Dr. Becker is an instructor in the Department of Psychiatry and Human Behavior and associate director of Consultation-Liaison Psychiatry; Dr. Mayor is clinical assistant professor of Psychiatry and Human Behavior; and Dr. Kunkel is professor of Psychiatry and Human Behavior, vice chair for Clinical Affairs, and director of Consultation-Liaison Psychiatry, all at Thomas Jefferson University in Philadelphia, Pennsylvania.

Disclosures: Drs. Becker and Mayor report no affiliation with or financial interest in any organiziation that may pose a conflict of interest. Dr. Kunkel is on the speaker’s bureaus of Intramed/Forest, Pfizer, and Wyeth.

Please direct all correspondence to: Madeleine A. Becker, MD, Thomas Jefferson University, Department of Psychiatry and Human Behavior, 1020 Sansom St, Suite 1652, Philadelphia, PA 19107; Tel: 215-955-1606; Fax: 215-955-8473; E-mail: Madeleine.becker@jefferson.edu.


 

Focus Points

• There is clinical evidence for significant benefit of breastfeeding for the infant.
• Psychiatric illness is common in the postpartum period.
• Psychotropic medications are often necessary to treat postpartum psychiatric illness.
• Based on the existing data, some psychotropic medications are more compatible with breastfeeding than others.
 

Abstract

World health experts encourage women to breastfeed, but many primary care physicians, obstetricians, and psychiatrists are hesitant to encourage new mothers who are taking psychiatric medications to do so. Unfortunately, there are only a few case-controlled studies on the safety of psychotropics in breastfeeding. This article outlines the benefits of breastfeeding, both for the infant and for the mother; postpartum illness and its effect on the mother and infant; and the existing data on the most commonly used psychotropics. The effect of psychotropics on the nursing infant is examined and summarized.

Introduction

Many new mothers who need to take medications for psychiatric illness would like to breastfeed but are hesitant, as they are uncertain about the safety of these medications for their infant. There are currently very few, and no large, case-controlled studies on the safety of psychotropics in lactation. Prospective, randomized, double-blind, placebo-controlled trials cannot be conducted for obvious ethical reasons. Consequently, most of the current information available is compiled from case series and case reports and remains limited in quality and quantity. Drugs that have been on the market for some time (selective serotonin reuptake inhibitors [SSRIs], some mood stabilizers, benzodiazepines, typical antipsychotics) have accumulated relatively large or stable data. Newer drugs (dual-action antidepressants, atypical antipsychotics) have only scarce data. As a result of the lack of controlled studies, physicians are often confronted with a dilemma as to whether or not to prescribe medications for women who want to breastfeed.

In cases in which medication is felt to be necessary, consultation between the mother’s physician (primary care physician [PCP], obstetrician, and/or psychiatrist) and the pediatrician is recommended for choosing the safest options. The potential benefits of breastfeeding should always be weighed against the risks to the neonate. This should be fully discussed with the patient. The treating physician should review with the patient the available information about the risks and benefits. Discussion of risks and benefits of breastfeeding for a mother using psychiatric medications should be documented. Mothers should be made aware that the use of psychiatric medication may have other adverse consequences on the infant that are not known, as our knowledge is based on the limited data we have available at this time. If the patient decides to continue breastfeeding while using psychiatric medication, the infant should be monitored by the pediatrician for possible side effects.

This article first reviews the benefits of breastfeeding both for the infant and the mother. It discusses postpartum psychiatric illness that requires psychotropic medication. It then provides an update on the current data published about the most commonly used psychotropic agents and their safety in breastfeeding.

A closer look into this topic has become timely with the recent (May 2008) public announcement of the Food and Drug Administration’s proposed final rule on pregnancy and lactation labeling. The letter system, which categorizes drugs into risk categories A, B, C, D, and X, will be eliminated. This system is outdated and does not account for new information about drug safety and risk profiles in pregnancy and lactation. Additionally, it is over-simplified, leading to imbalanced counseling of clients by healthcare providers. The new labeling system will have separate sections for pregnancy and for lactation, and each section will have three main components: risk summary, clinical considerations, and analysis of data (animal vs. human). Some of the information proposed for inclusion in the new labeling for lactation are discussed in this article, namely, compatibility of a specific drug with breast-feeding; amount of drug passed on to the infant from breast milk; possible effects of the drug on the breastfeeding infant; recommendations for monitoring these effects; and a review of the available data addressing these issues.1

The Benefits of Breastfeeding

The World Health Organization, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists recommend breast milk exclusively for at least the first 6 months of life,2-6 and continued breast milk with food through 6–12 months of age.7 There is evidence for significant health-related, nutritional, immunologic, developmental, psychologic, social, economic, and environmental advantages for breastfeeding.6-8

Breastfeeding is associated with a reduction in infant mortality rates.3,7,9-11 Other associated benefits include a reduction in the risk of infectious diseases (meningitis),12,13 gastrointestinal infection,14,15 deaths due to diarrhea,16 necrotizing enterocolitis,17 otitis media,18,19 respiratory infections,15,16,20,21 urinary tract infections,22,23 and sepsis.13 Breast-fed infants have reduced rates of sudden infant death syndrome.7,10 Other positive outcomes include a lower incidence of pediatric cancers,24,25 including lymphoma, leukemia, and Hodgkins disease. Reports also include a lower incidence of diabetes,26 obesity,27-31 and asthma32-35 in children and adults who were breastfed as infants. Increased analgesia during painful procedures for infants has also been reported in breastfed infants.36,37

Some research has also suggested a possible increase in cognitive development in infants who were breastfed.7,38 However, other more recent studies have found that this association with increased cognitive function is weaker than previously thought39 and possibly most significant for babies of small gestational size40,41 or attributable to factors other than breast milk.42 This area is still controversial and requires further study.

Maternal benefits of breastfeeding include decreased postpartum bleeding, more rapid uterine involution,43 and faster weight loss to pre-pregnancy weight.44,45 Studies have also shown a reduced risk of breast cancer46-51 and ovarian cancer,52-54 and possibly a lower prevalence of the metabolic syndrome.55

Other benefits of breastfeeding include lower overall healthcare costs for less infant illness.56 Breastfeeding is much more economical than buying formula. Environmental benefits include less waste generated by disposal of formula packaging.7 However, for women who are unable or disinclined to breastfeed, formula is a reasonable alternative to breastfeeding.

When Breastfeeding is Contraindicated

Some women should not breastfeed because of certain health risks it may pose to the baby. Breastfeeding is not recommended for mothers receiving certain chemotherapeutic agents or radioactive isotopes and selected other medications rated to be unsafe by the American Academy of Pediatrics. Mothers with herpes simplex lesions on the breast, HIV, or active tuberculosis, or those abusing drugs should also not breastfeed.7 Infants with galactosemia, premature children, and children with inherited disturbances in metabolism may be particularly vulnerable to the effects of psychotropics during breastfeeding.57

Another reason a women may choose not to breastfeed includes mental illness where the risk of sleep disruption could worsen the condition, such as bipolar disorder. In some instances, women may opt to bottle feed, as the burden of frequent night feedings and prolonged sleep deprivation may be shared with another caregiver.

 

Postpartum Psychiatric Illness

There is a high rate of psychiatric illness after childbirth. This may be attributable to hormonal factors, but also can be associated with psychological stress and previous psychiatric illness in the mother.58,59 Given the high rate of psychiatric illness during and after pregnancy, the healthcare practitioner should carefully and thoroughly evaluate the postpartum patient who is at risk for psychiatric illness to determine whether medication is necessary. They should understand the risks associated with psychiatric medications, and carefully assess the need for medication in the nursing mother.

Postpartum blues is a temporary and common condition affecting up to 85% of new mothers. This condition is characterized by tearfulness, mood lability, irritability, and anxiety. Symptoms usually begin around postpartum days 2–4 and resolve spontaneously, usually in ~2 weeks. Symptoms are generally transient and require no medication treatment. However, women with postpartum blues may be at increased risk for the subsequent development of postpartum depression.60

The highest rates of major depressive disorder (MDD) occur in women during the childbearing years, between 25–44 years of age.2,61 Postpartum depression is common, and occurs in up to 5% to 20% of women.57 Symptoms of postpartum depression are the same as for depression at other times and include depressed mood, insomnia, anhedonia, and suicidal ideation. The criteria of “postpartum onset” specifier in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision,62 is applied to the first 4 weeks after childbirth. The International Statistical Classification of Diseases and Health Related Problems, Tenth Revision,63 coding permits classifications of postpartum mental disorders 6 weeks after childbirth. In reality, many clinicians would consider depressive symptoms to be “postpartum depression” for a much longer period than this. Proposals for revisions of classifications include a specifier for onset within 3 months postpartum.64 The Edinburgh Postnatal Depression Scale is recommended for screening in women at risk for postpartum depression.

Women with a history of depression, postpartum depression, or previous psychiatric disorder are at an increased risk for postpartum depression.57,65-67 Social isolation, high parity, and psychological distress in late pregnancy are associated with postpartum depression.65 During pregnancy there is a high rate of relapse in patients with a history of MDD. A recent study68 of pregnant women with moderate-to-severe recurrent depression, who were taking antidepressants before conception and who then chose to discontinue medication, showed a 68% relapse rate of depression during their pregnancies. This was compared with a 25% relapse rate for those women who chose to continue antidepressants throughout their pregnancies.68

Postpartum psychosis is much less common, affecting ~0.1% to 0.2% of all women.69 It is characterized by mood lability, agitation, confusion, thought disorganization, hallucinations, and disturbed sleep. Postpartum psychosis has been associated with an increased risk of suicide, infant neglect, and infanticide,67,70 and is considered an emergency. Although relatively rare in the general population, the risk of postpartum psychosis in mothers with a history of previous inpatient psychiatric hospitalization is increased significantly compared to those without.71,72 There is also a very high risk of postpartum psychosis in mothers with bipolar depression, reported as high as 46%.2,58,59 Women who have had an episode of postpartum psychosis are at risk for developing bipolar affective disorder, suggesting that this could be a subcategory of bipolar disorder.67 Rates of relapse of bipolar disorder after pregnancy are high, ranging from 20% to 35%.67

Anxiety disorders are also very common, especially in the postpartum period. Postpartum panic disorder has been the most frequently reported anxiety condition.2,67 Rates of obsessive-compulsive disorder (OCD) have been reported to be higher postpartum than during pregnancy. Both OCD and generalized anxiety disorder (GAD) have been found to have higher rates in the postpartum population than in the general population.73

Although the DSM-IV-TR does not specifically identify childbirth as an example of a traumatic event, childbirth can be recognized as a stressful medical/surgical procedure that involves intense pain and invasive procedures, suggesting that it is relevant to consider it as a stressor. Posttraumatic stress disorder (PTSD) is also now being recognized in postpartum period.73 Stressful life events as well as depression during pregnancy and GAD have been identified as being related to PTSD symptoms.73-75 Anxiety late in pregnancy also was found to be predictive of PTSD.76

Schizophrenia in pregnancy has been associated with an increased risk of stillbirths, infant death, preterm delivery, and low birth weight.77,78 Postpartum schizophrenia and psychosis, particularly if left untreated, can lead to increased rates of refusal of care, maternal self-mutilation, postnatal death, and poor perinatal outcomes.2,70,78

Untreated Maternal Psychiatric Illness

Psychiatric illness has been known to negatively influence mother-child interactions. Maternal depression is associated with an increase in premature births, low birthweight infants, fetal growth restriction, and postnatal complications.2 Infants of mothers with untreated depression have been shown to cry more and are more difficult to console.79 There is evidence that having a maternal psychiatric disorder also increases the risk of childhood behavioral problems.80

Maternal depression may also result in poor compliance with care and increased exposure to additional medications, illicit drugs, herbal remedies, alcohol, and tobacco. Untreated psychiatric illness has also been associated with difficulties with maternal-infant bonding.2 Studies81 also show that mothers with depression have a poor pattern of infant healthcare utilization, including an increased use of acute care and emergency room visits as well as decreased utilization of preventative services such as well-care visits and up-to-date vaccinations. Depressed mothers are also less likely to continue to breastfeed82 and less likely to promote childhood development by playing and talking to their baby and following predictable routines.83,84 Maternal depression has been shown to increase the risk of subsequent childhood psychopathology, including disruptive behaviors, anxiety disorders, and depression.85-88 On the other hand, remissions in maternal depression positively affect both mother and child, resulting in a significantly lower rate of children’s psychiatric symptoms and diagnoses.89

There is a high risk of relapse of psychiatric illness during and after pregnancy, and there is much evidence that untreated maternal illness may be harmful to both mother and baby. Psychotherapy should always be considered as part of the treatment choices. However, there are often instances when medications are helpful and in many cases necessary. With this in mind, the risks of fetal exposure to medication must be carefully weighed against the risk of the untreated psychiatric illness.

Psychotropic Medications and Breastfeeding

All psychiatric drugs pass into breast milk. Most psychiatric drugs are lipid soluble and pass easily into breast milk through passive diffusion across cell membranes. The most reliable method for measuring infant drug exposure is by measuring the drug level in the infant’s serum.60 The relative infant dose is one way of quantifying infant drug exposure, and is defined as the percentage of the maternal plasma level, in mg/kg, received by the infant in a 24-hour period. This is the infant plasma drug level divided by the average maternal plasma drug level. Most medications are considered safe when the infant dose is <10%. Breast milk levels also are measured and used to gauge potential for infant drug exposure. The American Academy of Pediatrics (AAP) has rated the compatibility of drugs during lactation. This rating is based on the reports found in the literature and is intended to assist the physician in counseling the mother regarding breastfeeding while taking medication (Table 1).90

 

Antidepressants

The AAP Committee on Drug Safety rates all antidepressants as effects “unknown” and may be “of concern” in breastfeeding.90 However, a pooled analysis of antidepressant levels in lactating mothers suggests that it is probably safe to use antidepressants during lactation.91

SSRIs

The growing evidence is generally reassuring concerning safety of using SSRIs in breastfeeding mothers. There are few reports of adverse effects on exposed infants to these medications.57 The excretion of SSRIs into breast milk ranges from relatively low to undetectable.57,92,93 Long-term effects of infant exposure to SSRIs have been less well studied.

Fluoxetine
Fluoxetine 20–40 mg results in relatively low infant plasma levels.93-96 A PubMed search identified a total of 67 cases of exposure. Norfluoxetine, the active metabolite of fluoxetine, has a very long half-life; it may likely be responsible for higher levels than the other SSRIs and accumulation in infants.91,98 There have been several reports93,97-99 of tremulousness, excessive crying, colic, poor feeding, and in one case lethargy in infants exposed to fluoxetine through breast milk. However, in most studies, no adverse effects were seen in infants up to 1 year of age.57,93-96

Sertraline

Sertraline has been relatively well studied. Ninety-five cases were identified looking at breastfeeding level and effects on infants. Levels in nursing infants have been reported as low to undetectable in infant serum and low in breast milk. No adverse effects have been reported in the exposed infants.91,100-105 No significant change in serotonin transport in the infants were found in exposed infants.106

Citalopram
Citalopram exposure through breast milk produced relatively higher infant levels than the other SSRIs.91,107,108 Nevertheless, infant levels are still found to be very low to undetectable in most studies.109,110 One study108 reported poor sleep in an exposed infant, but symptoms resolved after the dose was reduced. Fifty-three cases were identified in the literature. Most studies did not report adverse events in infants who were breastfed while their mothers were taking citalopram, including a small case-controlled study of 31 women-infant pairs.110,111

Escitalopram
Few cases have been published to date on the safety of the use of escitalopram in nursing. In a total of nine mother-infant pairs, infant levels were found to be low to undetectable and no adverse effects were seen in infants who had normal developmental milestones.112,113 Another study114 with two mother-infant pairs showed breast milk levels as similar to levels found with citalopram, and infants showed no adverse effects.

Fluvoxamine
In the 10 case reports found on PubMed on fluvoxamine, the drug has shown to produce variable but relatively low levels in exposed infants with no adverse effects reported100,115-118 and no adverse effects after 2–3 years.119

Paroxetine
Infants exposed to paroxetine through breastfeeding have been found to have low to undetectable serum levels. A total of 88 mother-infant pairs were examined. All of these cases reported no significant adverse side effects in the exposed infants observed100,120-122 and did not appear to affect weight gain or developmental milestones.123

Summary of SSRI Data
Low infant plasma levels have been found with all the SSRIs, but higher concentrations have been reported for fluoxetine98,99 and citalopram.91 Sertraline and paroxetine usually produced undetectable infant levels.91,92 The reviewed literature suggests that sertraline and paroxetine should be considered first-line choices in breast-feeding mothers who need to take SSRIs.61 However, the risk of relapse should always be considered; if a woman has been stable on another antidepressant throughout her pregnancy, one should not necessarily change medication, as the evidence suggests that most SSRI levels have been found to be quite low in the infant. However, fluoxetine and citalopram should not be first choices, and if needed for their effectiveness in individual women, they should be used with caution. An alternative is the decision not to breastfeed. This should be considered and discussed with the patient.

Tricyclic Antidepressants

The AAP rates the effects of tricyclic antidepressants (TCAs) as “unknown but may be of concern.” The levels of TCAs ingested by nursing infants was found to be low (<1% of maternal dose).124 Most reports show no adverse effects in the nursing infant.57,125 In most cases, there have been no adverse effects found with exposure to nortriptyline, imipramine, desipramine, or clomipramine.2,57,124

Doxepin
Doxepin has a long half-life and can accumulate in exposed infants. Despite low transfer into breast milk and infant plasma, two cases126,127 of infants exposed to doxepin through breast milk were associated with sedation and respiratory depression, likely due to accumulation in the infant. Because of this limited data it has been suggested that doxepin should be avoided during breastfeeding.57 However, with such a small number of cases it is difficult to draw any conclusions regarding the safety of doxepin in lactation.

Nortriptyline

Nortriptyline levels have been shown to be low to undetectable in infant serum, and no adverse effects were noted in the exposed infants.91,128,129

Monoamine Oxidase Inhibitors

No current data was found regarding monoamine oxidase inhibitors.

Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine
There are very few case reports published on the safety of venlafaxine in nursing. These show low to variable infant plasma levels in breast-fed infants. The mean infant dose ranged from 4.7% to 9.2%, which is relatively high compared with data published for other antidepressants.130 None of the cases of exposure to venlafaxine showed any adverse effects to the exposed infants.57,130-132

Duloxetine

No data is currently available for duloxetine.

Dopamine Reuptake Inhibitors

Bupropion
There are no studies and only a few case reports on the safety of bupropion in breastfed infants. Low infant serum levels were found.133,134 No adverse effects in two exposed infants were found.133 One study135 reported a seizure in a 6-month-old infant, which was possibly attributable to the use of bupropion during breastfeeding.

Other Antidepressants

Trazadone
There is very little data on trazadone. In the few cases examined, levels in breast milk have been found to be low.136

Mirtazapine
There are few studies looking at mirtazapine—a total of six cases of infant exposure in the literature. In these cases, infant levels were low to undetectable. No adverse effects were seen in the exposed infants, including no sedation or weight gain.137-139

Benzodiazepines

The AAP Committee on Drug Safety considers effects of benzodiazepines as “unknown, but may be of concern” in breastfeeding. Generally, the evidence shows that benzodiazepines have lower infant milk/plasma ratios than other psychotropic medications. Benzodiazepines with shorter half-lives (ie, lorazepam, alprazolam, and oxazepam) have been found to be very low in breast milk. No adverse effects were found in most exposed infants.2,57,140-144

Diazepam

Diazepam levels are very low in breast milk.143,145,146 Generally, infants have not shown any adverse effects, although there have been two cases147,148 reported where exposed infants became lethargic. These effects resolved after cessation of breastfeeding. Because of the longer half-life of diazepam, however, woman taking high doses or having long-term treatment should probably not breastfeed.57

Non-benzodiazepines/Hypnotics

Zolpidem

There is very limited data on zolpidem at this time, but in cases of five nursing women the drug was excreted in very low levels in breast milk.149

Mood Stabilizers

Lithium

The AAP Committee on Drug Safety considers lithium to be associated “with significant effects on some nursing infants and should be given to nursing mothers with caution.”90 Breast milk levels have been found to be high, at ~50% of maternal serum levels.150-152 Infant levels have been reported as variable, but higher than many other medications; from 33% to 55% of maternal levels.151 In the few case reports,153,154 adverse infant effects reported have included cyanosis, hypotonia, heart murmur, electrocardiogram changes, lethargy, and hypothermia. A more recent case study152 of 10 mother-infant pairs found that infant serum levels are probably only 25% of mother’s serum level, which is somewhat lower than previously thought. Occasional and transient lab abnormalities of elevated blood urea nitrogen (BUN), creatine, and thyroid stimulating hormone were observed in the sample of infants studied. Another recent study155 found considerable variability (0% to 30% of maternal dose) in infant serum levels of lithium, but again, lower than previously thought.

Infants may be more susceptible to both dehydration and lithium toxicity due to their immature kidney function and the potential for rapid dehydration. Therefore, the hydration status, BUN and creatine, lithium level, and thyroid levels should be carefully monitored in both mother and baby if it is necessary to use lithium in nursing.

Valproic Acid

The AAP Committee on Drug Safety considers valproic acid to be “compatible” with breastfeeding. Levels have been found to be very low in breast milk156 and very low in infant serum (0.9% to 7.6%).157-159 Only one adverse event of thrombocytopenia and anemia in an exposed infant was reported.160

Carbamazepine

The AAP Commitee on Drug Safety considers carbamazepine to be “compatible” with breastfeeding. Levels reported in infant serum were highly variable, from 15% to 65% of maternal levels.158,161 However, in case reports,162-164 carbamazepine was associated with infant hepatotoxicity. Exposed infants should be monitored by serum levels and liver function tests.

Lamotrigine

The effects of lamotrigine are classified by the AAP as “unknown, but may be of concern.” Lamotrigine is excreted in relatively high levels in breast milk. Infant serum levels were ~30% of maternal levels, likely due to a slow immature elimination in infants. However, none of the case reports found adverse effects in the infants.165-169 There have been no reported cases of Stevens-Johnson syndrome in nursing infants to date. Because of this concern, however, infants should be closely monitored.167

Summary of Mood Stabilizers

Carbamazepine and valproic acid are more compatible with breast feeding than lithium. Lamotrigine is not recommended while breastfeeding.57

The physician, however, always needs to give careful consideration to the need of keeping the mother on the medication that has kept her stable in the past (or during the pregnancy), rather than to risk relapse.

