Problem of the Young

It is not so universally recognized that sleep disorders also affect the young. Although there are few large-scale epidemiologic studies of daytime sleepiness in adolescents and young adults, existing data suggest that problem sleepiness affects a significant percentage of youths. About 25% of American children aged 1–5 experience some kind of sleep disturbance. From 20%–25% of 9th through 12th grade students reportedly experience behaviors associated with problem sleepiness, such as difficulty getting up for school, falling asleep in school, or struggling to stay awake while doing homework. According to one report, 54%–75% of adolescents and young adults expressed “a wish for more sleep” because they were experiencing morning tiredness. In a survey of high school students, it was found that many students got less than 6.5 hours of sleep on school nights; only 15% reported sleeping 8.5 hours or more.

Together, these data indicate a widespread pattern in childhood of inadequate sleep and consequent problem sleepiness. The chart lists some of the more common problems associated with poor sleep patterns.

Physician Visits

Sleep problems in children 16 years old or younger are severe enough to trigger many visits to physicians by anxious parents. The most widely prescribed drugs for sleep disorders are psychotherapeutics, sedatives, and antihistamines. Drugs regularly prescribed include diphenhydra-mine, chloral hydrate and Imipramine (sold as Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil).

Since the 1983 report, many of the original study subjects have experienced multiple recurrences of major depressive disorder (MDD). In a study published in the Feb. issue of The American Journal of Psychiatry, David A. Solomon, M.D., and colleagues prospectively focused on the time to recurrence of MDD across multiple episodes. They predicted that the risk of recurrence would decrease as time of recovery increased. They also predicted that each recurrence would increase the risk of a subsequent recurrence.

The original collaborative depression group had a total of 955 patients. Of those, 318 recovered from their intake episode of major depression and were at risk of recurrence during the 10-year follow-up period. The study group for the Solomon et al. analysis consisted of these 318 subjects. Recovery was defined as at least eight consecutive weeks “with either no symptoms of major depressive disorder or only one or two symptoms at a mild level of severity”. Recurrence, which could occur only after recovery from the preceding depressive episode, was defined as the reappearance of major depressive disorder (MDD) meeting the full criteria for at least two consecutive weeks, beginning with the first of these two weeks. Episodes meeting criteria for minor depression and chronic intermittent depression were not included.

For the first five years of the follow-up study, patients were assessed every six months, and annually after that, using the Longitudinal Interval Follow-Up Evaluation. The analyses encompass data for up to 520 weeks of follow-up. As an observational study, treatment was not randomized or in any way controlled by anyone connected to the study.

Of the 318 subjects, 263 (83%) were followed for at least five years, and 208 (65%) were followed for the entire 10-year period. During those 10 years, 481 recurrences were observed. The mean number of episodes of major depressive disorder (MDD) per year of follow-up was 0.21 (SD=0.24).

Once the first eight-week recovery period was completed for the 318 subjects, 202 suffered a recurrence. Of those subjects, 172 recovered and remained healthy for the following eight-week period. A second recurrence was suffered by 115 of those patients. The median time to recurrence for the first episode was 150 weeks; for the second, 83 weeks; and for the third 77 weeks. These intervals were significantly longer than the time to recurrence for subsequent recurrences.

The investigators were also interested in the probability of a well patient experiencing a recurrence during a six-month period (the patient having began that period still well). They found the mean probability for recurrence during the first six months after recovery was 20% (SD=6) across the five prospectively observed recurrences. They wrote, “This indicates that, on average, of the subjects at risk for recurrence, 20% had a recurrence in the first 6 months after the onset of recovery from the preceding depressive episode”.

They found that rate of recurrence decreased in subsequent six-month intervals. In the second six months the probability of recurrence was 19% (SD=7), in the third six months it was 15% (SD=6), in the fourth six months it was 13% (SD=3), in the fifth six months it was 11% (SD=3). In the final six months after the onset of recovery from the preceding depressive episode the probability of recurrence was 9% (SD=6).

Solomon et al. found that the risk for recurrence increased by 16% for each successive episode of major depression. The number of lifetime episodes of major depressive disorder (MDD) was significantly associated with recurrence during this 10-year follow-up period. Analysis showed that there was very little consistency in the time to recurrence within the subject group.

When the researchers looked at treatment of these subjects, they called the low level of maintenance pharmacotherapy during any of the four weeks immediately preceding any of the prospectively observed recurrences striking. Up to 47% to 50% of subjects received no pharmacotherapy during the four weeks immediately preceding the first three recurrences. One-third received no pharmacotherapy in the four weeks immediately preceding the fourth and fifth recurrences. During any of the preceding four-week periods, only 33% to 45% of subjects received at least 100 mg/d of imipramine (Tofranil) or its equivalent. Only 18% to 30% of subjects received at least 200 mg/d of imipramine or its equivalent during the same time period prior to any of the five prospectively observed recurrences.

Solomon et al. wrote that, as predicted, “as the duration of recovery increases, the risk of recurrences decreases or decays.” Also as predicted, “With each successive recurrence, the risk of a subsequent recurrence increases by 16%.” Consistency in time to recurrence, however, was highly variable among this group, indicating that time to recurrence is also highly variable for any individual.

Limitations of this study, the researchers pointed out, included the progressively smaller group size following each recurrence. They speculate that this caused the data analyses to underestimate rates of recurrence over a patient lifetime. Another limitation was the exclusion of minor or intermittent depression, causing a possible underreporting of the extent of psychopathology in the subject group. Finally, the researchers suggest that variability in treatment may have influenced the findings. Patients may have discontinued treatment following recovery, putting themselves at greater risk of recurrence. Recurrence may have caused other patients to discontinue treatment due to discouragement, putting these patients at risk for further recurrence as well. Solomon et al. found the lack of maintenance pharmacotherapy unfortunate, given its role in preventing recurrences

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.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.