled case reports. Thus, it is hard to speak of “success rates” in any meaningful way. A good reference is the paper by FM Jacobsen, ( J Clin Psychiatry 1992; 53:119-122), discussing the use of yohimbine for Prozac-induced sexual dysfunction. Jacobsen, in a noncontrolled study, found that up to 90% of patients improved. Yohimbine boosts levels of norepinephrine, a chemical needed for normal sexual function (as well as normal mood). It is usually well-tolerated, but can occasionally cause nausea, anxiety, insomnia, or urinary frequency.

Cyproheptadine is a medication that interferes with the chemical serotonin- which is precisely the chemical that Prozac boosts. Thus, while cyproheptadine can counteract Prozac-induced sexual side effects, it can also “undermine” the antidepressant effect of the Prozac (or similar antidepressants). Bethanechol boosts yet another chemical called acetylcholine (as you can tell, sexual function involves a delicate balance of several chemicals), and is sometimes helpful in sexual dysfunction – though not spectacularly so, in my experience.

Other options include adding either a small amount of bupropion (Wellbutrin, another antidepressant) or buspirone (BuSpar) to the Prozac; both of these agents are usually well-tolerated, and may help counteract the Prozac’s sexual side effects. Another option, of course, is to switch to an agent (such as Wellbutrin or Serzone) that is less likely to cause sexual problems in the first place – but these are all options that should be discussed thoroughly with your doctor. As far as costs go, I suggest you check with a couple of pharmacies in your area, since prices can vary considerably.

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.