Antipsychotics

Typical Antipsychotics

The AAP Committee on Drug Safety rates the effects of haloperidol, chlorpromazine, thiothixene, mesoridazine, and trifluoperazine as “unknown and may be of concern” to nursing infants. Haloperidol is excreted in relatively high amounts in breast milk, but also has been shown to have no adverse effects on the infant.170,171 Chlorpromazine exposure has been associated with drowsiness and lethargy in one infant.172 In one study of seven infants with exposure to chlorpromazine through breast milk, there were no adverse effects reported at 16-month and 5-year follow-up evaluations.173 One study171 showed that infants exposed to haloperidol and chlorpromazine through breast milk exhibited developmental delays at 12–18 months of age. It is unclear if these delays were due to medication exposure or other factors.

Atypical Antipsychotics

Risperidone
Risperidone has not been rated by the AAP Committee on Drug Safety. There are only three case reports174-176 published to date on the safety of risperidone in lactation. Infant serum levels have been found to be low to undetectable in samples of nursing infants of women taking risperidone. No adverse effects in any of the exposed infants were reported.

Olanzapine
Olanzapine has not yet been rated for safety in breastfeeding, and there are few case reports at this time. Serum levels were low to undetectable in the small number studied.177,178 Most infants showed no adverse effects.177-179 In one infant exposed, there was a report179 of cardiomegaly, jaundice, and sedation. However, it is unclear whether this is accounted for by breastfeeding or in utero exposure.

Quetiapine
Quetiapine has not yet been rated on safety in breastfeeding. There are only two case reports180,181 to date on this medication. Breast milk levels were found to be low and there were no reported adverse effects in the exposed infants.

Clozapine
There are very few studies published on the safety of clozapine. The AAP rates effects as “unknown and of concern” in breastfeeding. It has been found in one case182 to have a relatively high accumulation in breast milk. There has been a case published,183 possibly attributing delayed speech acquisition to clozapine, in an infant after the mother was treated with clozapine both prenatally and during breastfeeding. Although no cases have been reported of agranulocytosis in nursing infants, it is a theoretical risk.184

Ziprasidone
Ziprasidone has not yet been rated. There are no studies published on its safety in breastfeeding.

Aripiprazole
There are no cases or studies published on safety of aripiprazole during lactation.

Summary of Antipsychotics

With limited data, if women breastfeed while taking antipsychotics, infants should be monitored closely for possible adverse effects. It is recommended that clozapine should not be used, as there is a theoretical risk of agranulocytosis in the infant.57

Table 21,56,60,85-87,92,93,118-120,122-152,155-176 summarizes the safety data of the major psychotropic medications when used during lactation.

 

Conclusion

The following clinical pearls summarize the guiding principles for using medications during breastfeeding.64,91,185 There is much evidence to suggest that untreated maternal psychiatric illness is harmful to both mother and baby. All psychotropic medications are transferred to human milk. One must ask if it is necessary to prescribe medications. If so, consultation between the mother’s physician (PCP, obstetrician, and/or psychiatrist) and the pediatrician is recommended for choosing the safest options. If the patient decides to continue breastfeeding while using psychiatric medication, the treating physician should review the available information with the patient. An alternative to consider in all cases is the decision not to breastfeed. When medication is necessary, the safest effective drug should be used. Exposure should be minimized by prescribing the lowest effective dosage of medication that achieves remission of symptoms. Short-acting medications are preferred over longer-acting medications. The decision to breastfeed should always be weighed against the risk to the neonate. This should always be fully discussed with the patient. Some medications may require blood monitoring in the nursing infant. Nursing should be stopped immediately if the nursing infant develops any abnormal symptoms. Discussion of benefits and risks of breastfeeding of a mother using psychiatric medications should be documented. Mothers should be made aware that the use of psychiatric medication may have other adverse consequences on the infant that are not always known, as current knowledge is based on the limited data available at this time. If the patient decides to continue breastfeeding while using psychiatric medication, the infant should be monitored by the pediatrician for possible side effects. The FDA’s proposed rule on pregnancy labeling will remove the letter-based category system. The proposed labeling will include more information about risks involved, clinical considerations, and quality of data used to determine them. PP

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178. Croke S, Buist A, Hackett LP, Ilett KF, Norman TR, Burrows GD. Olanzapine excretion in human breast milk: estimation of infant exposure. Int J Neuropsychopharmacol. 2002;5(3):243-247.
179. Goldstein DJ, Corbin LA, Fung MC. Olanzapine-exposed pregnancies and lactation: early experience. J Clin Psychopharmacol. 2000;20(4):399-403.
180. Lee A, Gliesbrecht E, Dunn E, Ito S. Excretion of quetiapine in breast milk. Am J Psychiatry. 2004;161(9):1715-1716.
181. Rampono J, Kristensen JH, Ilett KF, Hackett LP, Kohan R. Quetiapine and breast feeding. Ann Pharmacother. 2007;41(4):711-714.
182. Barnas C, Bergant A, Hummer M, Saria A, Fleishchhacker WW. Clozapine concentrations in maternal and fetal plasma, amniotic fluid and breast milk. Am J Psychiatry. 1994;151(6):945.
183. Mendheker DN. Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation. J Neuropsychiatry Clin Neurosci. 2007;19(2):196-197.
184. Jain AI, Lacy T. Psychotropic drugs in pregnancy and lactation. J Psychiatr Pract. 2005;11:(3):177-191.
185. Committee on Health Care for Underserved Women, American College of Obstetrics and Gynecologists.  ACOG Committee Opinion No 361: Breastfeeding: maternal and infant aspects. Obstet Gynecol. 2007;109(2 Pt 1):479-480.

Telephone Survey Finds Portion of Depressed and Anxious Patients Remain Ill Years After Treatment is Initiated

Although effective treatments are available, a large portion of patients suffering from depressive and anxiety disorders can remain ill for many years after initial diagnosis. Alexander S. Young, MD, MSPH, and colleagues from the University of California, Los Angeles, conducted telephone surveys of adults suffering from dysthymia, generalized anxiety disorder, panic disorder, or probable major depressive disorder from 1997–1998 as part of the “Healthcare for Communities” (HCC) project. On average, these patients were followed up with within 32 months. The surveys collected information about demographics; health and daily activities; mental health; alcohol and drug use; use of prescription and nonprescription medications; health insurance and coverage for mental health and substance abuse care; access, utilization, and quality of behavioral health care; labor market status; income and wealth; participation in public assistance programs; and life difficulties.

“The survey was conducted with a national probability sample,” Dr. Young said. “These households were randomly selected so that they are representative of the United States community populations of interest. The first wave of the survey, conducted in 1997–1998, consisted of ~9,600 adults who participated in the Community Tracking Study (CTS) household survey, affording an over-sample of persons at risk for alcohol, drug abuse, and mental health problems [as well as] of the poor. The second wave survey, conducted in 2000–2001, consisted of ~12,000 respondents, including those who participated in the first wave of HCC and some participants in the second wave of the CTS."

 Young and colleagues found that 59% of the originally surveyed population no longer met the criteria for the disorder they were initially suffering from. However, of the 41% of patients still suffering, 87% had a chronic comorbid medical disorder. They also found that 88% had seen a primary care physician and 22% had seen a mental health specialist in the past year.

“We have known about the cross-sectional prevalence of psychiatric disorders, from the National Comorbidity Study and related efforts,” Dr. Young said. “However, there has been too little accurate information regarding the prevalence of chronic and recurrent disorders. We found that chronic depressive and anxiety disorders are relatively common, and should be a major policy focus. We know that psychiatric disorders in general are becoming the leading cause of disability in the US, and our healthcare system needs to do a better job of helping people with these disorders. Persistent disorders appear to be a particular problem.”

At baseline, 21% of patients were taking medication. At follow-up, this increased to 29%. At baseline, 235 of patients were getting the appropriate amount of counseling. This decreased to 19% at follow-up. Combined, only 12% of the patient population received the appropriate amount of both counseling and medication treatment. The researchers also found that fewer men and people with less education sought treatment.

Lastly, Young and colleagues found that over half of the population (51%) were still suffering from suicide ideation at follow-up.

“Serious depressive disorders are often accompanied by suicidal ideation,” Dr. Young said. “It is not surprising that this is common; however, this study shows that suicidal ideation is in fact very common. Efforts to help with suicidality will need to address the fact that many people with these chronic disorders are not receiving specialty mental health care, rates of psychotherapy are particularly low, and rates of appropriate treatment (combined psychotherapy and medication) are very low.”

Young and colleagues believe that more strategies aimed at increasing treatment usage are needed. In addition, patients with persistent depressive and anxiety disorders need a more intense treatment program. Further research and policy will be needed to ensure equity of provision of mental health services to vulnerable populations, especially those with chronic and recurrent psychiatric illness.

Funding for this research was provided by a grant from the Robert Wood Johnson Foundation; and by grant P50MH54623, from the National Institute of Mental Health, to the UCLA–RAND Research Center on Managed Care for Psychiatric Disorders. Infrastructure support was also provided by the Department of Veterans Affairs. (Psychiatr Serv. 2008;59(12):1391.1398.) –CDN

Sleep Pattern Disturbances May Exacerbate Symptoms of Postpartum Depression for New Mothers

According to the National Institute of Mental Health, 10% to 15% of women experience postpartum depression (PPD)—characterized by feelings of hopelessness, exhaustion, anhedonia, among other symptoms—in the first year following childbirth. Prior research has also shown that PPD can negatively affect sleep quality, which may lead to deficits in the care a mother provides for her infant. In addition, studies have shown that patients with PPD who have irregular sleep patterns or who are sleep deprived may also alter their infant’s sleep quality as infants often adopt the sleep rhythm of their mothers. Recently, researchers at the College of Nursing and Health Professions of Drexel University in Newtown, Pennsylvania, sought to understand the degree of difference in sleep quality between mothers with or without PPD.

Bobbie Posmontier, CNM, PhD, and colleagues studied 46 women who were 6–26 weeks postpartum to determine the relationship between PPD and effects on sleep quality. Although most women experience some sleep loss postpartum (studies have shown that postpartum women remain awake for 20% longer over a 24-hour period than non-postpartum women), the researchers sought to understand if PPD contributed to greater sleep loss or if typical postpartum sleep loss had a causal connection or exacerbated symptoms of PPD.

Posmontier and colleagues utilized actigraphy to evaluate sleep quality. All patients wore wrist-bound actigraph units at home for 7 consecutive days. A structured clinical interview was used to determine the presence of PPD and the Postpartum Depression Screening Scale was then used to measure the severity of PPD symptoms. Other psychosocial measures, such as the presence of comorbid conditions, were also assessed to identify potential confounding variables. The authors found that ~50% of postpartum women in the study had PPD; two patients were removed from the study analyses because their data were outliers.

They found that patients with PPD experienced worse sleep quality that those without the disorder, and that as PPD symptoms worsened, sleep quality became poorer for women with PPD. When evaluating all patients in the study, researchers found that longer latency to sleep, increased wakefulness after sleep onset, and poor overall sleep efficiency predicted the presence of PPD. These results persisted after researchers accounted for the presence of other psychosocial variables.

Posmontier and colleagues concluded that primary care physicians (PCPs) should discuss various methods to improve sleep quality in new mothers with PPD in order to decrease overall symptom severity, which can further impair sleep quality. The importance of maintaining adequate sleep should be a significant topic in discussions between PCPs and mothers with PPD. The authors added that potential methods for improving sleep efficiency for mothers with PPD include creating a schedule for other family members to care for the infant at night as well as maintaining good sleep hygiene by avoiding caffeine or strenuous activity 4 hours prior to sleep and beginning sleep at the same time each night. In addition, researchers should develop more treatment interventions to facilitate improved sleep quality for patients with PPD. (J Obstet Gynecol Neonatal Nurs. 2008;37(6):722-735.) –CP

Psychiatric dispatches is written by Christopher Naccari and Carlos Perkins, Jr.

FDA Approves Milnacipran HCI for the Management of Fibromyalgia

The United States Food and Drug Administration approved milnacipran HCl (Savella, Forest Laboratories) for the treatment of fibromyalgia. It will be available in 12.5-mg, 25-mg, 50-mg, and 100-mg dosages.

The safety and efficacy of milnacipran HCI, a selective serotonin and norepinephrine dual reuptake inhibitor, was established in two clinical trials with a combined study population of 2,084 patients (1,460 milnacipran; 624 placebo). Both trials, with a 6- and 3-month duration for trials one and two, respectively, demonstrated clinically significant improvement compared to placebo. More milnacipran patients than placebo patients reported ≥30% reduction in pain (100 mg/day and 200 mg/day) in both studies by month 3.

Common adverse events included nausea, constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.

For complete safety, prescribing, and efficacy information, please visit www.frx.com. –LS

Psychological Distress Risk Increases for Siblings of Patients with Mental Health Disorders

Despite their prevalence, few studies have examined the effect of mental health disorders or intellectual deficits on the siblings of affected patients, siblings’ development during childhood, and the progression of any significant effect from that relationship into adulthood. Prior studies have shown that 5% of the adult population in the United States is affected by a serious mental health disorder, and >15% of the US adult population has intelligence testing scores that suggest mild to severe intellectual deficits. Research on siblings of patients with developmental disabilities have shown that the patient/sibling relationship is often quite different from a relationship between siblings without any disability. However, this finding has not been replicated for patients with mental illness or intellectual deficits.

Julie Lounds Taylor, PhD, of the University of Wisconsin–Madison, and colleagues studied 83 siblings of patients with mental health disorders and 268 siblings of patients with mild intellectual deficits to understand if such impairment affected the siblings’ development in childhood and into adulthood. They hypothesized that siblings of patients with mental illness would have relationships characterized by less closeness and contact, and would experience more distress than siblings of healthy controls. Siblings of patients with intellectual deficits were hypothesized to have similar levels of distress when compared to siblings of healthy controls, among other hypotheses.

Taylor and colleagues gathered patients from the Wisconsin Longitudinal Study, a sample of 10,317 people whose life course, including education, health, career, and family, have been evaluated since 1957. For study inclusion, patients with intellectual deficits had Henmon–Nelson Test of Mental Ability scores of ≤85. Patients with mental health disorders were determined via self-report responses. Of those who responded to being diagnosed with a mental health disorder, 85.5% were diagnosed with either a depressive and/or anxiety disorder. Patient siblings could not have IQ scores ≤100 or have been diagnosed in the past with a mental illness for study inclusion.

Patient/sibling relationship was measured using structured interviews, and sibling distress was measured using the Center for Epidemiological Studies–Depression Scale. The authors found that siblings of patients with mental health disorders had a 63% increased risk of having a depressive episode during their lifetime, when compared to 791 siblings of healthy controls. Siblings of patients with mental illness also reported more psychological distress, less psychological well-being, and less adaptive personality characteristics as compared to siblings of healthy controls.

Gender also contributed to the effect of patient mental illness on a sibling. Siblings of male patients with mental illness had significantly lower well-being scores than siblings of healthy controls. Siblings of patients with intellectual deficits showed reduced feelings of emotional closeness to patients, despite living in geographically nearer areas than siblings of patients without intellectual deficits. Neither sibling group showed differences in life course patterns (ie, marriage, childbirth) due to their relationship with patients.

Taylor and colleagues concluded that having a sibling with a mental health disorder or intellectual deficits does alter the sibling relationship, and can contribute to the development of psychological distress for the healthy sibling. The authors added that other social and environmental factors may also contribute to the development of depression and distress for siblings of patients with mental illness.

Funding for this research was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute on Aging. (J Fam Psychol. 2008;22(6):905-914.) –CP

Sertraline and CBT: Combination Therapy in Pediatric Anxiety Disorders

Pediatric anxiety disorders are common (10% to 20% prevalence estimates) and can have detrimental effects on family, educational, and social functioning. These disorders are typically treated with cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs).

John T. Walkup, MD, at the Johns Hopkins Medical Institutions in Baltimore, Maryland, and colleagues conducted a multicenter, randomized controlled trial to assess the relative and combined efficacy of SSRIs and CBT for pediatric anxiety disorders. Participants included 488 children, 7–17 years of age. Primary diagnoses included separation anxiety disorder, generalized anxiety disorder, or social anxiety disorder, as verified by the Anxiety Disorders Interview Schedule for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision, Child Version.

In the first of two phases of this study, Phase 1 represented a short-term, 12-week trial comparing CBT, sertraline, and sertraline/CBT combination with placebo. Phase 2 represented a 6-month open extension for Phase 1 treatment responders.

CBT included fourteen 60-minute sessions with progress and symptom reviews. Pharmacotherapy included eight 30–60-minute sessions, with sertraline and placebo starting at 25 mg/day and increasing up to 200 mg/day by week 8. Administration of sertraline monotherapy, CBT monotherapy, and placebo was double blind. Sertraline/CBT combination therapy was open label.

Patients who were very much or much improved, as defined by the Clinical Global Impression-Improvement scale, included 80.7% for combination therapy (P<.001), 59.7% for CBT (P<.001), 54.9% for sertraline (P<.001), and 23.7% for placebo. Combination therapy was superior to monotherapy, and all active treatment was superior to placebo. In addition, no adverse events were reported more frequently in the sertraline group than in the placebo group.

Funding for this research was provided by the National Institute of Mental Health; sertraline and placebo were provided by Pfizer. (N Engl J Med. 2008;359(26):2753-2766.) –LS


Psychiatric dispatches is written by Carlos Perkins, Jr. and Lonnie Stoltzfoos.

e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

Most practicing psychiatrists who are asked why they opt for use of new-generation antipsychotics will say that it is because of their lowered risk of causing tardive dyskinesia (TD). Had that same question been asked several years ago, the answer might have been that these drugs are more effective in treating negative symptoms; have fewer side effects overall, thus improving the probability of patient compliance; and are less likely to produce adverse cardiovascular events than the older medication. However, it seems that the justification for the prescription of new-generation antipsychotics becomes more difficult with each new independent study. 

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study,1 for example, found that patients with chronic schizophrenia discontinued their antipsychotics at a high rate; only 18% to 26% of patients remained on the initial medication for 18 months in all treatment groups except olanzapine (36%).  Such high rates of noncompliance reflect intrinsic limitations in the effectiveness of the drugs. Olanzapine appeared to be more effective than the other drugs studied, but there were no significant differences in effectiveness between the phenothiazine perphenazine and the other second-generation drugs.

A recent meta-analysis2 found that of the atypical antipsychotics approved in the United States, clozapine, olanzapine, and risperidone were more effective in treating overall symptoms of schizophrenia than first-generation antipsychotics. Aripiprazole, quetiapine, and ziprasidone were found to be as effective as first-generation antipsychotics in treating symptoms of the disease. With the exception of clozapine, none of the newer drugs were found to improve quality of life more than the older agents. All of the atypical antipsychotics caused fewer movement disorders than the first-generation antipsychotics haloperidol. Haloperidol, which is a “high-potency” antipsychotic, is notorious for causing extrapyramidal side effects in clinical practice. Therefore, it was not surprising that the study found that “low-potency” first-generation antipsychotics, such as chlorpromazine and thioridazine, caused fewer movement disorders than some of the atypical antipsychotics. The low-potency drugs, however, tended to induce weight gain and sedation like the atypical antipsychotics.

Clozapine, olanzapine, quetiapine, and risperidone were associated with statistically significantly more weight gain than haloperidol. The researchers found no significant differences in weight gain between the atypical antipsychotics and the lower-potency, first-generation antipsychotics. While there were no significant differences in the CATIE study among the agents in the time until discontinuation of treatment owing to intolerable side effects, “olanzapine was associated with greater weight gain and increases in glycosylated hemoglobin, cholesterol, and triglycerides, changes that may have serious implications with respect to medical comorbidity such as the development of the metabolic syndrome.”2

A recently published retrospective cohort study3 of Medicaid enrollees in Tennessee showed that the newer antipsychotics are associated with a risk of sudden cardiac death, particularly at higher doses. Researchers found that among patients taking high doses of atypical antipsychotics, there are ~3.3 cases of sudden cardiac death per 1,000 patients per year. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical antipsychotics, respectively, and 186,600 matched nonusers of antipsychotics. The conclusion, that current users of typical and atypical antipsychotics had a similar, dose-related increased risk of sudden cardiac death, raises questions about whether the second-generation antipsychotics are in fact a safer alternative to conventional antipsychotics, a point that was made in an editorial that accompanied publication of the study.4

The accumulating evidence that the newer antipsychotics have little or no advantages in terms of efficacy or safety presents both clinicians and academic psychiatrists with numerous questions when making treatment decisions. Do we revert back to use of drugs like haloperidol and perphenazine as initial treatments for schizophrenia? Does the presumed lower risk of TD by itself justify using the newer agents, given the disabling nature of that movement disorder? Can we be certain that over time the lower risk of TD will also be proven to be false? Will the risk of TD be higher among the increasing patient population with mood disorders that are treated with atypical antipsychotics? PP

References

1.    Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
2.    Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41.
3.    Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360(3):225-235.
4.    Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death—how should we manage the risk? N Engl J Med. 2009;360(3):294-296.

 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Johnson and Johnson, PGxHealth, and Takeda.


 

Vitamins B9 (folic acid) and B12 (cobalamin) may be determinants of mental illness in older adults.1,2 Deficiencies of these vitamins have been implicated in the etiology and treatment of both mental and neurologic disorders.3,4 Both vitamins have import because they subserve vital functions in the synthetic pathways for the monoamine neurotransmitters norepinephrine, serotonin, and dopamine. Cross-sectional data from epidemiologic surveys3-5 of adult subjects suggest that low levels of one or both of these vitamins may predispose to clinical depression. One well-controlled trial6 found that folate treatment significantly augmented therapeutic response to fluoxetine compared to placebo. Poor nutrition alone does not appear to fully account for low levels of folate and B12 observed in some depressed subjects. Data from longitudinal studies in progress and a recently reported trial7 should help define what role vitamin therapy may play in prevention and treatment of depressive disorders.

Role of Folic Acid and Vitamin B12 in the Synthesis of Monoamines

It is known that plasma levels of folate and vitamin B12 decrease with age.8 Both vitamins are essential nutrients, which are not synthesized in the body and rely solely on sufficient dietary intake. Naturally occurring sources of these vitamins in food products must be converted after absorption to active forms to function as catalysts in intermediary metabolism. Activated moieties of folic acid and vitamin B12 govern two vital steps in biogenic amine synthesis—the metabolic transfer of one-carbon units and hydroxylation of the amino acids tyrosine and tryptophan.3 Methylfolate, a metabolically active form, is needed to form tetrahydrobiopterin, the essential cofactor for hydroxylating tyrosine and tryptophan, the rate-limiting step in the synthesis of norepinephrine, dopamine, and serotonin.9,10

Metabolism of Vitamin B12

Cobalamines (vitamin B12) from dietary sources are tightly protein bound and require the concerted action of gastric acid and pepsin in the stomach to be released into solution.8 Vitamin B12 itself is poorly absorbed and must be bound to a carrier protein produced by the gastric mucosa, so-called intrinsic factor (IF). The B12-IF complex is absorbed from distal small intestine with ~10% bioavailability, an amount sufficient to meet the average daily requirement of B12 10 μg/day.8 IF deficiency occurs secondary to gastric resection, premature atrophy of gastric IF cells (the hereditary disorder, pernicious anemia), and gastric atrophy due to aging.

Because body stores of B12 are extensive, deficiency develops insidiously over a period of years. Neurologic manifestations of B12 deficiency are variable and include neuropathies, dementia, depression, and psychosis. B12 deficiency may present as a characteristic megaloblastic anemia, but neurologic deficits are usually manifest as well.  The preferred treatment for this anemia is the parenteral administration of B12 (cyanocobalamin) since malabsorption is the likely etiology due to IF deficiency. Aggressive B12-replacement therapy is recommended in order to prevent progression of the neurologic deficits, which tend to be less reversible.

It is postulated that subclinical B12 deficiency, presumably as a consequence of gastric atrophy due to aging, could manifest as dementia or depression. With diminished gastric acid, pepsin, and IF production, older individuals could become susceptible. Substantial numbers of elderly with loss of acid-producing gastric cells, atrophic gastritis, as well as chronic users of acid-lowering drugs to control gastric reflux, may have impaired absorption. The role of B12 in psychiatric and neurologic disorders of the elderly warrants investigation to determine the value of nutritional supplements for prophylaxis or treatment of depression and dementia. Nutritional supplements need to employ sufficient doses of B12 (>1,000 μg/day) because in the face of diminished gastric acidity and IF, as little as 1% of an oral dose may be absorbed.

Metabolism of Folic Acid

Folate is present in a wide variety of foods so a deficiency generally reflects poor diet (rarely, malabsorption such as sprue may cause it).8 Adults require folate 100–200 μg/day. Body stores are depleted within a few weeks if intake is inadequate. Folates, which exist in polyglutamate forms in fresh vegetables, fruits, dairy products, meat, and other foods, are highly water soluble but require conversion by the intestinal mucosa to the monoglutamate form for systemic absorption. In the body, it is converted to L-methylfolate, which can cross the blood-brain barrier.8,9 Intracellularly, methylfolate is then converted by a B12-dependent reaction to a biologically active form, tetrahydrofolate.

There are several mechanisms by which folate may affect central nervous system (CNS) pathways implicated in the depressive disorders. Biopterin, which is dependent on L-methylfolate for synthesis, serves as an essential co-factor for converting phenylalanine to tyrosine, and for hydroxylation of tyrosine and tryptophan to yield dopamine, norepinephrine, and serotonin. Tyrosine and tryptophan hydroxylases are the rate-limiting steps in the synthesis of these monoamine neurotransmitters. Folate is also involved in formation of S-adenosyl methionine (SAM), which serves in the CNS as the sole methyl donor.3 SAM-dependent methylation is involved in synthesis of biogenic amines, membrane phospholipids, and nucleoproteins. 

Linking Depression to Deficient Folate and Vitamin B12 Levels

Folic acid deficiency during gestation can cause neural tube defects in infants and has been linked to cardiovascular disease in adults.3 In 1989, Coppen and colleagues11 reported that biopterin excretion is diminished in depressed patients compared with control subjects. It was previously shown that biopterin cofactor activity decreases with age in cerebrospinal fluid of normal subjects.12 Although preliminary studies had noted low folate levels in various psychiatric populations, it was not until studies utilizing radioimmunoassays yielded reliable epidemiologic data linking depression to low levels of folate and B12.

As part of a survey of older (>55 years of age) inhabitants of a Rotterdam district, several thousand subjects underwent home interviews for presence of a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition13 depressive disorder.4 Those with major or minor depression or dysthymia had significantly (P=.02) lower plasma B12 levels than age-matched controls. They also had elevated homocysteine levels, an index of reduced folate stores, although plasma folate levels did not differ significantly from age-matched controls. These findings comport with those of a study14 of physically disabled older women residing in a Baltimore community. This study, which involved 700 women ≥65 years of age, found that subjects with severe depression were more likely to have lower B12 levels than controls but not low folate levels.

Other cross-sectional surveys have found that low plasma levels of folate, but not B12, associate with depression.15-18 Some studies have detected elevated plasma homocysteine levels in depression, suggestive of reduced body stores of folate, but no aberrations of  plasma levels of folate or B12.19,20 A double-blind, placebo-controlled study found that folic acid as adjunctive therapy significantly enhanced the antidepressant efficacy of fluoxetine.6

There have been few prospective, longitudinal studies of the value of B12 and folic acid supplementation. One study21 quantified the daily folate and B12 intake of community-dwelling middle-aged men and followed subjects for several years as part of an ischemic heart disease study. Participants who experienced a depressive episode during that time were more likely to have low dietary intake of folate but not B12.

Recently, Australian investigators reported a prospective trial of a supplement containing vitamins B6, B9, and B12 to reduce the incidence of clinically significant depressive symptoms.7 As part of a large population-based study of hypertensives, a random sample of 299 men ≥75 years of age who were selected for absence of depression were recruited for a 2-year trial. Subjects were randomly assigned to a supplement containing vitamin B12 400 μg, folic acid 2 mg, and niacin 25 mg, or identical-appearing placebo. Subjects were assessed every 6 months using a self-rated depression scale. Slightly more men receiving the vitamin supplement remained free of clinically significant depressive symptoms compared with placebo, but the difference was not statistically significant. It is unclear from these findings whether the oral dose of B12 employed might have been too low due to impaired B12 absorption, or whether the results might have been different if subjects with pre-existing depression had been included in the study.

Conclusion

There are theoretical reasons why deficiencies of folic acid or B12, two vitamins vital to CNS synthesis of monoamine neurotransmitters, may impact depression. Population surveys have found low levels of these vitamins to be correlated with depression, but results of these studies are mixed; both reduced and normal levels of these vitamins have been observed in depression. Prospective long-term trials are needed to fully assess the value of nutritional supplements of folic acid and B12 in preventing or treating depression. PP

References

1.    Crellin R, Bottiglieri T, Reynolds EH. Folates and psychiatric disorders: clinical potential. Drugs. 1989;45(5):623-636.
2.    Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38(6):305-314.
3.    Paul RT, McDonnell AP, Kelly CB. Folic acid: neurochemistry, metabolism, and relationship to depression. Hum Pharmacol. 2004;19(7):477-488.
4.    Tiemeier H, vanTuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002:159(12):2099-2102.
5.    Morris NS, Fava M, Jacques PF, et al. Depression and folate status in the US population. Psychotherap Psychopharm. 2003;72:89-87.
6.    Coppen A, Bailey J. Enhancement of the antidepressant fluoxetine by folic acid: a randomized placebo-controlled trial. J Affective Disord. 2000;60(2):121-130.
7.    Ford AH, Flicker L, Thomas J, et al. Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry. 2008;69(8):1203-1209.
8.    Toskes PP. Folate, cobalamin, and megaloblastic anemias. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill Medical; 2006.
9.    Stahl SM. L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry. 2008;69(9):1352-1353.
10.    Levitt M, Spector S, Sjoerdsma A, Udenfriend S. Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea pig heart. J Pharmacol Exp Ther. 1965;148:1-8.
11.    Coppen A, Swade C, Jones SA, Armstrong RA, Blair JA, Leeming RJ. Depression and tetrabiopterin: the folate connection. J Affect Dis. 1989;16(2-3):103-107.
12.    Levine RA, Williams AC, Robinson DS, et al. Analysis of hydroxylase cofactor activity in the cerebrospinal fluid of patients with Parkinson’s disease. In: Poirier LJ, Sourkes TL, Bedard PJ, eds. Advances in Neurology. Vol. 24. New York, NY: Raven Press; 1979:303-307.
13.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
14.    Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women’s Health and Aging Study. Am J Psychiatry. 2000;157(5):715-721.
15.    Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM.. Folate, vitamin B12, homocysteine, and the MTHFR 677→T polymorphism in anxiety and depression: the Horland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
16.    Alpert JE, Mischanton D, Rubenstein GE, et al. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14(1):33-38.
17.    Ramos MI, Allen LH, Haan MN, Green R, Miller JW. Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr. 2004;80(4):1024-1028.
18.    Sachdev PS. Parslow RA, Lux O, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-age community sample. Psychol Med. 2005;35(4):529-538.
19.    Tolmunen T, Hintikka J, Voutilainen S, et al. Association between depressive symptoms and serum concentrations of homocysteine in men: a  population study. Am J Clin Nutr. 2004;80(6):1574-1578.
20.    Almeida OP, Lautenschlager N, Flicker L, et al. Association between homocysteine, depression, and cognitive function in community-dwelling older women from Australia. J Am Geriatr Soc. 2004;52(2):327-328.
21.    Tolmunen T, Hintikka J, Ruusunen A, et al. Dietary folate and the risk of depression in Finnish middle-aged men: a prospective follow-up study. Psychother Psychosom. 2004;73(6):334-339.

 

Dr. Collop is associate professor in the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine. He is also medical director of the Psychiatry Mobile Treatment Program at the Johns Hopkins Bayview Medical Center.

Disclosure: Dr. Collop reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Neubauer is a consultant to and on the speaker’s bureaus of sanofi-aventis and Takeda.

Please direct all correspondence to: David N. Neubauer, MD, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Box 151, Baltimore, MD 21224; Tel: 410-550-0066; E-mail: neubauer@jhmi.edu.


 

Focus Points

• Obstructive sleep apnea causes sleep disruption, daytime sleepiness, cognitive impairment, and depressive symptoms.
• Psychotropic medications may exacerbate sleep apnea.
• Depression, anxiety, and psychosis may undermine sleep apnea treatment.

 

Abstract

Obstructive sleep apnea (OSA) is a common clinical problem that produces symptoms that overlap with depression. Obesity is the strongest predictor of OSA, although other factors influencing upper airway patency may also predispose individuals to OSA. The key treatment approaches for OSA are nasal continuous positive airway pressure (CPAP) or bilevel positive airway pressure, oral devices, and upper airway surgery. Bariatric surgery may also be beneficial. The presence of OSA with comorbid psychiatric disorders may result in clinical challenges related to diagnoses, evaluations, and treatment adherence. Selected psychiatric medications have the potential to exacerbate OSA due to sedating effects and a propensity for weight gain. Antipsychotics and OSA independently may increase the risk for metabolic abnormalities, including glucose intolerance. Patients with OSA should be evaluated for symptoms of psychiatric disorders, just as psychiatric patients with sleep abnormalities and daytime sleepiness should be assessed for symptoms of OSA.

Introduction

There are numerous forms of sleep-disordered breathing, including obstructive sleep apnea (OSA), central sleep apnea, and hypoventilation syndromes. This article predominantly focuses on the common problem of OSA. The first part of the article will provide an overview of sleep-disordered breathing and the second part will examine unique issues related to sleep apnea, mental disorders, and psychiatric patients.

Sleep-Disordered Breathing

Definition and Types

Obstructive sleep-disordered breathing (SDB) exists on a continuum from narrowing of the upper airway to snoring to complete obstruction. Snoring occurs when air is forced through the restricted space of a narrowed airway, causing the surrounding tissues to vibrate. Although snoring has been associated in epidemiologic studies with cardiovascular disease, it is extremely common and is not necessarily “pathologic.” However, as the upper airway decreases in caliber with muscle relaxation, airflow is further restricted and breathing events termed hypopneas can occur. A hypopnea is defined as ≥30% reduction in airflow followed by a 3% to 4% fall in oxyhemoglobin saturation and/or an arousal from sleep. An obstructive apnea is complete collapse of the upper airway during sleep. OSA syndrome is usually defined by an apnea-hypopnea index (apneas + hypopneas/hours of total sleep time or apnea-hypopnea index (AHI) of ≥5 and symptoms of excessive daytime sleepiness, unrefreshing sleep, or chronic fatigue. Furthermore, although OSA accounts for the vast majority of sleep-disordered breathing cases, there are two additional types of apnea that may be noted on a sleep study, namely, central and mixed. Central sleep apnea occurs when there are breathing pauses without respiratory effort lasting ≥10 seconds; mixed apneas are a combination of central and obstructive apneas—usually starting with a central apnea and ending with an obstructive apnea. These events are determined during a sleep study (polysomnography) where brain waves (electroencephalography), muscle tone (electromyography), eye movements (electrooculography), and breathing parameters are monitored.

Epidemiology

The prevalence of OSA ranges from 3% to 7.5% in males and 2% to 3% in females.1 It is more common in males, approximately 2–3 times that of females, until menopause, when the prevalence in females increases.2 Interestingly, clinic referrals for OSA display a greater gender discrepancy, with ≥5 times as many men being referred for evaluation than women. Studies suggest OSA may be more common in African Americans at age extremes (<25 years or >65 years) and in Asians at lower body mass indexes (BMI), perhaps due to differences in craniofacial structure.3-5 The prevalence also appears to increase with increasing age, although the severity decreases.6,7

Risk Factors

There are several risk factors for OSA, the strongest being obesity. The BMI (weight in kg/height in m2) shows a relationship of BMI >26 kg/m2 and OSA.1 There is a relationship between BMI and AHI as well as between BMI and excessive daytime sleepiness. Weight gain has consistently been associated with an increase in SDB. In one community-based longitudinal study, individuals whose weight increased by 10% were found to have a 32% increase in AHI and were at six times the risk for development of moderate or severe OSA, relative to individuals whose weight remained constant.8

Neck circumference has also been associated with increased risk of OSA,9,10 with a neck circumference of >43 cm in males being highly correlated with OSA.11 Neck circumference may correlate better with OSA than BMI and there may be a relationship between neck circumference and the severity of OSA.

Certain craniofacial features have been shown to increase the risk for OSA, including a high and narrow hard palate, elongated soft palate, small chin, and abnormal distance between upper and lower incisors. Tonsillar enlargement and narrowing of the airway by the lateral pharyngeal walls is also predictive of OSA.11 The Mallampati classification, which was developed by anesthesiologist to determine intubation risk, has also been used to grade degree of upper airway narrowing for OSA patients. Indeed, one study13 showed that on average, for every 1-point increase in the Mallampati score, the odds of having OSA increased >2-fold. Craniofacial structures also differ across racial groups, and these differences have also been associated with higher prevalences of OSA. In part because it decreases muscle tone in the upper airway, drinking alcohol can cause apneic episodes in otherwise normal-breathing individuals, and can worsen the severity of apneic events and oxyhemoglobin desaturation in apnea patients.14 Smoking and exposure to second-hand smoke have been associated with snoring and OSA.11

Numerous clinical instruments have been developed to assist in screening for OSA, including the Berlin questionnaire,15 STOP questionnaire (Table 1),16 and Sleep Apnea Clinical Score (SACS).17 These usually incorporate physical attributes like BMI or neck circumference with questions about snoring and witnessed apneas and/or presence of hypertension. The use of these instruments may assist physicians and other health care providers in determining the need for polysomnography.

 

Signs and Symptoms

A number of signs and symptoms are associated with OSA. The cardinal symptom of OSA is daytime sleepiness. This is due to the sleep fragmentation resulting from repetitive upper airway obstructions culminating in arousals. Not all patients will exhibit this symptom; some complain of chronic fatigue or tiredness and it has been suggested that the latter occur more in females.18 Differentiating fatigue and tiredness from sleepiness can usually be done by asking how likely someone is to “fall asleep” in certain situations. The Epworth Sleepiness Scale was developed for this purpose and is often used to assist in such determinations (Table 2).19

 

 

Snoring is common in OSA and frequently disrupts the bedpartner’s sleep; the bedpartner also may note breathing pauses during sleep. Concern on behalf of the bedpartners, therefore, is a common reason that OSA patients are brought to medical attention. Other common signs and symptoms include awakening with a headache,20 dry throat, gasping, or with a smothering sensation, and impotence.

Consequences and Associations

Numerous comorbid conditions have been associated with OSA. The association with hypertension has been extensively studied. Large epidemiologic,21,22 clinic-based,23,24 and case control studies25 have consistently shown that the risk for hypertension increases with increasing levels of apnea-hypopnea indices even after correction for a number of frequently encountered comorbid conditions such as obesity, age, and gender. A metanalysis examining 572 patients from 12 randomized, controlled trials did show that use of continuous positive airway pressure (CPAP) resulted in a net decrease of 1.69 mm Hg in 24-hour mean blood pressure, suggesting that treating OSA with CPAP can improve blood pressure.26

In patients who present to the hospital with transient ischemic attacks or stroke, the prevalence of OSA is very high.27,28 Data29 from Yale University showed that the OSA syndrome significantly increased the risk of stroke or death from any cause independent of other risk factors, including hypertension, in a population of >1,000 patients who had undergone sleep studies. Another study30 followed 132 patients after a stroke; those with OSA, both at baseline and after adjustments, were found to have a significantly increased mortality than those with central sleep apnea or no sleep apnea. Other studies31 have also shown that patients with concomitant stroke and OSA have a worse functional outcome.

OSA has also been associated with diabetes and glucose intolerance.32-34 This association is thought to be related to sleep fragmentation and deprivation as well as repetitive hypoxemia accompanying obstructive events.35 However, similar to hypertension, data regarding whether treatment of OSA will result in a change in glucose intolerance or insulin resistance is conflicting.36-38

In addition to hypertension, OSA has been associated with numerous cardiovascular disorders including cardiac arrhythmias, coronary artery disease, congestive heart failure, and pulmonary hypertension. The hypoxemia and hypercapnia that occur repetitively during the night have been shown to lead to systemic inflammation, oxidative stress, sympathetic activation, endothelial dysfunction and hypercoagulability.39 Arrhythmias are very common and include nonsustained ventricular tachycardia, sinus arrest, second-degree heart block, and premature ventricular contractions.40 Patients with severe OSA have been shown to have 2–4-fold higher risk of sleep-related complex arrhythmias.41 OSA also has been found to complicate heart failure in 11% to 37% of patients.42,43 Treatment of OSA independently has been shown to improve ejection fraction as measured by echocardiogram,44 and a recent study45 suggests that treatment of OSA may reduce mortality, although this has not been tested in a randomized trial.

Pulmonary hypertension is noted in ~15% of OSA patients. It is usually mild in nature or occurs only during exercise.46 Again, small trials have shown some improvement in pulmonary artery pressures after treatment with CPAP.47,48

Treatment Options

The aim of treatment for OSA is to eliminate obstructed breathing events and snoring, maintain SaO2 >90%, and improve associated symptoms including, but not limited to, daytime sleepiness. OSA treatment options include weight loss, devices (positive airway pressure and oral appliances), and surgery.

It is well documented that even minor amounts of weight loss will decrease AHI in obese OSA patients.49 All obese OSA patients should be counseled on the benefits of weight reduction. Bariatric surgery can result in dramatic weight loss, reduced AHI, and improved arterial blood gases and pulmonary and cardiac function.50,51 These obesity operations are associated with low morbidity and mortality with operative death rates of ~1% and major complication rates of 5% to 8%.52 Bariatric procedures should be considered in morbidly obese patients with life-threatening OSA. However, recent data suggest that despite dramatic weight loss, most patients continue to experience OSA, albeit at a lesser severity.53

Nasal CPAP is the treatment of choice for patients with moderate or severe OSA. It works by creating a “pneumatic splint” in the upper airway and increases functional residual capacity, which improves ventilation perfusion matching and oxygenation.54 Nasal CPAP has been shown to be very successful in the treatment of OSA. It decreases or eliminates excessive daytime sleepiness, improves quality of life (even in mild cases), improves neurocognitive function, and decreases hospitalizations.55-58

Bilevel positive airway pressure (BPAP) varies pressure from inspiration to expiration. It has been shown that lower expiratory pressures can be used with AHI reductions similar to CPAP.59 BPAP, however, was found not to improve compliance compared to CPAP in one study.60 Other studies61,62 in hypercapnic patients with OSA who could not be adequately treated with nasal CPAP showed dramatic improvement in symptoms and arterial blood gases following treatment with BPAP. BPAP should be considered in patients with concomitant hypoventilatory syndromes (obesity hypoventilation or neuromuscular diseases) or those who require excessive CPAP pressures (>16 cm of H2O).

A variety of oral appliances have been invented to treat OSA. These devices alter the oral cavity to increase airway size and improve patency. Oral appliances have been shown to result in significant decreases in AHI (usually >50%) and improvement in oxygenation, although some patients do not improve and may worsen.63 Subjective improvement in sleepiness has also been consistently shown.64 When nasal CPAP has been compared to an oral appliance, the appliance does not reduce the AHI as much as nasal CPAP; however, patients had fewer side effects and preferred the oral appliance.65,66 In general, the higher the AHI, the less benefit obtained with oral appliances.63,67,68

Side effects of these devices include excessive salivation, transient discomfort after awakening, temporomandibular joint discomfort, and changes in occlusive alignment. Although complications are common, most are minor and appear to be infrequent.69,70 Minor changes have been noted on dental exams after prolonged use of the appliances.71

Regarding surgical procedures for OSA, a tracheotomy is the only procedure that is consistently effective; however, due to its morbidity, it usually is performed in situations in which the patient has life-threatening OSA with cor pulmonale, arrhythmias, and/or severe hypoxemia that cannot be controlled with nasal CPAP.

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure which enlarges the airway by removing redundant tonsillar tissue, trimming tonsillar pillars, and excising the uvula and posterior soft palate. The “cure” rate of UPPP is usually quoted as <50%72 and one study73 showed that 31% of patients actually had worse OSA after undergoing UPPP. Use of an anatomy-based staging system has been shown to improve treatment outcomes.74

Maxillomandibular advancement (MMA) has being used as a treatment for OSA. In this procedure, both the maxilla and mandible are advanced with a sliding osteotomy; the mandible advancement is more than the maxilla to increase the posterior airway. The success rates of this surgery vary; in most cases, MMA is conducted as part of a stepwise program, usually following an ineffective UPPP.75,76 Other surgical procedures are also available for OSA such as Pillar implants, laser-assisted UPP, and genioglossus suspension. However, none has a high success rate or evidence for long-term efficacy.

The Relationship of OSA with Psychiatric Symptoms and Disorders

The considerable overlap in symptoms of sleep-disordered breathing and psychiatric disorders generates numerous challenges in relation to the identification, evaluation, diagnosis, and treatment of individuals experiencing the effects of diseases in one or both of these clinical realms.77 Psychiatric disorders and sleep-disordered breathing independently may result in significant impairment in daytime functioning, health-related quality of life, cognitive performance, and many other parameters of mental health. The negative synergistic effects resulting from comorbidity may be exacerbated further by inadequate treatment of either and potentially by the effects of certain psychotropic medications. The mental health impairments of sleep-disordered breathing foster misdiagnosis and missed opportunities for optimal treatment of comorbid conditions.

Patients with OSA, whether or not it is identified, may complain of disrupted nighttime sleep, excessive daytime sleepiness, fatigue, poor concentration and memory, irritability, an impairment in daytime functioning, an inability to enjoy usual activities, and a general sense of discouragement.78 They may express feelings of discouragement and depression, and may question the value of living with their burdensome and often unexplained symptoms. Does the OSA mimic a major depressive episode (MDE) or does the constellation of mood disorder symptoms demonstrate comorbidity of OSA and major depressive disorder (MDD)? Both are possible.

Exactly how sleep apnea impairs cognitive and emotional functioning has not been fully explained. Clearly, repeated sleep disruptions and a decrease in the total sleep time can cause daytime sleepiness with poor attention and concentration, and perhaps lead to low energy, irritability, and moodiness. It has been suggested that OSA-related sleep stage alterations, such as decreased slow-wave and rapid eye movement (REM) sleep, and recurrent oxyhemoglobin desaturations further exacerbate mental impairment and increase the risk for depressive disorders. Furthermore, shared predispositions may contribute to the high prevalence of OSA and depressive symptoms. Schroeder and O’Hara79 note that serotonin has key roles in the neurobiology of depression and arousal, but also in the control of upper airway muscle tone during sleep. Decreased serotonin activity may increase the risk of developing depressive symptoms and, perhaps, increase the probability of pharyngeal collapsibility during sleep.

Problems arise when a mood disorder or related psychiatric condition is diagnosed, but the possibility of sleep-disordered breathing is not considered as a possible contributor to nighttime sleep disruption or daytime fatigue and sleepiness. Although selected symptoms may improve with antidepressant therapy, the patient could be labeled as treatment resistant due to limited improvement in core daytime and nighttime symptoms. Accordingly, sleep-disordered breathing should always be in the differential diagnosis of patients with complaints of disrupted nighttime sleep or excessive daytime sleepiness. This is especially important since psychotropic medications may both directly and indirectly exacerbate sleep apnea.

General Population Studies

Representative population studies have explored the presence of sleep-disordered breathing and symptoms representing psychiatric and medical disorders. Ohayon80 performed a large-scale, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,81 diagnosis-based structured telephone survey of 18,980 randomly selected individuals in four European countries. The presence of OSA specifically was reported by 2.1% of the subjects, and in general 4.6% reported any type of breathing-related sleep disorder, although these were not objectively confirmed by polysomnography. An MDE was diagnosed in 4.3% of the overall sample. Psychotic symptoms, such hallucinatory or delusional experiences, were reported by 4.8% of the individuals as occurring at least several days per week. The prevalence of breathing-related sleep disorders were markedly elevated among subjects with MDEs with psychotic features (19.6%) and in those with MDEs without psychotic features (17.7%). A breathing-related sleep disorder was present in 6.2% of the subjects with psychotic symptoms who did not have an MDD diagnosis. The MDD diagnoses and presence of psychotic symptoms independently remained strongly associated with the disordered breathing when multifactorial analyses controlled for obesity and hypertension.80

A population-based epidemiologic study by Peppard and colleagues82 found the presence of a causal link with a sleep-related breathing disorder increasing the probability of depressive symptoms. The sleep-related breathing disorder diagnoses and severity ratings were based on sleep laboratory polysomnographic recordings and the presence of depression determined by Zung depression rating scores in 788 men and 620 women participating in the Wisconsin Sleep Cohort Study. Statistical models adjusting for numerous variables (eg, age, BMI, antihypertensive use) demonstrated that depression (Zung score ≥50) was associated, respectively, with odds ratios of 1.6, 2.0, and 2.6 for subjects with minimal, mild, and moderate or worse sleep-related breathing disorders. A longitudinal analysis82 showed that an increase of one level of disordered breathing severity was associated with a 1.8-fold increase for developing depression.

Surveys of OSA Patients

The presence of psychiatric symptoms also has been surveyed in populations of patients diagnosed with OSA in a large number and wide variety of studies.83 For example, Sharafkhaneh and colleagues84 analyzed Veterans Health Administration healthcare records of >4 million patients and identified sleep apnea diagnoses in 118,105 of the individuals. The records indicated the presence of psychiatric symptoms with disproportionately higher prevalence rates. Comorbid diagnoses among the sleep apnea patients included depression (21.8%), anxiety (16.7%), posttraumatic stress disorder (PTSD; 11.9%), psychosis (5.1%), and bipolar disorder (3.3%).

McCall and colleagues85 examined depressive symptoms using the Beck Depression Inventory in 92 men and 29 women who had been diagnosed with moderate-to-severe OSA. At least mild degrees of depression were present in 44.6% of patients, representing 62% of the women and 39% of the men. At least a moderate level of depression was found in 11.6% of patients, including 28% of the women and 6% of the men. A significant relationship between daytime sleepiness and depression was not evident in the patient population.

Schizophrenia and OSA

The relationship of schizophrenia and sleep-disordered breathing is complicated by numerous factors. People with schizophrenia prior to treatment have increased risk for developing obesity and metabolic dysfunction (eg, type 2 diabetes and metabolic syndrome), which may be exacerbated further as a result of psychiatric medications. Weight gain significantly increases the likelihood of OSA. Moreover, sleep-disordered breathing independently increases the risk of type 2 diabetes and hypertension. Profound increases in morbidity and excess mortality may be especially problematic among schizophrenia patients.

Metabolic abnormalities, such as impaired carbohydrate metabolism and an increased risk for the development of type 2 diabetes, are more likely to be present among schizophrenic patients compared with the general population. Increased visceral adiposity and the predisposition for diabetes has been demonstrated in research studies86,87 conducted prior to the introduction of antipsychotics and with newly diagnosed and untreated schizophrenic patients.

Weight gain among schizophrenia patients may be exacerbated with the use of antipsychotics, especially atypical agents clozapine and olanzapine.88 It has been argued that atypical antipsychotic-induced weight gain relates to antihistaminic effects from selective activation of hypothalamic adenosine monophosphate-activated protein kinase.89

The relationship of obesity and antipsychotic use in primary care settings was examined in a longitudinal, retrospective analysis90 of 42,437 patients, of which 1.3% were taking an antipsychotic. The medications were approximately equally divided among the typical and atypical antipsychotics. Significantly increased obesity, diabetes, hypertension, and dyslipidemia all were associated with the use of antipsychotics.

Several studies have explored the presence of OSA in populations of patients diagnosed with schizophrenia. Winkelman and Lajos91 retrospectively evaluated 397 psychiatric inpatient consultations to the Sleep Disorder Program at McLean Hospital. They found that the rate of OSA was disproportionately higher among male and female schizophrenia patients, in contrast with those diagnosed with depression, bipolar disorder, PTSD, and substance abuse. The severity of the OSA also was greater for the schizophrenia patients. The authors91 speculate that medication-related weight gain, poor nutrition, and inadequate exercise contributed to the higher severity in the schizophrenia patients. An increased prevalence of sleep apnea was also found by Ancoli-Israel and colleagues,92 who prospectively studied 52 older schizophrenia patients (mean age=59.6 years) with home recordings of their sleep electroencephalograph, respirations, and leg movements. A relatively high percentage of these patients (48%) had at least 10 respiratory events per hour.

OSA Treatment in Psychiatric Patients

The strategy recommended for the treatment of OSA depends upon the patient’s clinical characteristics, including physical features (eg, upper airway anatomy, obesity), sleep laboratory testing results, and the ability of the individual to adhere to the therapy. The symptoms of patients with major mental illnesses also may influence the decisions regarding treatment approaches. Many psychiatric patients will benefit from weight loss and related strategies to improve any metabolic abnormalities. Longitudinal monitoring of weight, waist circumference, blood pressure, fasting plasma glucose, and the fasting lipid profile are recommended for patients on antipsychotics.

The treatment of OSA may be associated with a broad spectrum of beneficial effects in relation to psychiatric symptoms and cognitive functioning. Most obviously, improvements in nighttime sleep quantity and quality should promote alertness and help facilitate greater physical activity. However, psychiatric and other cognitive parameters also may improve with effective treatment of OSA.

The potential benefits of OSA treatment on psychiatric symptoms have been examined in several studies of different therapeutic modalities. Generally, the results support improvement in depressive symptoms, but there is limited literature regarding psychotic symptoms. Millman and colleagues93 surveyed 55 OSA patients with the Zung Self-Rating Depression Scale and found that 45% had scores signifying depression (≥50). The patients in the depression group had higher rates of sleep apnea. There also was a significant decline in the depression score for the group of 11 OSA patients initially in the depressed group that were treated with nasal CPAP.

In a Japanese study,94 measures of mood, daytime sleepiness, and quality of life were assessed in 38 control subjects and 132 patients with severe OSA. At baseline, the OSA patients had worse scores in all of these parameters. The OSA patients were treated with nasal CPAP and were reassessed after 8 weeks of treatment. The CPAP use was associated with significant improvements in mood, sleepiness, and quality of life.

Schwartz and colleagues95 studied OSA patients treated with nasal CPAP and who demonstrated a significant disordered-breathing response to the treatment. Their mood was assessed with the Beck Depression Inventory at the beginning of CPAP treatment and with short-term (4–6 weeks) and long-term (~1 year) follow up. The study found significant and sustained improvement in mood in the patients continuing to use CPAP regularly.

Strakowski and colleagues96 found improvements in manic symptoms in four patients described as having treatment-resistant mania and OSA when treated with nasal CPAP. At the opposite end of the mood spectrum, Krahn and colleagues97 reported a case study of a severely depressed and suicidal man whose psychiatric symptoms resolved rapidly with the initiation of nasal CPAP for his newly diagnosed severe OSA.

While most psychiatric outcome studies have investigated the potential benefits of CPAP in OSA patients, a few reports have examined surgical approaches. In a prospective longitudinal Taiwanese study98 of 84 OSA patients, mental health scales were completed by the patients before and after extended uvulopalatal flap procedures. The baseline mental health scores of the patients were below the national average, but improved to a moderate degree postoperatively. Li and colleagues98 reported a case study of a 30-year-old man with recurrent psychotic episodes and intellectual impairment. There was a complete resolution of the OSA with a tonsillectomy and at a 2-year postoperative visit there had been a full remission of the psychotic symptoms, but persistent intellectual impairment.

OSA Treatment Challenges Among Psychiatric Patients

The first obvious challenge of OSA treatment among psychiatric patients is case identification. Sleep disturbances and daytime symptoms associated with OSA often are assumed to be psychiatric in origin by patients, as well as by their families and healthcare providers. Furthermore, excessive daytime sleepiness may be attributed to effects of sedating antipsychotic, antidepressant, anxiolytic, and mood-stabilizing medications. Disabled patients not following a regular schedule will not necessarily experience daytime sleepiness and impairment as a practical problems requiring treatment and, therefore, may not seek help. Patients with poor insight and motivation, perhaps exacerbated by their illnesses, may not pursue or even may resist efforts to evaluate possible sleep disorders with sleep laboratory testing and subsequently cooperate with recommended treatments. Symptoms of both anxiety and depression have been associated with decreased CPAP use.99 Educational efforts with patients and their families should help optimize the management of people with OSA and comorbid psychiatric disorders. Wells and colleagues100 noted that the subjective benefits and CPAP may be diminished in patients with depressive symptoms and, therefore, may undermine adherence with nightly CPAP use. Broad-based support and encouragement may be necessary to promote CPAP adherence with selected patients.101

The treatment of patients at risk for sleep-disordered breathing with antipsychotics necessitates a careful risk-benefit analysis. The antipsychotic risks of weight gain and metabolic abnormalities must be weighed against their therapeutic efficacy in patients with mood disorders or with schizophrenia and related psychotic disorders. Medication-related sedation and weight gain independently can exacerbate OSA. Weight loss strategies, appropriate nutritional guidelines, and routine laboratory screening for metabolic abnormalities may all be beneficial for patients prescribed antipsychotics, particularly those with the greatest risk for weight gain, abnormal carbohydrate metabolism, and hyperlipidemia.

Conclusion

Sleep-disordered breathing is a common problem in the general population that in some cases shares overlapping symptoms with mood, anxiety, and psychotic disorders. The result may be a complex clinical presentation with diagnostic confusion and significant treatment challenges. Mental health professionals should be mindful of possible sleep-disordered breathing in patients with disrupted sleep or daytime sleepiness. Patients with chronic mental illnesses should be screened for possible sleep disorders. Conversely, healthcare professionals managing patients with sleep apnea should evaluate patients for symptoms associated with psychiatric disorders. Optimized management of both sleep and psychiatric disorders likely will be necessary to allow patients the maximum opportunity for recovery. PP

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33. Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med. 2002;165(5):677-682.
34. Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med. 2002;165(5):670-676.
35. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435-1439.
36. Brooks B, Cistulli PA, Borkman M, et al. Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: Effect of continuous positive airway pressure treatment on insulin responsiveness. J Clin Endocrinol Metab. 1994;79(6):1681-1685.
37. Smurra M, Philip P, Taillard J, Guilleminault C, Bioulac B, Gin H. CPAP treatment does not affect glucose-insulin metabolism in sleep apneic patients. Sleep Med. 2001;2(3):207-213.
38. Vgontzas AN, Zoumakis E, Bixler EO, et al. Selective effects of CPAP on sleep apnoea-associated manifestations. Eur J Clin Invest. 2008;38(8):585-595.
39. Lopez-Jimenez F, Sert Kuniyoshi FH, Gami A, Somers VK. Obstructive sleep apnea: Implications for cardiac and vascular disease. Chest. 2008;133(3):793-804.
40.    Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease. an American Heart Association/American College of Cardiology Foundation scientific statement from the american heart association council for high blood pressure research professional education committee, council on clinical cardiology, stroke council, and council on cardiovascular nursing council. Circulation. 2008;52(8):686-717.
41. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The sleep heart health study. Am J Respir Crit Care Med. 2006;173(8):910-916.
42. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med. 1999;160(4):1101-1106.
43. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. types and their prevalences, consequences, and presentations. Circulation. 1998;97(21):2154-2159.
44. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003;348(13):1233-1241.
45. Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007;49(15):1625-1631.
46. Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. results in 220 consecutive patients. Chest. 1996;109(2):380-386.
47. Arias MA, Garcia-Rio F, Alonso-Fernandez A, Martinez I, Villamor J. Pulmonary hypertension in obstructive sleep apnoea: Effects of continuous positive airway pressure: A randomized, controlled cross-over study. Eur Heart J. 2006;27(9):1106-1113.
48. Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165(2):152-158.
49. Harman EM, Wynne JW, Block AJ. The effect of weight loss on sleep-disordered breathing and oxygen desaturation in morbidly obese men. Chest. 1982;82(3):291-294.
50. Sugerman HJ, Fairman RP, Sood RK, Engle K, Wolfe L, Kellum JM. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr. 1992;55(2 Suppl):597S-601S.
51. Rasheid S, Banasiak M, Gallagher SF, et al. Gastric bypass is an effective treatment for obstructive sleep apnea in patients with clinically significant obesity. Obes Surg. 2003;13(1):58-61.
52. Livingston EH. Obesity and its surgical management. Am J Surg. 2002;184(2):103-113.
53. Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med. 2008;4(4):333-338.
54. Abbey NC, Cooper KR, Kwentus JA. Benefit of nasal CPAP in obstructive sleep apnea is due to positive pharyngeal pressure. Sleep. 1989;12(5):420-422.
55. Mohsenin V. Sleep in chronic obstructive pulmonary disease. Semin Respir Crit Care Med. 2005;26(1):109-116.
56. Engleman HM, Kingshott RN, Wraith PK, Mackay TW, Deary IJ, Douglas NJ. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep Apnea/Hypopnea syndrome. Am J Respir Crit Care Med. 1999;159(2):461-467.
57. Ballester E, Badia JR, Hernandez L, et al. Evidence of the effectiveness of continuous positive airway pressure in the treatment of sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med. 1999;159(2):495-501.
58. Bahammam A, Delaive K, Ronald J, Manfreda J, Roos L, Kryger MH. Health care utilization in males with obstructive sleep apnea syndrome two years after diagnosis and treatment. Sleep. 1999;22(6):740-747.
59. Sanders MH, Kern N. Obstructive sleep apnea treated by independently adjusted inspiratory and expiratory positive airway pressures via nasal mask. Physiologic and clinical implications. Chest. 1990;98(2):317-324.
60. Reeves-Hoche MK, Hudgel DW, Meck R, Witteman R, Ross A, Zwillich CW. Continuous versus bilevel positive airway pressure for obstructive sleep apnea. Am J Respir Crit Care Med. 1995;151(2 Pt 1):443-449.
61. Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe obstructive sleep apnea and hypercapnia. Chest. 1994;105(2):434-440.
62. Schafer H, Ewig S, Hasper E, Luderitz B. Failure of CPAP therapy in obstructive sleep apnoea syndrome: Predictive factors and treatment with bilevel-positive airway pressure. Respir Med. 1998;92(2):208-215.
63. Schmidt-Nowara W, Lowe A, Wiegand L, Cartwright R, Perez-Guerra F, Menn S. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. Sleep. 1995;18(6):501-510.
64. Menn SJ, Loube DI, Morgan TD, Mitler MM, Berger JS, Erman MK. The mandibular repositioning device: Role in the treatment of obstructive sleep apnea. Sleep. 1996;19(10):794-800.
65. Ferguson KA, Ono T, Lowe AA, Keenan SP, Fleetham JA. A randomized crossover study of an oral appliance vs nasal-continuous positive airway pressure in the treatment of mild-moderate obstructive sleep apnea. Chest. 1996;109(5):1269-1275.
66. Clark GT, Blumenfeld I, Yoffe N, Peled E, Lavie P. A crossover study comparing the efficacy of continuous positive airway pressure with anterior mandibular positioning devices on patients with obstructive sleep apnea. Chest. 1996;109(6):1477-1483.
67. Engleman HM, McDonald JP, Graham D, et al. Randomized crossover trial of two treatments for sleep apnea/hypopnea syndrome: Continuous positive airway pressure and mandibular repositioning splint. Am J Respir Crit Care Med. 2002;166(6):855-859.
68. Krishnan V, Collop NA, Scherr SC. An evaluation of a titration strategy for prescription of oral appliances for obstructive sleep apnea. Chest. 2008;133(5):1135-1141.
69. Clark GT, Arand D, Chung E, Tong D. Effect of anterior mandibular positioning on obstructive sleep apnea. Am Rev Respir Dis. 1993;147(3):624-629.
70. Nakazawa Y, Sakamoto T, Yasutake R, et al. Treatment of sleep apnea with prosthetic mandibular advancement (PMA). Sleep. 1992;15(6):499-504.
71. Pantin CC, Hillman DR, Tennant M. Dental side effects of an oral device to treat snoring and obstructive sleep apnea. Sleep. 1999;22(2):237-240.
72. Shepard JW,Jr, Olsen KD. Uvulopalatopharyngoplasty for treatment of obstructive sleep apnea. Mayo Clin Proc. 1990;65(9):1260-1267.
73. Sasse SA, Mahutte CK, Dickel M, Berry RB. The characteristics of five patients with obstructive sleep apnea whose apnea-hypopnea index deteriorated after uvulopalatopharyngoplasty. Sleep Breath. 2002;6(2):77-83.
74. Li HY, Wang PC, Lee LA, Chen NH, Fang TJ. Prediction of uvulopalatopharyngoplasty outcome: Anatomy-based staging system versus severity-based staging system. Sleep. 2006;29(12):1537-1541.
75. Waite PD, Wooten V, Lachner J, Guyette RF. Maxillomandibular advancement surgery in 23 patients with obstructive sleep apnea syndrome. J Oral Maxillofac Surg. 1989;47(12):1256-61; discussion 1262.
76. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a review of 306 consecutively treated surgical patients. Otolaryngol Head Neck Surg. 1993;108(2):117-125.
77. Jaffe F, Markov D, Doghramji K. Sleep-disordered breathing in depresion and schizophrenia. Psychiatry 2006. 2006;3(7):62-68.
78.    Brown WD. The psychosocial aspects of obstructive sleep apnea. Semin Respir Crit Care Med. 2005;26(1):33-43.
79. Schroder CM, O’Hara R. Depression and obstructive sleep apnea (OSA). Ann Gen Psychiatry. 2005;4:13.
80.    Ohayon MM. The effects of breathing-related sleep disorders on mood disturbances in the general population. J Clin Psychiatry. 2003;64(10):1195-1200.
81. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
82. Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 2006;166(16):1709-1715.
83. Saunamaki T, Jehkonen M. Depression and anxiety in obstructive sleep apnea syndrome: a review. Acta Neurol Scand. 2007;116(5):277-288.
84. Sharafkhaneh A, Giray N, Richardson P, Young T, Hirshkowitz M. Association of psychiatric disorders and sleep apnea in a large cohort. Sleep. 2005;28(11):1405-1411.
85. McCall WV, Harding D, O’Donovan C. Correlates of depressive symptoms in patients with obstructive sleep apnea. J Clin Sleep Med. 2006;2(4):424-426.
86. Thakore JH, Mann JN, Vlahos I, Martin A, Reznek R. Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia. Int J Obes Relat Metab Disord. 2002;26(1):137-141.
87. Kohen D. Diabetes mellitus and schizophrenia: Historical perspective. Br J Psychiatry Suppl. 2004;47:S64-S66.
88. Nasrallah H. A review of the effect of atypical antipsychotics on weight. Psychoneuroendocrinology. 2003;28(suppl 1):83-96.
89. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A. 2007;104(9):3456-3459.
90. Sicras-Mainar A, Navarro-Artieda R, Rejas-Gutierrez J, Blanca-Tamayo M. Relationship between obesity and antipsychotic drug use in the adult population: A longitudinal, retrospective claim database study in primary care settings. Neuropsychiatr Dis Treat. 2008;4(1):219-226.
91. Winkelman JW, Lajos L. Is schizophrenia a risk factor for obstructive sleep apnea? Sleep Research. 1997;26:305.
92. Ancoli-Israel S, Martin J, Jones DW, et al. Sleep-disordered breathing and periodic limb movements in sleep in older patients with schizophrenia. Biol Psychiatry. 1999;45(11):1426-1432.
93. Millman RP, Fogel BS, McNamara ME, Carlisle CC. Depression as a manifestation of obstructive sleep apnea: Reversal with nasal continuous positive airway pressure. J Clin Psychiatry. 1989;50(9):348-351.
94. Kawahara S, Akashiba T, Akahoshi T, Horie T. Nasal CPAP improves the quality of life and lessens the depressive symptoms in patients with obstructive sleep apnea syndrome. Intern Med. 2005;44(5):422-427.
95. Schwartz DJ, Karatinos G. For individuals with obstructive sleep apnea, institution of CPAP therapy is associated with an amelioration of symptoms of depression which is sustained long term. J Clin Sleep Med. 2007;3(6):631-635.
96. Strakowski SM, Hudson JI, Keck PE,Jr, et al. Four cases of obstructive sleep apnea associated with treatment-resistant mania. J Clin Psychiatry. 1991;52(4):156-158.
97. Krahn LE, Miller BW, Bergstrom LR. Rapid resolution of intense suicidal ideation after treatment of severe obstructive sleep apnea. J Clin Sleep Med. 2008;4(1):64-65.
98. Li HY, Huang YS, Chen NH, Fang TJ, Liu CY, Wang PC. Mood improvement after surgery for obstructive sleep apnea. Laryngoscope. 2004;114(6):1098-1102.
99. Kjelsberg FN, Ruud EA, Stavem K. Predictors of symptoms of anxiety and depression in obstructive sleep apnea. Sleep Med. 2005;6(4):341-346.
100. Wells RD, Freedland KE, Carney RM, Duntley SP, Stepanski EJ. Adherence, reports of benefits, and depression among patients treated with continuous positive airway pressure. Psychosom Med. 2007;69(5):449-454.
101.  Wickwire  EM. Behavioral management of sleep-disordered breathing. Primary Psychiatry. 2009;16(2):34-41.

 

Dr. Ivanenko is assistant professor of Clinical Psychaitry and Behavioral Sciences in the Division of Child and Adolescent Psychiatry at Northwestern University Feinberg School of Medicine at Children’s Memorial Hospital in Chicago, Illinois, and Pediatric Sleep Medicine Director at Children’s Memorial at Central DuPage Hospital in Winfield, Ilinois. Dr. Patwari is assistant professor of Clinical Pediatricsin the Department of Critical Care Medicine at Northwestern University Feinberg School of Medicine at Children’s Memorial Hospital.

Disclosure: Dr. Ivanenko is a consultant to Boehringer Ingelheim, NextWave Parmaceuticals, Inc., and Takeda Global Research & Development Center, Inc; and on the speaker’s bureau of sanofi-aventis. Dr. Patwari reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Anna Ivanenko, MD, PhD, 800 Biesterfield Rd, Suite 510, Elk Grove Village, IL 60007; Tel: 847-981-3660; Fax: 847-956-5108; E-mail: aivanenko@sbcglobal.net.


 

Focus Points

• Insomnia, parasomnias, and sleep-disordered breathing are common among children and adolescents.
• Behavioral insomnia includes limit-setting and association types.
 

Abstract

Disturbances of sleep-wake function are common in children and adolescents, but still remain unrecognized and undertreated. Sleep disorders are even more prevalent in children with psychiatric disorders. Thus, it is important for healthcare providers to diagnose and manage sleep disorders in order to achieve most optimal patient outcomes. This article provides an overview of the most common pediatric sleep disorders, discusses the use of instrumental assessment of sleep and validated sleep questionnaires, and describes non-pharmacologicand pharmacologic treatments currently available for children and adolescents with sleep disorders.

Introduction

Sleep disorders remain among the most prevalent clinical conditions in children and adolescents. In the past 2 decades, there has been an increased number of research studies emphasizing the importance of sleep for children’s growth, neurobehavioral development, and learning.

A multi-system heuristics model has been proposed to define the relationship between sleep and daytime functioning in children.1 The model implies bi-directional and mediational relationships between multiple intrinsic and extrinsic systems involved in the regulation of sleep-wake processes, and with behavioral and emotional control in children as they develop.

This article reviews the prevalence of sleep disorders in the pediatric population, describes subjective and instrumental methods of assessment currently used in sleep medicine, and defines available treatment options for children and adolescents with disorders of sleep and alertness.

Sleep Requirements Among Children and Adolescents

Sleep requirements and distribution of sleep stages vary across ages. Infants enter rapid eye movement (REM) sleep (also termed active sleep at this age) at the beginning of their sleep phase, and REM sleep constitutes ~50% of their total amount of sleep. The ratio between non-REM (NREM) sleep (also termed quiet sleep) and REM sleep increases dramatically during the first year of life, with REM sleep approaching ~20% to 25% of the total sleep duration by the end of the first year. According to a parental survey conducted by the National Sleep Foundation,2 total sleep amount decreases from an average 13.2 hours in newborns to 11.4 hours in 2-year-olds. 

Napping requirements vary among individuals and are influenced by cultural and social factors. Most children, however, stop napping by 5 years of age with few children requiring naps at 6–7 years of age.

Brief nocturnal awakenings are a normal part of the sleep process and occur in infants and toddlers on an average of 1.3 and 0.73 times, respectably.3 Infants that return to sleep without parental intervention are referred as “self-soothers,” as opposed to “signalers” that require parental interaction to fall back to sleep. Difficulty with falling asleep may progress into behavioral sleep disorders as they continue to be behaviorally reinforced by parents.

Numerous laboratory and field studies conducted in the past 25 years have indicated that the need for sleep does not decline with puberty, but remains an average of 9–10 hours/night. Adolescent growth and development is associated with physiologic changes in sleep homeostasis and a characteristic delay in the circadian sleep phase, leading to a later sleep onset time and often to subsequent sleep loss due to early school start times.

Epidemiology of Common Sleep Disorders in Children

Insomnia

The prevalence of sleep disorders in the general population of children is estimated to be between 25% and 40%, depending on the study sample.4 Difficulty falling and staying asleep with frequent nocturnal awakenings, fear of darkness, and bedtime refusal are among the most common types of sleep complaints reported by the parents. Because symptoms of insomnia in children are very distinct from those in adults and are highly influenced by behavioral and family factors, the diagnosis of “behavioral insomnia in childhood” was introduced into the International Classification of Sleep Disorders, Second Edition.5

Behavioral insomnia is defined as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep, and results in daytime functional impairment for the child or family.” Two types of behavioral insomnia in childhood have been defined as the limit-setting type and sleep-onset association type. In the limit-setting type, the child stalls or refuses to go to bed at an appropriate time, while the sleep-onset association type is characterized by the inappropriate or maladaptive associations, such as rocking, feeding, watching TV or listening to the radio, and parental presence in bed. The absence of certain conditions can cause significant delay in sleep onset and subsequent reduction in a total sleep time. Combined types present with both subtypes at the same time and are frequently seen in the families where parents have difficulties enforcing consistent behavioral limits.

Behavioral insomnia is commonly associated with prolonged nocturnal awakenings; once the child awakens in the middle of the night he is unable to return back to sleep without recreating the same sleep association.

The pathophysiology of insomnia in children is far less studied and understood compared to adults. However, there are reported cases of lifetime primary insomnia starting during childhood and continuing into adult age, as well as cases of psychophysiologic insomnia triggered by a stressful event and associated with increased somatized tension and arousal conditioned to the bedroom and bedtime activities.

Symptoms of insomnia have frequently been reported by parents of children and self-reported by many adolescents. According to the Sleep in America Poll,2 69% of parents reported their children having sleep problems, mainly with falling and staying asleep, occurring a few times a week, with up to 51% of adolescents reporting difficulties initiating sleep at least once a week.6 The prevalence of insomnia among adolescents varies depending on the sample and definition of insomnia used in the research study. Two of the most recent studies that used Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,7 classification criteria for insomnia found that 4% of teens reported symptoms of insomnia in the European countries sample.8 In the United States, 10.7% of adolescents had primary insomnia.9 Children with psychiatric, neurodevelopmental, and chronic medical conditions have a much higher prevalence of insomnia compared to healthy controls.10 For example, one of the studies indicated that ~50% of children and adolescents with insomnia who were referred to the pediatric sleep center had coexisting psychiatric diagnosis.11

Parasomnias

Parasomnias are defined as behaviors associated with incomplete partial arousals during sleep or transitions into sleep, or following arousal from sleep. They occur both during NREM and REM sleep and can be very disruptive to the child and the family. Frequently seen parasomnias are rhythmic movements, sleepwalking, sleeptalking, nightmares, confusional arousals, sleep terrors, and nocturnal enuresis. Parasomnias are far more prevalent among children than adults, appear to be highly heritable, and tend to resolve spontaneously over the course of child development. Sleepwalking is reported occasionally in 20% to 40% of children 4–8 years of age. Frequent episodes of sleepwalking occur in ~3% to 4% of children. The prevalence of sleep terrors prevalence is ~3% in the general pediatric population. Confusional arousals are more frequently observed in infants and toddlers. They tend to be more disturbing to the family members and may last for up to 30–45 minutes with the child appearing confused, agitated, and incoherent. The exact pathophysiology of parasomnias is unknown, but they seem to represent maturation of systems within the central nervous system (CNS) involved in regulation of sleep and arousal. Psychological, environmental, and developmental factors influence parasomnias. Increased stress, emotional excitement, irregular bedtime, and sleep deprivation are known to increase the frequency of parasomnias and complicate their course.12 Parasomnias are more prevalent in children with psychiatric and neurologic disorders, and can be induced or exacerbated by certain psychological, medical conditions, and psychopharmacologic agents. Parental education and reassurance with regular and appropriate bedtime routines and stress management are effective interventions for parasomnias. While treating children with parasomnias, safety issues should be emphasized to prevent the child from possible accidental injury. Medication should be reserved only for severe or potentially dangerous cases.

Sleep Disordered Breathing

Primary snoring, upper airway resistance syndrome (UARS), and obstructive sleep apnea (OSA) are among the most common sleep-related breathing disorders in children. Habitual snoring has been estimated to have a prevalence of 10% to 27% among school-aged children with the peak at 2–8 years of age when adenotonsillar hypertrophy develops relative to the size of the upper airway. The prevalence of OSA among children is estimated to be 2% to 3%.13,14 Clinical symptoms of sleep disordered breathing (SDB) include continuous snoring, mouth breathing, witnessed breathing pauses, restlessness in sleep, and unusual sleeping positions. Nocturnal enuresis and parasomnias are overrepresented in children with SDB, and are frequently resolved after the treatment of SDB.

It is especially important for healthcare providers to be aware and to recognize symptoms of SDB in children and adolescents as it has a significant impact on their neurocognitive and behavioral development. Hyperactivity, inattention, aggressiveness, and impulsive behaviors have consistently been reported in children with SDB, along with some cognitive and performance deficits, academic failure, and excessive sleepiness.15-18 Sleep deficits, especially in younger children, often manifest with increased behavioral disinhibition, agitation, and mood lability. School problems and academic deficits have been reported in children with OSA, with subsequent improvement in academic grades following successful treatment of OSA.15-19 Quality of life is shown to be reduced in children with OSA and obesity, which can lead to depression, fatigue, and a decreased interest in daily life activities.20

Narcolepsy

The classical narcolepsy tetrad includes excessive daytime sleepiness, cataplexy, hypnogogic/hypnopompic hallucinations, and sleep paralysis. The pathophysiology of narcolepsy involves loss of orexin (ie, hypocretin) neurons in the hypothalamus that are involved in the control of sleep-wake cycle. The exact prevalence of narcolepsy is unknown. In Japan, the prevalence rate is as high as .16% versus only .02% among Israeli Jews. This discrepancy in the prevalence rate seems to be associated with certain human leukocyte antigen (HLA) haplotypes. HLA DQB1-0602 has been confirmed as one of the best markers of narcolepsy.21 The presence of cataplexy is specific for the diagnosis of narcolepsy. However, the vast majority of cases demonstrate excessive daytime sleepiness as a presenting symptom. The differential diagnosis of narcolepsy, especially in preadolescent children, frequently includes attention-deficit/hyperactivity disorder (ADHD), epileptic seizures, and depressive disorders. Since hypersomnia is frequently associated with major depressive disorder, it may be viewed as a part of the depressive symptomatology rather than intrinsic sleep disorder. There are cases of secondary narcolepsy caused by genetic disorders (eg, myotonic dystrophy type 1), Prader Willi syndrome, brain tumors, and head injuries.

Two or more sleep-onset REM periods on the Multiple Sleep Latency Test (MSLT; see below) are thought to be indicative of narcolepsy in adolescents and adults. Since the MSLT has not been validated in prepubertal children, it is more difficult to establish the diagnosis of narcolepsy in this age group. A thorough clinical history with daily sleep logs, actigraphy, polysomnography, and an MSLT should be used in the attempt to establish the diagnosis of narcolepsy in younger children.22

Restless Legs Syndrome and Periodic Limb Movement Disorder

RLS is a sensorimotor disorder manifest mostly at night and associated with an unpleasant sensation and urge to move one’s legs. The prevalence of RLS in the pediatric population is ~2%.23 Diagnostic criteria of RLS in children were published24 in 2003 with three different proposed categories, namely, definite RLS, probable RLS, and possible RLS. While RLS is a clinical diagnosis, periodic limb movement disorder (PLMD) requires nocturnal polysomnography or actigraphy to establish diagnosis. Periodic limb movements (PLMS) are brief muscle jerks lasting 0.5–5.0 seconds that usually occur at 20–90-second intervals during sleep. PLMS affect legs, toes, feet, and arms and may cause electroencephalogram (EEG) arousals from sleep. Most patients with RLS have PLMS, but there are cases of RLS that fail to demonstrate PLMS in sleep studies.25

Establishing the diagnosis of RLS in children is far more challenging than in adolescents or adults. Children typically describe their sensations as “bugs,” “ants crawling inside my legs,” “tickle,” “feeling uncomfortable,” or “hurts.” Parents usually report restless sleep in the children; they frequently observe their child rubbing or moving their legs excessively prior to falling asleep. Many children with RLS ask their parents to massage their feet or legs at bedtime to help with falling asleep. The differential diagnosis of RLS in children includes orthopedic problems, muscle soreness, skin problems, or neuropathies. It has been shown that ferritin serum levels <50 ng/ml are associated with RLS severity in children and adults.26,27 Supplementation with iron to achieve ferritin levels >50 ng/ml was shown to be effective in improving symptoms of RLS. Vitamin C usually enhances iron absorption, and children are usually recommended to take an iron supplement with orange juice or other fruit drinks that contain Vitamin C.

Numerous studies reported an association of RLS, PLMD, and ADHD in pediatric and adult patient populations. The prevalence of RLS/PLMD in children with ADHD varies between 25% and 44% depending on the study sample.28,29 The exact pathophysiology of these disorders and their complex relationship is poorly understood. However, the role of iron as part of the dopamine metabolic pathway has been proposed as one of the etiologic factors in both RLS and ADHD.30

Evaluation of Sleep Disorders in Children and Adolescents

The key difference between adults and children is that the developing child also has an evolving sleep pattern with continual changes in sleep requirements. As with most medical evaluations, the strongest clue to the underlying diagnosis lies with a thorough history. A focused history should be directed at determining abnormalities in sleep quantity or quality. Furthermore, a focused pediatric sleep history should include attention to the psychosocial history, daytime functioning, bedtime behaviors and routines, and nocturnal behavior. In addition to information gleaned from the history, objective information and quantitative evaluation can be obtained from questionnaires, sleep logs or diaries, polysomnography, actigraphy, and MSLT.

Psychosocial History

Psychosocial history speaks to the strong influence that environmental factors and consistencies with caretakers play in a child’s life. Questions should be directed at obtaining information regarding parental marital status, living arrangements, significant life events, and significant changes or stressors.

Daytime Functioning

In adults, a key question is whether the patient falls asleep at inappropriate times or has difficulty staying awake during certain daytime activities. However, rather then having a primary complaint of daytime sleepiness, young children often manifest daytime sleepiness with increased activity and teenagers may manifest sleepiness with emotional instability.4 Whether daytime sleepiness is a primary complaint or one that needs to be uncovered, it can result in poor daytime functioning such as problems with cognitive and school performance.31 Other important items to address are whether the patient takes naps and if he or she feels refreshed upon awakening in the morning or from the naps. It is important to keep in mind that depending on the age of the infant or child, daily naps may be normal. Further pathology can be uncovered when patients have complaints of unintentional sleep episodes, sleep paralysis, hypnagogic hallucinations, or cataplexy.32

Bedtime Routine

For parents of young children, dealing with bedtime behaviors can be both frustrating and exhausting. Parents should be asked about the patient’s evening routine, including the timing and consistency of bedtime activities. This includes any variances during weekends and holidays. Children with behavioral insomnia of childhood may interrupt this routine with behaviors such as stalling and resistance.4 Questions about the child’s sleeping environment should include co-sleeping, room sharing, light and noise level, room temperature, and presence of electronics (cell phone, computer, or television).

Nocturnal Behavior

The quality of sleep can be determined, in part, from asking about the timing and events related to night awakenings. This should include the frequency, duration, and parental response to awakenings. Respiratory symptoms, such as snoring, gasping, cessation of breathing, and mouth breathing also should be elucidated. Partial arousal parasomnias, such as sleep walking and talking, are common complaints and often are familial.33,34 A child with RLS may complain of leg pain, “creepy-crawly” feelings in the legs, or simply feeling the need to get out of bed several times to move around.35 Other questions regarding nighttime behaviors should include difficulties with seizures, enuresis, nightmares, night terrors, or rhythmic movements of extremities.

Questionnaires and Scales

Several questionnaires and scales exist for use by clinicians and researchers to evaluate sleep disorders. Useful questions that are designed for screening for sleep problems by the primary care physician are described in Table 1.31,36,37 Two common sleep scales that are used clinically for adults are the Stanford Sleepiness Scale and the Epworth Sleepiness Scale. The Pediatric Daytime Sleepiness Scale is an 8-item questionnaire used by clinicians for evaluating younger school age children.36 Other brief questionnaires designed for the screening of sleep problems include the BEARS and Ten-item Sleep Screener (TISS). The BEARS can be used for children 2–18 years of age and consists of five items, namely, “B”edtime problems, “E”xcessive daytime sleepiness, “A”wakenings during the night, “R”egularity of evening sleep time and morning awakenings, and “S”leep-related breathing problems or “S”noring.37 Another quick and simple questionnaire is the TISS. The TISS includes questions regarding the child’s snoring, excessive daytime sleepiness; difficulty with falling asleep at night; frequent moving at night; frequent waking at night; difficulty awakening in the morning; gasping, choking, and snorting in sleep; cessation of breathing during sleep; enough sleep compared to peers; and existence of a difficult temperament.31 If any of the answers suggest a sleep problem, then the clinician should seek further evaluation by a sleep specialist for the child.

 

 

 
More extensive questionnaires and scales include the Children’s Sleep Habits Questionnaire (CSHQ), Pediatric Sleep Questionnaire (PSQ), and Sleep Disorders Inventory for Students (SDIS). The CSHQ consists of 33 questions for children 4–10 years of age and is used primarily for pediatric sleep research.31

The PSQ is a 22-item instrument for children ages 2–18 years that yields a higher score based upon the presence of abnormal breathing during sleep, snoring, excessive sleepiness, abnormal behavior, and periodic limb movement disorder.38 Finally, the SDIS questionnaire, which is used to create the TISS, can be given to children 2–10 years of age (SDIS-C) or to adolescents 11–18 years of age (SDIS-A). The SDIS has 25 or 30 questions that can help diagnose OSA syndrome, PLMD, delayed sleep phase syndrome (DSPS), and excessive daytime sleepiness. The SDIS-A also covers RLS and narcolepsy.31

Sleep Diaries

The sleep diary provides a graphic method to track a 24-hour sleep-wake cycle. The patient or parent is instructed to record the times of daily sleep onset and awakenings over a period of 1–2 weeks. This can provide valuable information about consistencies and insufficiency in the patient’s sleep schedule, and can function as a reference to assess changes associated with different therapeutic interventions.

Polysomnography

Polysomnography (PSG) is the primary method for determining sleep architecture and is the gold standard for evaluating sleep disorders (Table 2). This test is generally performed overnight in a sleep lab with supervising technicians. It records multiple channels of information including the EEG, electrooculogram (EOG), electromyogram (EMG), respiratory activity, electrocardiogram, and audi-visual monitoring.39 The different sleep stages are determined with the use of the EEG, EMG, and EOG signals. The EEG montage in adults requires placement of central and occipital leads. Additional leads can be used to evaluate for seizure activity and can be useful for pediatric sleep evaluations. The EMG and EOG are necessary to identify REM sleep. For respiratory activity, effort is determined by monitoring chest and abdominal wall movements, nasal and oral airflow is recorded with the use of thermistors or pressure transducers, and gas exchange is determined by the use of pulse oximetry and end-tidal carbon dioxide monitoring. The audiovisual components of a sleep study are important in providing information about seizures, sleep walking, snoring, and ensuring safety of the patient.

 

 

 

Actigraphy

Actigraphy is used to provide an objective measure of the sleep-wake cycle based on the assumption that movement indicates wakefulness (Table 2). It is useful in assessing sleep quality and circadian rhythm patterns in a patient. The recording can be conducted over a series of days or weeks while the person follows a normal routine. Actigraphy can be conducted as outpatient with the patient wearing a small device similar in size to a large watch.

Multiple Sleep Latency Testing

The MSLT is used to determine daytime sleepiness and diagnose narcolepsy (Table 2). It is often performed the day after overnight PSG. The patient is instructed to take 4–5 naps at 2-hour intervals. REM latency is the time from the onset of sleep to first REM episode. A long latency to sleep onset indicates an alert patient. A short time to sleep onset indicates sleepiness. Normal sleep onset time in adults is 10–20 minutes and in children 10–12 minutes. An average sleep onset that is <5 minutes suggests the possibility of pathology. In children, this test is limited because it requires patient cooperation, daytime napping can be normal, and it has not been validated in children <6 years of age.35

Pharmacologic Treatments of Pediatric Sleep Disorders

Although pharmacologic agents are frequently prescribed to children with sleep disorders, none of them are approved by the US Food and Drug Administration for pediatric use, and there is significant lack of well-designed clinical research on the safety and tolerability of sedative hypnotics in pediatric populations.40
One recent study indicated that up to 81% of children with insomnia were prescribed medication to treat their clinical condition.41 Proper assessment and diagnosis of sleep disorders is the critical step in selecting a treatment approach that would address pathophysiology of sleep dysfunction rather than simply sedating the child. Non-pharmacologic treatments should always be considered prior to prescribing medications.

Clonidine

According to surveys, Clonidine is a central alpha-2-adrenergic receptor agonist with the onset of action within 1 hour. Clonidine is one of the most commonly prescribed medications by pediatricians to children and adolescents.41,42 It is being used off label in pediatrics for insomnia, especially among children with neurodevelopmental disorders and ADHD. The usual starting dose is 50 mcg with the gradual increase in 50 mcg increments.

Diphenhydramine

Diphenhydramine is a histamine-1 receptor antagonist frequently used for sleep initiation and sleep maintenance problems in children of all ages. The minimal effective dose in children has been reported at 0.5 mg/kg. However, a recent randomized controlled clinical trial43 of diphenhydramine in infants showed it being no more effective than placebo for the treatment of nocturnal awakenings. Significant side effects can occur even at the therapeutic doses and may include impaired consciousness and anticholinergic side effects.

Melatonin

Melatonin, a product not regulated by the FDA, has been shown to be effective in the treatment of sleep-onset problems in children and adolescents. Double-blind, placebo-controlled trials of melatonin 5 mg were conducted in healthy normal elementary school-age children44 and in children with ADHD and comorbid insomnia45 showing significant improvement in sleep-onset latency.

Non-benzodiazepine Hypnotics

Non-benzodiazepine hypnotics are now available in the US and include zolpidem, zaleplon, and eszolpiclone. This group of pharmacologic agents is characterized by a rapid onset of action and relatively short half-lives. Only one study46 examined the pharmacokinetics of zolpiden in children and concluded that clearance of zolpidem is three times higher in children than in adults. Zolpidem appeared to be well tolerated by children and adolescents up to maximum dose of 20 mg. Episodes of hallucinations, sleep walking, and other complex behaviors in sleep has been reported from use of zolpidem and related hypnotics. Patients and their parents should be warned about potential risks associated with the use of non-benzodiazepines hypnotics.

Benzodiazepines

Benzodiazepines are used infrequently in children with sleep disorders except in the treatment of parasomnias, such as sleep-walking and sleep terrors. Low doses of clonazepam from .25–.5 mg at bedtime is usually recommended for the treatment of parasomnias. Clonazepam has also been used to relieve symptoms of RLS and improve sleep continuity in children.

Modafinil

Modafinil is a non-stimulant-alerting agent that is well tolerated by children and adolescents. The pharmacologic treatment of excessive sleepiness associated with narcolepsy or idiopathic hypersomnia includes modafinil at 100–400 mg/day in divided doses.47

Stimulants

Stimulants, such as methylphenidate and dextroamphetamine products, have been widely used to treat excessive sleepiness but are far less studied in children with narcolepsy compared with those diagnosed with ADHD.48

Sodium Oxybate

Sodium oxybate was approved by the FDA in 2002 for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. It is a powerful CNS depressant that increases slow-wave sleep, but has serious potential side effects in cases of overdose or abuse. One study49 demonstrated the effectiveness of sodium oxybate for the treatment of excessive daytime sleepiness associated with narcolepsy in a small sample of children.

Antidepressants

Antidepressants with noradrenergic reuptake-inhibiting qualities have been used for the treatment of cataplexy in both adults and children. Tricyclic antidepressants, fluoxetine, venlafaxine, and more recently atomoxetine, have been shown to be effective in controlling cataplexy and other REM-related symptoms.

Dopaminergic Agents

Dopaminergic agents, such as carbidopa/levodopa, pramirexole, and ropinorole have been shown to be effective in the treatment of RLS in children in a few reports. In general, they appear to be well tolerated but may be associated with an augmentation phenomenon where symptoms of RLS worsen and appear earlier in the day with an increased dose of medication.

Gabapentin

Gabapentin is a g-aminobutyric acid agonist approved for use in children with epilepsy and has shown to reduce RLS symptoms in children.

Nasal Steroids

Nasal steroids, like fluticasone alone50 or in combination with montelukast, have been shown to be effective in reducing the severity of OSA in children and helping to resolve residual symptoms of sleep-disordered breathing after adenotonsillectomy.51

Non-Pharmacologic Treatments of Pediatric Sleep Disorders

Parental Education

Parental education, especially during the prenatal period or shortly after the child’s birth, has shown to be very effective in preventing the development of behavioral sleep problems in the future. Parents are usually instructed on healthy bedtime routines, sleep and nap schedules, and how to entrain their infants into a normal circadian sleep cycle and how to develop appropriate sleep associations. Recent studies52 indicated that infants whose parents received sleep education achieved an average 1.3 hours more sleep per day than those whose parents did not have preventive education.

Disengagement of feeding from bedtime routine is shown to be helpful in reducing the need for further feedings during the night. Parents are usually instructed to place their infant in a crib while he or she is still awake to prevent sleep-onset association disorder requiring lengthy parental interventions like rocking, holding, and so forth.

Behavioral Interventions

Behavioral interventions represent the first-choice therapy for children with sleep disturbances associated with bedtime resistance, behavioral insomnia of childhood, circadian sleep disorders, and parasomnias.

Unmodified Extinction

Unmodified extinction, also known as the “crying out” approach, has been shown to be effective but particularly difficult for parents to implement.

Graduated Extinction

Graduated extinction involves putting the child to bed and checking periodically while progressively increasing the intervals between checks until the child learns to fall asleep without the need for parental presence.

Extinction with Parental Presence

Extinction with parental presence is another version of behavioral intervention where parents are instructed to sleep in a separate bed in the child’s room while ignoring the child’s crying. This type of sleeping arrangement is recommended to continue for ≥1 weeks until the child learns to fall and stay asleep consistently. Then, the parent returns to sleeping in a separate bedroom.

Positive Bedtime Routines

Positive bedtime routines along with sleep hygiene interventions have been shown to be effective in treating behavioral insomnias and bedtime resistance. Reinforcement can be used to improve the child’s sleep behavior and increase the compliance with a sleep schedule. Examples of tangible reinforcers include sticker charts, candy, toys, and desired play activities.

Scheduled Nocturnal Awakenings

Scheduled nocturnal awakenings are effective in reducing the frequency of spontaneous nocturnal awakenings, confusional arousals, night terrors, and other parasomnias. The protocol usually involves awakening the child for a brief period of time before his usual spontaneous awakening or partial arousal. In most cases, the combination of several interventions is used to achieve the optimal response and to minimize stress for the child and family.

Sleep Hygeine

Sleep hygeine, or improved sleep habits, is an essential intervention in the treatment of sleep disorders. Generally, sleep hygiene recommendations help promote a conducive environment for better nighttime sleep and daytime alertness.

Chronotherapy

Chronotherapy is an intervention directed toward improvement in the timing of the sleep-wake cycle. The approach is most commonly used to treat adolescents with delayed sleep-phase syndrome. Chronotherapy involves a gradual delay in the bedtime by ~2–3 hour increments every 2 days until a desired earlier bedtime is reached.

Light Therapy

Light therapy has been successfully employed to treat circadian rhythm sleep disorders by therapeutic bright light exposure (5,000–10,000 lux) in the morning for sleep phase advancement in cases of DSPS, and in the evening to delay sleep onset in patients suffering from advanced sleep phase syndrome.53

Imagery Rehearsal Therapy

Imagery rehearsal therapy was shown to be effective in one study54 of adolescents with chronic recurrent nightmares.

Surgical Treatment

Surgical treatment, including adenotonsillectomy, is usually the first-choice therapy for pediatric OSA.55 In up to 80% of children, OSA is resolved following adenotonsillectomy.56

Continuous Positive Airway Pressure

Continuous positive airway pressure is indicated for children and adolescents who either failed surgical intervention or are not surgical candidates.55

Conclusion

Sleep disorders are highly prevalent in children and adolescents, and often have a significant impact on their neurocognitive, emotional, and behavioral development. Consequences of sleep loss and sleep fragmentation in children include daytime sleepiness, inattentiveness, fatigue, impaired performance, increased irritability, aggression, and behavioral dyscontrol. It is important for practicing psychiatrists to differentiate psychiatric symptoms that might be attributable to sleep loss, and to intervene to prevent further deterioration in regulation of sleep and wakefulness.

There are few well-designed clinical studies addressing treatment algorithms for pediatric sleep disorders, especially using pharmacologic agents. Further studies on the effective practical approaches to treatment of insomnia, parasomnias, and disorders of excessive sleepiness in children are needed with the emphasis on psychiatric comorbidities and neurocognitive development. PP

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Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, Maryland. He is also medical director of the Psychiatry Mobile Treatment Program at the Johns Hopkins Bayview Medical Center.

Disclosure: Dr. Neubauer is a consultant to and on the speaker’s bureaus of sanofi-aventis and Takeda.

Off-label disclosure: This article includes discussion of unapproved/investigational treatments for insomnia, obstructive sleep apnea, restless legs syndrome, and disorders of excessive sleepiness.

Please direct all correspondence to: David N. Neubauer, MD, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Box 151, Baltimore, MD 21224; Tel: 410-550-0066; E-mail: neubauer@jhmi.edu.


 

Focus Points

• Knowledge regarding the regulation of sleep and waking highlights potential new pharmacologic compounds to target sleep disorders.
• New compounds are being investigated to treat insomnia, disorders of excessive sleepiness, restless legs syndrome, and obstructive sleep apnea.

 

Abstract

Increasing knowledge regarding the physiologic regulation of the normal sleep-wake cycle has paralleled the expanding recognition of sleep disorders and the growing field of sleep medicine. The most commonly encountered sleep disorders in clinical practice are insomnia, obstructive sleep apnea, restless legs syndrome (RLS), and disorders of excessive sleepiness, such as narcolepsy. A variety of compounds have been used for millennia to promote sedation or arousal. Currently, medications approved by the United States Food and Drug Administration have indications for the treatment of insomnia, RLS, and narcolepsy. This article reviews the available sleep disorder medications and describes pharmacologic strategies currently being investigated as possible future treatments.

Introduction

There has been growing recognition of the importance of sleep in our lives. That includes getting a sufficient amount of sleep and achieving good quality sleep. Together, these may enhance our health and the quality of our waking lives. Evidence demonstrating detrimental effects of inadequate sleep is mounting. There are well-documented adversities associated with sleep disorders and sleep deprivation.1 Thus, there are two major challenges, namely, helping to ensure that people have the opportunity and motivation to devote sufficient time to sleeping and encouraging the evaluation and treatment of sleep disorders. Both challenges are formidable. Schedules and interests compete with time in bed. Formal education on sleep and sleep disorders is limited in general and particularly in healthcare professional training programs. However, there have been significant scientific developments in recent years regarding basic sleep physiology, pathologic processes associated with sleep disorders, and therapeutic strategies. In recent years, new medications have become available to treat sleep disorders and many others currently are being tested. This article provides an overview of our current understanding of the regulation of the sleep-wake cycle and an update on new pharmacologic treatment directions. Although most current and investigational medications are for the treatment of insomnia, this article also will address new approaches for disorders of excessive sleepiness, restless legs syndrome (RLS), and obstructive sleep apnea (OSA).

Sleep-wake Cycle Regulation

The physiologic basis of sleep is best appreciated with a model highlighting processes related to the control of the amount of sleeping and waking that operate in conjunction with mechanisms that facilitate sleeping during the nighttime and remaining awake throughout the daytime.2,3 Generally, these two processes, respectively, are termed homeostatic and circadian. The model effectively accounts for characteristics of the normal sleep-wake cycle, as well as for the effects of sleep or wakefulness during irregular schedules. Emerging physiologic evidence supports the roles of these processes, although fundamental questions do remain to be answered.

The homeostatic process represents the balance of how much time is spent asleep and awake. The process promotes for humans an optimum balance of roughly 8 hours of sleep in a 24-hour period. Insufficient sleep results in increased sleepiness that may be acute or chronic, and which may lead to severe and dangerous impairment. Purely from the homeostatic perspective, the timing of sleep would be inconsequential, as long as one obtained the proper amount. Hypothetically, one might achieve adequate total sleep in numerous brief episodes throughout the day and night. Circadian influences play a key role in the timing of sleep.4

The arousal of the waking state is reinforced by redundant neurotransmitter systems, which include the stimulating action of acetylcholine, glutamate, norepinephrine, serotonin, dopamine, and histamine. Several of these neurotransmitters contribute to the ascending reticular activating system generated in the brainstem. Histamine is unique with cell bodies within the hypothalamus. The waking and sleeping states appear to be stabilized within the hypothalamus through the effects the hypothalamic neuropeptide orexin. While numerous central nervous system (CNS) regions support waking, only highly selected hypothalamic regions, such as the ventrolateral preoptic nucleus, actively reinforce the sleep state.5 Beginning with the transition into sleep, inhibitory projections reduce stimulatory transmissions. The widespread inhibitory neurotransmitter, g-aminobutyric acid (GABA), appears to have a central role in sleep promotion in the hypothalamus and perhaps more globally within the CNS. The ligand-gated central chloride channel GABAA receptor complex has been especially well described with regard to subunit subtypes and corresponding physiologic effects.6,7 Further, adenosine has been hypothesized to play an important homeostatic function related to the accumulation of a sleepiness drive throughout the waking state.8

Our predisposition to sleep ~8 hours during the nighttime and remain awake during the daytime and evening hours results from the coordinated effects of the homeostatic and circadian processes. While the homeostatic drive determines the amount of needed sleep, the circadian system generates evening arousal to promote maintained wakefulness, a decline of circadian arousal as bedtime approaches to leave the accumulated homeostatic sleep drive unopposed, and a maximum of circadian-driven sleepiness toward the end of the night to help sustain sleep as the homeostatic sleep drive is dissipated. The integrated action of these systems normally allows bedtime sleepiness with a rapid sleep onset and relatively consolidated nighttime sleep of a sufficient duration to facilitate daytime and evening wakefulness.4

This typical pattern of sleep during the nighttime and waking during the daytime and evening is entrained by the photoperiod with a key role being performed by the rhythm of melatonin secretion. The biochemical mechanisms coordinating the timing of the circadian rhythm receive input from the retina initiated by photochemical reactions in ganglion cells with a compound called melanopsin.9 Light exposure information is transmitted through the retinohypothalamic tract to the tiny paired suprachiasmatic nuclei (SCN) within the anterior hypothalamus. Selected neurons within this region are able to maintain near 24-hour periodicity through complex transcription-translation feedback loops involving several different genes.10 The SCN is able to function as a master clock, providing temporal information to influence various physiologic processes.

The temporal information from the SCN influences other hypothalamic nuclei and also rather circuitously directs the functioning of the pineal gland in the production and release of the hormone melatonin. The pattern of melatonin secretion is able to influence oscillating systems throughout the body. The fluctuating melatonin levels also reinforce the mechanisms that generate the cycle through SCN melatonin receptors. The serum melatonin level is low during the daytime, increases in the evening as bedtime approaches, plateaus during the normal nighttime sleeping hours, and then declines as typical awakening and daylight approach. Agonist activity at the melatonin (MT)1 receptor subtype within the SCN is thought to decrease the evening circadian arousal to enhance sleep onset, while the MT2 receptor subtype is hypothesized to contribute to the periodicity and phase of the 24-hour rhythm.4

One curious feature of the sleep-related activity of melatonin is that it is species specific. Melatonin is elevated during nighttime darkness; however, its effects are not necessarily directly sedating. In humans and other diurnal species the increased nighttime melatonin serves to promote sleep. However, melatonin also is elevated during the nighttime in nocturnal species active during these hours. The SCN output is not different, but rather, the information is employed with opposite results through a relay mechanism in associated hypothalamic nuclei.

It is evident that the states of sleep or wakefulness are influenced by numerous CNS regions and by numerous neurotransmitters and related substances that have effects which may depend upon the time of day or night. Accordingly, this complex model highlights numerous potential targets for pharmacologic interventions as treatments for sleep-disordered patients.

Insomnia

Historic Perspective

Difficulty sleeping must have been experienced throughout the history of mankind. Ancient writings refer to individuals with persistent sleep problems; although it is unclear what remedies may have been employed in the attempt to promote improved sleep. Fermented beverages and sedating plant preparations, such as opium, have been used for millennia. An extensive pharmacopoeia evolved during the medieval period. Laudanum, a mixture of alcohol and opium, was one compound frequently used to treat insomnia for hundreds of years until the mid-20th century. Chloral hydrate was widely used beginning in the mid-19th century. Barbiturates and related compounds were the mainstay of insomnia treatment for much of the 20th century. The regular use of these medications was replaced by the benzodiazepines beginning in the 1960s and 1970s, followed by the more selective nonbenzodiazepine hypnotics beginning in the 1990s. Although there are significant pharmacodynamic differences among these compounds, they all share significant sedating characteristics. Many of the substances commonly used prior to the benzodiazepines were associated with significant safety problems, including tolerance and dependence, respiratory depression, and lethality.11,12 In addition to the United States Food and Drug Administration-approved insomnia treatment medications, various other prescription drugs, not fully evaluated for efficacy and safety in the treatment of insomnia (eg, antidepressants, antipsychotics, mood stabilizers), are sometimes recommended on an off-label basis. Additionally, people may use over-the-counter antihistamines and a wide range of dietary supplement compounds, such as valerian and melatonin.

FDA-approved Medications

The currently approved insomnia treatment medications available in the US include nine formulations of benzodiazepine receptor agonists (BZRAs) and one selective melatonin receptor agonist (Table 1). The BZRA hypnotics function as allosteric modulators of GABA responses at the GABAA receptor complex. Essentially, these hypnotics enhance the action of the inhibitory neurotransmitter GABA. The direct action of GABA at the pentameric GABAA receptor complex is an influx of negative chloride ions through a central ion channel resulting in a shift in the transmembrane electrical charge and increased membrane polarization that decreases the likelihood of an action potential. BZRA compounds interact with the GABAA receptor complex at an allosteric recognition site at the interface of alpha and gamma subunits. The presence of a BZRA allows a greater influx of chloride ions and, subsequently, an enhanced inhibitory effect. The hypnotic sedating action likely is a combination of BZRA effects globally in the CNS and locally in the hypothalamus.

 

 

 
The BZRA hypnotics approved for the treatment of insomnia include five older benzodiazepines (estazolam, flurazepam, quazepam, temazepam, and triazolam), characterized by a core defining chemical structure, and several unique nonbenzodiazepine compounds which function as agonists at the GABAA benzodiazepine recognition site. To a limited extent, these hypnotics can be differentiated according to their affinity for GABAA a subunit subtypes. The benzodiazepines have similar affinity for multiple a subtypes, while the nonbenzodiazepines all have greater affinity for a1 and, in one case, additionally for alpha-3 subtypes. These two a subtypes are the most strongly associated with a sedating effect. It has been argued that this nonbenzodiazepine selectivity and the generally shorter elimination half-lives contribute to improved tolerability of these newer hypnotics.

The nonbenzodiazepine hypnotics available in the US include the immediate-release formulations of eszopiclone, zaleplon, and zolpidem, and the controlled-release version of zolpidem. The rationale for a controlled-release hypnotic is the ability to extend the nighttime duration of action of a relatively short half-life compound while limiting the potential for residual next-morning sedation and impairment.

Ramelteon, a selective melatonin receptor agonist, has a unique, nonsedating mechanism of action in its effect on sleep-wake cycle processes in the SCN. It is hypothesized that the medication’s agonist activity at the MT1 and MT2 receptor subtypes promotes sleep onset by decreasing the evening circadian arousal and by reinforcing the timing of the circadian rhythm.

There have been several important changes in the FDA approval of insomnia treatment medications over the past few years. Previously, hypnotics were granted indications for the short-term treatment of insomnia; however, all insomnia medications approved since 2005 no longer have had implied limitations on their duration of use. This likely is due to the long-term clinical experience with the BZRA hypnotics and the submission of clinical trial data documenting continued efficacy and safety for extended periods. The recent FDA approvals also have specified sleep onset and/or sleep maintenance indications. This information is useful regarding the appropriate medication selection for individual patients depending on their insomnia symptoms. Finally, while all of the previous insomnia medications were categorized by the US Drug Enforcement Agency as Schedule IV agents due to their relatively low abuse liability, ramelteon is considered nonscheduled because of its absence of abuse liability.

New and Investigational Medications

A broad array of compounds in widely differing pharmacologic categories is currently being investigated in clinical trials in the search for future insomnia treatment medications. Some are new formulations or variations on existing medications currently employed to treat insomnia, while others are entirely unique and based upon the theoretical models of sleep-wake regulation described above (Table 2).

 

 

 
Benzodiazepine Receptor Agonists

Investigational BZRA compounds represent either familiar medications that employ alternate delivery strategies or new molecules with variations in receptor selectivity or agonist activity. The one recent pharmacokinetic innovation among FDA-approved insomnia medications was the release of a BZRA controlled-release formulation.13 Although other BZRA compounds have been investigated with controlled-release formulations, no new products of this type are likely to be approved in the near future. Other new directions with BZRA hypnotics include compounds that are highly selective for the GABAA alpha-3 subunit, or that combine subtype selectivity with partial agonist or inverse agonist activity at the GABAA receptor complex.

Currently, all approved BZRA hypnotics are intended for bedtime use with the duration of action depending upon the elimination half-life and formulation. At present, none are specifically indicated for middle-of-the-night dosing, although very short-acting hypnotics are occasionally used in this manner. Investigational approaches include formulations designed to bypass stomach absorption in order to promote rapid sleep onset with short-acting compounds (eg, zolpidem, zaleplon, triazolam) at low doses for a relatively brief duration of action. Clinical trials14,15 have been performed with sublingual and orally dissolvable tablets, as well as inhalation and nasal spray formulations. If approved, these types of medications might be granted indications for middle-of-the-night use. The rapid onset and earlier maximum serum concentration should allow an earlier decrease in the medication sedating effects to avoid undesired next-morning effects.

Melatonin Receptor Agonists

While ramelteon is the only FDA-approved melatonin receptor agonist currently available in the US, several other are currently being studied in clinical trials. Compounds of this type have been shown to improve sleep onset. Due to effects on the circadian system, melatonin receptor agonists may also be beneficial for circadian rhythm disorders, especially the delayed sleep phase syndrome, and for circumstances involving circadian phase shifting conditions, as with shift work and jet lag.4 One investigational melatonin receptor agonist incorporates serotonin (5-HT)2C antagonist activity and, therefore, may demonstrate efficacy for improving depression and insomnia. In Europe, where melatonin is not available without a prescription, a sustained-release formulation of melatonin was recently approved for the treatment of primary insomnia in adults ≥55 years of age. This product is not currently available in the US; however, various other unregulated immediate- and sustained-release melatonin products are readily available.

Histamine Receptor Modulators

Histamine produced in the hypothalamus is among the key stimulating neurotransmitters.16 Histamine (H)1 receptor antagonists, such as diphenhydramine, have sedating properties and are popular over-the-counter sleep aids. However, they tend to be excessively long acting and have other receptor activities which can cause adverse effects, such as anticholinergic symptoms. Shorter acting and more selective antihistamine compounds, or those which increase histamine by alternate mechanisms, may be helpful in treating insomnia patients.

Doxepin is one of the older tricyclic antidepressants which has prominent antihistaminic action and tends to be rather sedating. Recent clinical trials17 have investigated the efficacy and safety of very low doses of doxepin at 1, 3, and 6 mg. It has been shown to be especially helpful for sleep maintenance symptoms with sleep efficacy benefits through the last hour of the night. Therefore, it may be especially useful for early morning awakening. It is presumed that the antihistaminic action remains prominent at these very low doses, but that potential adverse effects from other lower affinity receptors are avoided. Pending FDA approval, low-dose doxepin may be available for the treatment of insomnia.

An alternate approach to decreasing the availability of histamine is the use of an agonist for the presynaptic H3 autoreceptor. In theory, this agonist activity should reduce the release of histamine and indirectly promote sedation. This pharmacologic strategy remains speculative with regard to the treatment of insomnia. As noted below, antagonist activity at this autoreceptor may be valuable to enhance alertness.18,19

5-HT2A Receptor Antagonists

Although no 5-HT2A receptor antagonists are presently approved for the treatment of insomnia, this pharmacodynamic action is inherent in many psychotropic medications, including some antidepressants and antipsychotics prescribed on an off-label basis for insomnia patients. It is possible that an appropriately selective compound with a desirable duration of action might represent an attractive medication to treat insomnia.20 Clinical trials are currently underway with several different 5-HT2A receptor antagonists. These compounds are especially interesting due to their tendency to increase slow wave sleep. Some of these investigational compounds have this primary pharmacodynamic activity, while related molecules function as inverse agonists or incorporate additional receptor effects, such as H1 antagonism. The FDA may evaluate the first of the 5-HT2A antagonists in the very near future.

Orexin Antagonists

The recognition that patients with narcolepsy are deficient in orexin activity raises the intriguing question of whether pharmacologically decreasing orexin could be beneficial for insomnia patienst. If too little orexin leads to excessive sleepiness, perhaps some people with insomnia have too much orexin activity.21

Clinical trials are currently being performed with the orexin antagonist, almorexant.

Miscellaneous Agents

Other unique compounds that have been investigated in recent years as possible insomnia treatments have included an alpha-2-delta calcium channel modulator, a 5-HT6 antagonist, a 5-HT1 agonist, a 5-HT6 antagonist, a glucocorticoid receptor antagonist, and some with unknown mechanisms of action. The potential sleep benefits of hormone replacement in postmenopausal women are also being investigated.

Future Issues

No doubt there will be major paradigm shifts both in our understanding and treatment of insomnia. It does seem likely that the pharmacologic treatment of insomnia in the future will include many of the current medications or related compounds with variations in selectivity, delivery, and pharmacokinetic properties. These and similar sedating drugs may be applicable for a wide range of insomnia patients. However, it is also likely that subsets of insomnia patients will be recognized as having specific vulnerabilities and responsiveness only to particular pharmacologic interventions. Patients with particular genetic patterns may be identified. Some patients may benefit from drugs that bring about significant changes in certain types of electroencephalograph activity, such as slow wave sleep or pre-sleep b and g activity. Insomnia patients with nighttime and daytime symptoms of hyperarousal may benefit from strategies targeting the hypothalamic-pituitary-adrenal axis. Some medications will have no sedating effects and may take several weeks to be effective, and some may not even be taken at bedtime.

Excessive Sleepiness

As is the case with sedating substances, the historic record documents the use of stimulants for several millennia, although there is little recognition of excessive sleepiness as a disorder until the modern era. The origins of the stimulant ephedrine are unclear, but it does have a very long history in Chinese medicine and the compound ultimately was extracted in the 19th century. The beverage coffee dates back over 1 millennium and coffee beans were a key commodity of international trade by the 17th century. The stimulating effects were appreciated at that time. Amphetamine and related stimulants became widely available beginning in the 1930s with racemic amphetamine sulfate and later with dextroamphetamine formulations. Several amphetamine compounds were given specific indications for the treatment of narcolepsy. The stimulant methylphenidate was developed in the 1950s and remains available in various formulations. Pemoline became available in 1975 and frequently was prescribed for the treatment of narcolepsy until 2005 when approval was withdrawn due to reports of liver failure.

FDA-approved Medications

Amphetamine medications are potent stimulants and are frequently prescribed for patients with narcolepsy and other selected disorders of excessive sleepiness. The specific medications may include formulations of dextroamphetamine, amphetamine mixed salts, and methamphetamine. Various formulations of methylphenidate are also prescribed for these conditions. While generally effective, these medications are associated with a high potential for abuse. The Drug Enforcement Administration (DEA) classifies these as Schedule II drugs.22

Modafinil, approved by the FDA in 1998, and armodafinil, approved in 2007 but not yet marketed, have indications for treating excessive sleepiness associated with narcolepsy, appropriately treated OSA, and shift work sleep disorder. While the wake-promoting effect of these medications is well established, the mechanism of action remains unclear. These are DEA Schedule IV medications.22

Sodium oxybate (gamma-hydroxybutyrate) was approved by the FDA for the treatment of narcolepsy in 2002. The initial indication specifically was for cataplexy symptoms, but it later was extended to include excessive daytime sleepiness due to narcolepsy. It is a sedating medication taken twice during the night. Sodium oxybate is associated with significant increases in slow wave sleep. It is classed by the DEA as a Schedule III agent.22

The pathophysiology of narcolepsy includes the abnormal intrusion of rapid eye movement (REM) sleep features into the waking state in the form of cataplexy, sleep paralysis, and hypnagogic hallucinations. REM-suppressing medications, including selected antidepressants, may be beneficial but are not specifically indicated for this purpose. Only sodium oxybate has been granted an FDA-approved indication for the treatment of cataplexy.

New and Investigational Medications

As with the insomnia medications, new approaches to the treatment of excessive sleepiness include both variations of current drugs and unique mechanism-of-action compounds. New formulations of amphetamine and related compounds may become available. Possibilities include prodrugs and formulation with modified pharmacokinetic features. As noted above, armodafinil, a single isomer of modafinil, has been FDA approved, but has not yet been marketed. While it currently has the same indications as modafinil, clinical studies may warrant additional applications. Armodafinil has a longer duration of action than modafinil and may be effective at promoting wakefulness at lower doses.23 Another new direction is the use of ampakines, which are alertness-enhancing substances that modulate glutaminergic activity. Although not specifically approved for treating excessive sleepiness, the irreversible monoamine oxidase type-B inhibitor, selegiline, is effective in reducing excessive sleepiness and has been prescribed for narcolepsy patients.24 Amphetamine compounds are among the metabolites of selegiline. Agonists of thyrotrophin-releasing hormone have alerting properties and may be investigated for the treatment of excessive sleepiness.25 Compounds that could enhance the release of orexin or function as agonists might promote alertness and treat other narcolepsy-related symptoms.
A rather active area of investigation is the application of H3 antagonists or inverse agonists to promote wakefulness or improved cognition. The rationale is that antagonizing the H3 presynaptic autoreceptor will promote greater histamine release and, therefore, greater stimulation. Some studies also suggest that H3 antagonists can decrease REM sleep, a characteristic that may be therapeutic for the abnormal REM manifestations experienced by narcolepsy patients.19

Restless Legs Syndrome

Although the etiology of RLS is not established, research has demonstrated abnormalities in brain dopamine systems and iron levels. Clinical experience with carbidopa/levodopa confirmed the value of dopaminergic compounds in treating RLS. The two medications currently approved by the FDA for the treatment of RLS are the nonergot-derived dopamine agonists pramipexole and ropinirole.

New and Investigational Medications

In addition to the above-noted FDA-approved medications, drugs from several other classes are often prescribed for RLS patients who have not responded adequately to standard treatments or who are believed to experience RLS due to particular clinical conditions. Some medications are regarded as likely efficacious based on clinical trials and other are considered investigational. Among those shown to be beneficial in some studies are levodopa, gabapentin, bromocriptine, rotigotine, carbamazepine, valproic acid, clonidine, cabergoline, lisuride, and oxycodone. Currently considered under investigation in the treatment of RLS are various other opioids (eg, methadone, tramadol) and benzodiazepines receptor agonists (eg, clonazepam, zolpidem), as well as dihydroergocriptine, aplindore, and topiramate. Oral or intravenous iron formulations may be efficacious for selected iron-deficient RLS patients.26 An extended-release gabapentin formulation intended to treat RLS is currently being reviewed by the FDA. Future RLS medications may include transdermal patch and prodrug formulations.

Sleep-disordered Breathing

Presently, no medications are approved specifically for the treatment of OSA, although modafinil and armodafinil do have indications for treating residual sleepiness in patients being treated for OSA. However, numerous compounds have been investigated to determine whether they might decrease the rate of apneic events or the degree of oxygen desaturation associated with OSA. While OSA is viewed fundamentally as an anatomic problem, neuromuscular control of the upper airway does influence its collapsilibility. Therefore, medications increasing upper airway tone hypothetically would improve OSA.27 In fact, increased serotonergic activity has been shown to be beneficial in animal models. Several studies28,29 of OSA patients have examined the use of serotonergic antidepressants, but the results have been mixed and inconsistent. That may be due in part to the fact that activation at different serotonin receptor subtypes may produce opposite effects on upper airway dilator muscles.

Pharmacologic investigations of OSA treatment have also included REM sleep suppressants (eg, selected antidepressants), clonidine, methylxanthine derivatives, opioid antagonists, nicotine, medroxyprogesterone in males, and hormone replacement therapy in menopausal women. The argument for suppressing REM sleep is that for some OSA patients, the apneic events are longer and associated with more profound oxygen desaturations during REM sleep. Other strategies have attempted to enhance the ventilatory drive or otherwise modulate the upper airway tone.30 Some medications have resulted in minor OSA improvements, but have impaired sleep onset, duration, and quality. Research continues to explore wake-promoting agents that might help with the daytime sleepiness associated with OSA, as long as patients are simultaneous treated for the underlying condition.

Conclusion

In recent years, the FDA has approved several new medications for the treatment of sleep disorders and many compounds with diverse pharmacologic properties are currently being investigated as possible future treatments for insomnia, OSA, RLS, and disorders of excessive sleepiness. Historically, sedating and stimulating medications have been discovered serendipitously. Emerging knowledge regarding the normal regulation of sleep-wake cycle and the pathophysiology of sleep disorders has highlighted new potential targets for pharmacologic intervention. New trends in the treatment of sleep disorders should allow improved efficacy and safety in the management of sleep disorders and should expand the range of disorders that can be treated pharmacologically. It must be emphasized, however, that behavioral strategies are essential components in the treatment of patients with sleep disorders. Future research should demonstrate where pharmacologic and cognitive-behavioral approaches will offer optimal benefits for patients. PP

References

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8.    Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science. 1997;276(5316):1265-1268.
9.    Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295(5557):1070-1073.
10. Shearman LP, Sriram S, Weaver DR, et al. Interacting molecular loops in the mammalian circadian clock. Science. 2000;288(5468):1013-1019.
11. Kleitman N. Sleep and Wakefulness. Chicago, IL: University of Chicago Press; 1963.
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13. Greenblatt DJ. Pharmacokinetic determinants of hypnotic drug action: the art and science of controlling release. Sleep Med. 2006.
14.    Roth T, Hull SG, Lankford DA, Rosenberg R, Scharf MB; Intermezzo Study Group. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings. Sleep. 2008;31(9):1277-1284.
15.    Staner L, Eriksson M, Cornette F, et al. Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: a polysomnographic study. Sleep Med. 2008 Nov 7. [Epub ahead of print].
16. Montoro J, Sastre J, Bartra J, et al. Effect of H1 antihistamines upon the central nervous system. J Investig Allergol Clin Immunol. 2006;16(suppl 1):24-28.
17. Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561.
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23. Nishino S, Okuro M. Armodafinil for excessive daytime sleepiness. Drugs Today (Barc). 2008;44(6):395-414.
24.    Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: An update. an american academy of sleep medicine report. Sleep. 2006;29(11):1415-1419.
25.    Billiard M. Narcolepsy: Current treatment options and future approaches. Neuropsychiatr Dis Treat. 2008;4(3):557-566.
26. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord. 2008;23(16):2267-302.
27. Conduit R, Sasse A, Hodgson W, Trinder J, Veasey S, Tucker A. A neurotoxinological approach to the treatment of obstructive sleep apnoea. Sleep Med Rev. 2007;11(5):361-375.
28.    Marshall NS, Yee BJ, Desai AV, et al. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep. 2008;31(6):824-831.
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30. Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD, Magalang UJ. Medical therapy for obstructive sleep apnea: a review by the medical therapy for obstructive sleep apnea task force of the standards of practice committee of the american academy of sleep medicine. Sleep. 2006;29(8):1036-1044.

 

Dr. Wickwire is postdoctoral fellow at the Behavioral Sleep Medicine Program at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Disclosure: Dr. Wickwire reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Emerson M. Wickwire, PhD, Clinical and Research Fellow, Behavioral Sleep Medicine Program, Johns Hopkins University School of Medicine, Meyer 1-108, 600 N. Wolfe St, Baltimore, MD 21287; Tel: 410-614-3396; Fax: 410-614-3366; E-mail: ewickwi1@jhmi.edu.


 

Focus Points

• Symptoms of sleep-disordered breathing (SDB) are easily mistaken for other medical or psychiatric disorders.
• Simple behavioral interventions may help reduce disease severity.
• Psychological interventions can greatly increase the likelihood of a patient’s adherence to positive airway pressure therapy, the most effective and frequently prescribed treatment for SDB.

 

Abstract

Sleep-disordered breathing (SDB) is a common medical condition with significant health consequences. Primary care and mental health practitioners are frequently unaware of the often subtle presentation of SDB, which can mask as conditions including depression, anxiety, attention deficit, and other cognitive complaints. SDB is a progressive disease, increasing from mild snoring to complete blockage of the upper airway. For patients whose disease has not progressed beyond the mild stage, numerous simple behavioral interventions can be considered as minimally invasive or adjunctive treatments. Nonetheless, most SDB patients are treated with continuous positive airway pressure (CPAP) therapy. However, adaptation and poor adherence are significant problems associated with this treatment approach. This article reviews the most common behavioral treatments for SDB and provides a theoretical framework for factors influencing CPAP use.

Introduction

Recent decades have seen a steady increase in knowledge related to sleep-disordered breathing (SDB) and its consequences. Long-term disease correlates of SDB include hypertension, stroke, cardiovascular disease and death, and overall mortality.1 Because they are often sleepy, SDB patients are also at increased risk for serious accidents. A recent literature review2 found that 80% of published studies reported that SDB patients were at significantly increased risk for motor vehicle accidents. Furthermore, symptoms of SDB, such as loud snoring, irritability, and decreased libido, affect the sleep and quality of life of bed partners and other household members.

Of particular relevance to primary care and mental health professionals is the complex and often subtle clinical presentation of SDB. Patients referred for evaluation of SDB are unlikely to recall the repeated airway obstructions that they experience during the night. Instead, patients with SDB frequently report fatigue, lethargy, and excessive daytime sleepiness. They may present with complaints of restless or nonrestorative sleep, or daytime tiredness. Patients frequently seek care at the insistence of a bed partner concerned about their snoring or breathing pauses during sleep.

Most physicians, psychologists, and nurses remain unaware of the degree to which symptoms of SDB might mask as other medical or psychiatric disorders. These symptoms include irritability, depressed mood, and poor executive function. Smith and colleagues3 conducted qualitative interviews with patients and their spouses to identify problems associated with SDB. Findings were notably consistent with clinical experience and included marital discord, increased irritability and depression, loss of sexual and social intimacy, loss of sleep by family members, and family members’ worrying about the patient’s health. Cognitive and memory impairment and other performance deficits, including difficulty concentrating and staying awake at work or school, are common.

Like many diseases involving pathophysiology, SDB exists on a continuum from no obstruction to snoring to complete airway blockage. The most severe blockages are referred to as either hypopneas (partial blockages) or apneas (total blockages) and are discussed in detail elsewhere.4 Depending on the severity of SDB, diagnoses can range from snoring and upper airway resistance syndrome (UARS) to obstructive sleep apnea (OSA) and have been described in detail.5 In parallel fashion, common treatments for SDB range from conservative weight loss to invasive otolaryngological surgery. For a vast majority of patients, the most effective and “gold standard” treatment for OSA is continuous positive airway pressure (CPAP). However, many patients struggle to adjust to CPAP, and adherence is often problematic.

This article reviews the most common minimally invasive behavioral interventions for SDB and provides an overview of factors influencing CPAP use. Strategies for improving CPAP adherence are presented. Although an efficacious treatment for many patients with mild to moderate SDB, oral mandibular-repositioning devices are not a focus of this review. Clinical recommendations are provided throughout.

Minimally Invasive Behavioral Treatments for SDB

Evidence suggests that over time patients experience a worsening of SDB even in the absence of significant weight gain or changes in upper airway anatomy.6,7 To explain this phenomenon, Friberg8 proposed that the progression from mild to severe snoring and ultimately OSA may be due to neuropathy associated with repeated vibration in the upper airway. Regardless of its cause, the known progression of SDB highlights the need for prompt intervention.

For the primary care physician (PCP), the most important clinical skill is being able to recognize the symptoms of potential SDB and knowing when to refer for further evaluation. Although an overnight sleep study, or polysomnogram (PSG), is usually performed to confirm the diagnosis, the screening question, “Do you snore?” should be included as part of every routine health assessment. The second most important skill is the ability to understand advanced SDB as a chronic disease that requires lifelong treatment. For most patients, there is no cure for OSA. This insight enables care providers to partner with and guide their patients toward the attitude and practical strategies needed to adapt and adjust to lifelong treatment.

Each of the following minimally invasive behavioral interventions represents a potential component of a conservative prescription for mild SDB. These treatments are not mutually exclusive, and their beneficial effects can be additive. Clinicians are encouraged to think creatively and collaboratively with each patient to develop solutions based on the patient’s preferences, strengths, and weaknesses. At the outset, it should also be noted that alcohol worsens disease severity in OSA patients, and smoking and exposure to second-hand smoke also disturb breathing during sleep.9,10 At minimum, patients who engage in these behaviors should be counseled about these effects.

Losing Weight

Although not all SDB patients are overweight or obese, body mass is positively associated with SDB. For example, Newman and colleagues11 reported that individuals whose weight increased by 10% experienced a 32% increase in disease severity. Moreover, individuals who reported this weight gain were at six times the risk for development of moderate or severe OSA relative to individuals whose weight remained constant.

Weight loss should be a cornerstone clinical recommendation for SDB patients who are overweight or obese. It is non-invasive, very low risk, and likely to be associated with numerous health benefits beyond the presenting complaint. For overweight or mild-to-moderately obese patients, weight loss is typically achieved via a combination of restricting the number of calories consumed and increasing the frequency and intensity of exercise. Although weight loss can reduce the severity of mild SDB, it is unlikely to cure OSA. Therefore, it is especially important to recommend weight loss to snorers who have not yet developed full-blown OSA. Once patients have developed OSA, weight loss should be viewed as an important adjunctive treatment. It is also important to reassess disease severity following significant weight loss or gain.

Among morbidly obese patients with SDB, weight loss surgery is another option and can be an effective means of reducing disease severity. In a large-scale study comparing bariatric surgery and conservative weight loss treatment among morbidly obese patients with OSA, Grunstein and colleagues12 found surgery to be associated with reductions in self-reported apnea symptoms and snoring at 2 years post-treatment. Further, patients who reported improved SDB symptoms were less likely to have diabetes, hypertension, and other serious disease.

Elevating One’s Head and Using Special Pillows

In clinical practice, it is not uncommon for untreated OSA patients to report that they sleep in a recliner or other upright position. Although patients are generally unaware of the mechanism, such elevated postures improve sleep by reducing the angle of gravitational force on the throat and thus reducing upper airway collapse. Several studies have supported elevated postures as an adjunctive treatment for SDB.13-15 For patients who can tolerate such a sleeping arrangement, it is a low-cost way to reduce disease severity. Other patients might benefit from sleeping with an extra pillow or two.

A small number of studies have evaluated pillows specifically designed to reduce SDB via an improved cervical neck position. In the earliest of these reports, Kushida and colleagues16,17 evaluated a cervical pillow and reported reduction in objectively measured disease severity in mild, but not severe, OSA. More recently, a pillow designed for sleeping with the arm under the head while in the lateral position was found to reduce disease severity and improve oxyhemoglobin saturation.18 Another study19 found no benefit from the use of a support collar designed to prevent neck flexion during sleep. In summary, although findings have been inconsistent, there is some evidence that certain pillows may help selected patients with mild disease.

Avoiding Sleeping on One’s Back

Many patients experience more frequent or prolonged breathing events while sleeping on their backs. When this supine component is present, patients are considered to have positional SDB. Although definitions of positional OSA vary across studies, patients with a positional component tend to represent the mild end of the SDB disease continuum. Importantly, these patients may experience a reduction or elimination of breathing abnormalities if they sleep in the lateral position.20 Numerous methods have been employed to encourage sleeping on the side. Of these, the “tennis ball technique” is the most basic. Patients are instructed to sew a pocket for a tennis ball onto the back of a nightshirt, causing discomfort but not pain in the supine position. Shirts and vests that discourage back sleeping are also available for purchase and can be easily found on the Internet. In a small sample of positional OSA patients, Oksenberg and colleagues21 used a similar strategy and found that >50% of patients who wore a positional belt device reported learning to sleep on their sides. Further, sleeping in the lateral position was associated with reductions in self-reported snoring and increases in daytime alertness. Similar reductions in disease severity have been reported by others,22,23 and the most effective of the specialized pillows also involved a side-sleeping component. Perhaps surprisingly, patient preference for positional therapy and associated adherence have been low. Jokic and colleagues24 suggested that patients may be more likely to adhere with CPAP than with positional therapy, although additional research is needed. If a patient or bed partner reports mild to moderate snoring that is worse in the supine position, attempting lateral sleeping and monitoring results is a reasonable minimally invasive first step. Careful follow-up is essential.

Opening Nasal Passages

Several studies have documented an increase in SDB due to nasal congestion resulting from seasonal allergies, colds, or anatomic features such as large turbinates or deviated septum.25 Numerous strategies have been employed to alleviate this nasal blockage. Nasal irrigation is the most conservative (and least expensive) treatment recommendation. Many patients report improved nose breathing from these rinses, performed with a neti-pot or squeezable plastic bottle, especially during allergy season. Although the data is limited, clinical experience supports that steroidal anti-inflammatory nasal sprays can improve nasal breathing during sleep.26

Of the nasal dilators, non-pharmalogic external nasal strips have received the most research attention and are frequently of interest to many patients. Dilators work by increasing the volume of the nasal passages. One obvious limitation of this approach is that dilators do little to alleviate obstruction that occurs in lower parts of the airway. Overall, they may improve mild SDB that is primarily related to nasal airflow in some patients. In the only study to report objective improvement as measured by PSG, Gosepath27 reported that patients with nasal but minimal pharyngeal obstruction and <55 years of age were most likely to benefit from nasal strips. Nasal strips have also been found to reduce bed partner reports of snoring and patient-reported dry mouth.28 Using PSG to assess SDB, Todorova29 reported reductions in snoring frequency and lowered maximal snoring intensity associated with use of nasal strips. Although no objective differences in sleep were observed, participants in this study also reported improved sleep quality and symptomatic improvements. Wenzel and colleagues30 found nasal strips led to no improvement in PSG-measured sleep disturbance or self-reported sleep quality among snorers or patients with OSA, but a majority of participants did report improvements in nose breathing during sleep. In aggregate, these studies suggest consistent subjective improvement from nasal strips. Objective findings are less encouraging. Like weight loss or head elevation, nasal strips might help some snorers. For patients whose disease has progressed beyond the snoring stage, nasal strips are best viewed as an adjunctive treatment. In a 2003 report,31 the American Academy of Sleep Medicine concluded that external nasal dilators appeared to be safe and noted that they “may be efficacious in people with mild, nonapneic snoring, but data are inadequate to determine patient characteristics associated with favorable treatment.” It is also noteworthy that nasal strips can make nasal CPAP easier to tolerate, as long as mask fit is not affected.

Continuous Positive Airway Pressure Therapy

In addition to the minimally invasive procedures described above, the most frequently prescribed and efficacious treatment for OSA is CPAP. Patients on CPAP wear a mask that covers the nose (nasal CPAP) or nose and mouth (full-face mask) that applies air pressure to the upper airway through a tube connected to a shoebox-sized machine. Multiple dozens of mask variations are available. Many patients prefer nasal “pillows,” soft silicone forms that fit snugly into the base of the nostrils, without the burden of a larger mask.32 Regardless which mask is selected, generated air pressure functions as a pneumatic splint and prevents the airway from collapsing, permitting the patient to breathe freely. Although CPAP is an effective treatment for many OSA patients, it is not a cure. As indicated, patients and their family members must adjust to CPAP as a long-term treatment. The attitude of the healthcare provider can play an important role in guiding patients toward acceptance of their condition and successful treatment.

Adjustment and Adherence to CPAP

In the broader medical literature, adherence to prescription medications is generally ~50%.33 Given numerous potential complaints, such as claustrophobia, feeling restricted, sore eyes, nasal/sinus dryness, condensation build-up in the CPAP air hose itself, skin irritation and erosion from the mask, machine noise, and embarrassment and perceived social stigmatization, it is not surprising that poor acceptance and adherence are substantial problems associated with CPAP use.34 Acceptance is defined as willingness to try CPAP at all, and a small but appreciable number of patients are reluctant to even attempt the treatment. In one of the earliest investigations of CPA adherence, Kribbs and collleagues35 reported objective CPAP use in a small sample. As few as 6% of patients for whom CPAP had been prescribed used it at least 7 hours on the majority of nights monitored, and <50% used it for even 4 hours/night. On nights that patients used the machine at all, mean usage was 4.9±2.0 hours. Although a wider range of usage has been reported in more recent literature, findings pertaining to CPAP adherence have generally remained consistent with these early results. Further, in spite of a lack of consensus, the most commonly accepted definition of CPAP adherence, 4 hours of use per night on 70% of nights, also stems from this early Kribbs study.35 Nonetheless, this 4-hour cutoff is ultimately arbitrary. More recent reports36,37 have demonstrated that CPAP has a dose-response relationship, and clinical experience suggests that patients should be strongly encouraged to wear their CPAP mask all night, every night, as well as during any naps. This also includes traveling with the machine, which is easily portable yet does involve additional burden for patients.

Correlates of CPAP Use

In light of increasing awareness of SDB and rates of CPAP use, it is perhaps not surprising that there has been a dramatic rise in clinical and research attention given to factors associated with CPAP use and improving CPAP adherence. Numerous correlates of CPAP adherence have been identified, and several clinical recommendations can be made. The next sections of this article address pertinent predictors of CPAP use and related interventions designed to enhance CPAP adherence. Technical modifications likely to improve CPAP adherence, such as mask selection and humidification, are often helpful for patients new to CPAP but are beyond the scope of this article.

Demographic Characteristics and Psychosocial Functioning

There is mixed evidence regarding the relations between demographic characteristics such as age, gender, and socioeconomic status and CPAP usage. However, numerous psychological characteristics have been indicated in CPAP use. For example, poorer daytime functioning,38-40 depression and anxiety,40 panic,41 and claustrophobia42,43 have all been associated with lower CPAP use. Conversely, higher functioning predicts greater CPAP adherence.44-47

Disease Knowledge

Patients with greater knowledge of OSA and CPAP and who believed that CPAP was likely to improve their condition are more likely to use the treatment.48,49 Further, studies have supported the use of interventions designed to increase knowledge, including educational literature, videos, telephone support, additional follow-up appointments, support groups, and group educational sessions.50-55 Golay and colleagues56 described a particularly comprehensive educational program for patients and their bed partners, which is delivered over six meetings and addresses aspects of CPAP from maintenance and cleaning the machine to romantic intimacy. Although such a comprehensive program will not be feasible in all treatment settings or healthcare systems, providers can incorporate these educational principles into their patient care.

CPAP Use within a Social-Cognitive Framework

An increasing number of investigators have postulated a social-cognitive model for understanding CPAP use,57 and this framework will be reviewed here. From within this perspective, behavior is explained by the relations between three primary constructs, namely, perceived environment, including social influences and vicarious experience; outcome expectancies, including perceived risks and benefits; and self-efficacy, including both task-specific and general components. Social cognitive theory does not discount the influence of demographic factors or disease knowledge but postulates that their influence is exerted through the aforementioned psychosocial constructs. As will be discussed, considerable evidence supports this social-cognitive understanding of CPAP adherence. More importantly, the model provides clinicians an easy way to identify psychosocial barriers and modifiable factors likely to increase adherence. Figure 1 depicts social cognitive theory as applied to CPAP usage.57

 

 

Outcome Expectancies

Within the domain of outcome expectancy, perceived costs and benefits impact CPAP use. For example, patients who report side effects are less likely to use CPAP than patients who do not report these complaints.35,58 However, the strongest and most consistently identified predictors of CPAP adherence are perceived benefits from use. This is true for both novice and experienced users.46,59-61

Importantly, many patients fail to perceive the effects of their disease and are, therefore, less likely to be aware of the benefits of CPAP.62 In light of the mixed evidence regarding objective disease severity and CPAP adherence, patient awareness and perceived impairment appear to mediate objective breathing disturbance. Engleman and colleagues63 were among the first to emphasize the need for patients to be educated about their impairment. Often, this requires including collateral information from multiple sources to help the patient develop a frame of reference for his or her level of impairment. A recent review64 identified four categories of benefit: improvements in symptoms including reduced daytime sleepiness and improved quality of life, improved bed partner sleep, reduced risk for serious disease, and reduced risk for motor vehicle accident.

Perceived Environment

Perceptions of environmental influence also play a role in CPAP use. Within a social-cognitive framework, the likelihood of CPAP use is influenced by patient perceptions of social stigmatization regarding CPAP and by perceptions of supportive attitudes toward CPAP use and behavior models. Variables in the perceived environment function as either barriers or facilitators of CPAP use and exist in theoretical proximity to adherence. For example, media portrayals of SDB are theoretically more removed from CPAP use than are bed partner attitudes. The nature of many patients’ resistance to the diagnosis illustrates the importance of perceived environmental factors. Clinical experience suggests that men are likely to associate the disease with being overweight or obese, and women tend to consider snoring and CPAP use “unladylike.” These attitudes are likely influenced by media portrayals supporting the common misconception that only overweight individuals experience SDB. Unfortunately, many persons of influence, including healthcare providers, also propagate this myth. More proximally, perceived familial support and bed partner attitudes are also consistently related to CPAP adherence. Based on these associations, treatment providers have been encouraged to include a caregiver when discussing CPAP, and a family problem-solving approach has been recommended.3,65,66

Family members and bed partners can be powerful allies in providing the support needed to adapt and adjust to CPAP as well as valuable information about patient behavior. Indeed, including a bed partner in treatment can increase CPAP adherence.67 In a study by Smith and colleagues,3 patients’ spouses identified barriers to CPAP use, including falling asleep in a chair before bed, changes in evening schedule or routine, staying out late, forgetting to use CPAP, and traveling and forgetting to bring CPAP. Each of these can be addressed in a simple behavioral manner and through consistent self-monitoring.

A few bed partners will discourage SDB patients from using CPAP. Such challenges can be discussed with the patient. Often, working to include a non-supportive bed partner in treatment discussions is an effective antidote. In this vein, providers, patients, and bed partners should be aware that when OSA is treated with CPAP, quality of life and daytime sleepiness improve for both patients and their bed partners.68 This information can be especially helpful for patients; although a majority of patients expected CPAP to improve their bed partner’s sleep, <50% reported they would use CPAP if it disturbed their bed partners.69 In aggregate, this evidence supports a partner-based approach to adjusting to CPAP. Providers should be aware, however, that when compared to patients initiating their own treatment, patients who sought care at their spouses’ request were less likely to use CPAP at all time points measured.70 As will be discussed, assessing patient motivation and addressing ambivalence are key aspects of improving CPAP adherence.

Self-Efficacy

Both self-efficacy and adaptive coping strategies have also been found to be predictive of greater CPAP usage.71-73  As with any major life change, adaptive coping is important to acclimating to CPAP. Recent work by Stepnowsky and colleagues74 highlights the importance of general self-efficacy to improving CPAP use. Clinical experience further supports this approach, which enables patients to improve both self-monitoring and self-management. Telephone calls, additional follow-up visits, and even wireless monitoring of machine use,75 combined with positive reinforcement, are effective at guiding patients toward increased self-efficacy. These relational factors are often of particular importance to the PCP, who will often have a stronger relationship with the patient than the sleep specialist.

Motivational Enhancement for CPAP

A brief cognitive-behavioral intervention has shown initial promise in increasing CPAP adherence. Based on social-cognitive theory and the transtheoretical model of change,76 motivational enhancement for CPAP (ME-CPAP) is delivered over two 45-minute sessions and a 15-minute telephone follow-up.77 ME-CPAP integrates the principles and practices of motivational interviewing78 with the provision of personalized, objective feedback about SDB and CPAP.

In the first session, patient perceptions of the risks of SDB and costs and benefits of CPAP are explored. Ambivalence toward CPAP use is explored using a “readiness ruler” or simply by asking the patient, “On a scale of 1–10, how ready are you to use CPAP?” The patients complete a decisional balance exercise, which asks them to identify the specific costs and benefits of using CPAP and not using CPAP. The decisional balance is a powerful tool and resonates with patients, especially when time is taken to help elicit the benefits of not using CPAP. Although patients initially struggle to realize the emotional valence of the comfort of continuing to do things the same way, it is precisely the awareness of these factors that moves patients from precontemplation to contemplation, action, and beyond (Figure 2).76

 

 

 
In the second session, the therapist seeks to elicit the patient’s subjective appraisal regarding CPAP use since the first treatment session, help the patient consider the effects of untreated OSA, explore the patient’s ambivalence about routine use of CPAP, identify discrepancies between the patient’s current CPAP use and future life goals, help to identify rewards for using CPAP, and set goals and small steps to facilitate CPAP usage. The identification of important life goals and personal values can be especially helpful. For example, if a patient would be better able to play with his grandchildren were he less sleepy during the day, this is often an effective motivator to use CPAP. A manual detailing ME-CPAP has been published elsewhere.77

Although results of ME-CPAP have been encouraging and the treatment continues to be refined, one shortcoming of the approach as initially presented is that it allowed patients to use CPAP for 1 week prior to the first session. Hence, a feedback loop between behavior and perception was already developed. Of course, there is still no algorithm to identify patients likely to fail at CPAP. Nonetheless, recent reports confirm that sleep during CPAP titration and CPAP usage as early as the first 3 nights of treatment are strongly predictive of subsequent adherence.79-82 It is also likely that the modifiable factors addressed in this article influence CPAP well before the patient sleeps in his or her own bed with a new CPAP machine. Together, these factors support a proactive, comprehensive, and flexible approach to preparing patients for CPAP.

Conclusion

SDB is related to numerous medical diseases as well as increased risk for accidents, and awareness of SDB as a condition with serious consequences is increasing. PCPs and mental health practitioners are frequently unaware that the symptoms of SDB can mirror those of depression, anxiety, attention deficit, and other cognitive and somatic complaints. For mild SDB, simple behavioral interventions can provide partial or adjunctive treatment benefit. However, the gold standard treatment for OSA is CPAP therapy. Clinical experience suggests that roughly a third of patients will adjust to CPAP without prolonged difficulty, a third need some extra support, and a third will struggle to adjust to this lifelong treatment. Patients who are unable to accept or adjust to CPAP can consider alternative treatments, including oral mandibular repositioning devices which can be effective in mild and moderate OSA,83 and in select cases, uvulopalatopharyngoplasty or other surgery; data, however, is less supportive of surgical approaches and suggests surgery may be a last resort.84 PCPs should understand the progressive and chronic nature of SDB and that there is no cure for OSA for most patients. From a treatment perspective, patients will benefit when providers consider social cognitive factors as well as the importance of patient experiences throughout the SDB evaluation and early treatment phases, in addition to careful and consistent follow-up. PP

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Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, Maryland. He is also medical director of the Psychiatry Mobile Treatment Program at the Johns Hopkins Bayview Medical Center.

Disclosures: Dr. Neubauer is a consultant to and on the speaker’s bureaus of sanofi-aventis and Takeda.

Please direct all correspondence to: David N. Neubauer, MD, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Box 151, Baltimore, MD 21224.


 

The past decade has been an exciting time in the field of sleep medicine. There has been greater attention to sleep in the popular media and much more published literature focusing on sleep disorders. For example, Primary Psychiatry has had several past issues highlighting sleep disorders and has published a quarterly column devoted to sleep-related topics. There has been considerable clinical research on the treatment of sleep disorders and several new medications have become available for treating common sleep problems, such as insomnia, excessive daytime sleepiness, and restless legs syndrome (RLS). Over the past few years the National Institutes of Health coordinated a state-of-the-science conference on chronic insomnia and the Institute of Medicine published reports1,2 on sleep disorders and sleep deprivation. However, while many people with sleep disorders have been identified and treated very effectively, many others represent clinical challenges, either because of overlapping symptomatology, diagnostic confusion, lack of initial treatment response, or difficulty with treatment adherence. Four articles in this issue address what still needs to be done in relation to the evaluation and management of patients with sleep disorders.

Nancy A. Collop, MD, FCCP, and David N. Neubauer, MD, discuss key features of sleep apnea and the mental health implications of sleep-related breathing disorders. Types of sleep apnea, their clinical presentations, diagnostic screening questions, and primary treatment options are reviewed. The challenges in identifying, evaluating, and treating sleep apnea in patients with chronic mental illnesses are then explored. People with chronic psychiatric disorders may have risk factors associated with the development sleep apnea and symptoms which complicate the effective treatment of the apnea. For example, patients with certain mental disorders, such as schizophrenia, have a tendency to be overweight or obese, which may be exacerbated further by the use of several commonly prescribed psychotropic medications. Further, sleep-disordered breathing patients often experience depressive symptoms. The dual presence of sleep and mental disorders may lead to greater health risks, functional impairment, and decrements in quality of life. The authors suggest that mental health professionals should be alert to the possibility of sleep-disordered breathing among their patients and that providers managing sleep disorder patients should be mindful of coexisting psychiatric disorders. Optimal treatment of both will likely be required for significant clinical recovery.

Once sleep apnea has been suspected in an individual, making the diagnosis is usually uncomplicated. Generally, a night in a sleep laboratory for polysomnographic testing is sufficient. This should demonstrate the presence, type, and severity of any sleep-disordered breathing. The results also will influence the treatment recommendations. However, the rapid rise in sleep laboratories diagnosing obstructive sleep apnea (OSA) does not necessarily translate to successful management in all of the patients. Emerson M. Wickwire, PhD, discusses a variety of practical issues related to treating sleep apnea patients. Behavioral modifications may be adequate for mild OSA cases. These may involve weight loss and sleeping position. Continuous positive airway pressure (CPAP) and related devices are often recommended for patients with moderate to severe OSA. Unfortunately, many patients have difficulty adapting to wearing a CPAP mask on a nightly basis and, subsequently, have poor treatment adherence. The author employs a cognitive framework to explore the patient motivations that affect the use of CPAP and offers suggestion to help patients use CPAP to a greater extent.

Anna Ivanenko, MD, PhD, and Pallavi P. Patwari, MD, strongly support the adage that children are not simply little adults. Children and adolescents commonly suffer with sleep disorders, which sometimes are not recognized and often are not treated. Children and adolescents have particular risks for sleep disturbances related to psychological, behavioral, physiologic, and anatomic factors. Children may exhibit several types of insomnia related to bedtime routines and conditioning associated with their sleep environment. Several types of parasomnias are common in children, in part due to their sleep stage characteristics. Among these childhood parasomnias are sleep terrors, sleepwalking, nocturnal enuresis, and nightmares. OSA is not uncommon in children, but for them it most often is due to enlarged tonsils and is cured by a tonsillectomy. However, OSA in children is often not identified and they suffer with unexplained cognitive and behavioral consequences. The symptoms of RLS, periodic limb movement disorder, and disorders of excessive sleepiness, such as narcolepsy, may begin in childhood or adolescence. Ivanenko and Patwari provide practical advice regarding the evaluation of children and adolescents for possible sleep disorders, as well as an overview of pharmacologic, behavioral, and other nonpharmacologic treatment strategies that may be beneficial for these populations.

David N. Neubauer, MD, offers a review of the evolution of medications that have been recommended to treat insomnia, excessive sleepiness, RLS, and other sleep disorders. He highlights the most recent innovations with the Food and Drug Administration-approved medications and discusses some of the new pharmacologic compounds that are currently being investigated for these disorders. There have been major advances in understanding the regulation of sleep and wakefulness. As a result of the emerging science of sleep, it is likely that several new medications with entirely different mechanisms of action will become available over the next few years for the treatment of insomnia. In the future, there should also be a greater focus on treatment outcomes related to the daytime effects of insomnia and not just the traditional measures of nighttime sleep onset and sleep maintenance. Further, there may be interesting new medications for RLS, narcolepsy, and sleep apnea. A medication for sleep apnea would be intriguing, since OSA typically has been considered an anatomic problem with airway collapsibility. However, it may be feasible to address the neural control of the upper airway tone with medication.

In spite of the basic science advances related to normal sleep and sleep disorders, the growing field of sleep disorders medicine, and the widespread availability of clinical sleep laboratories, there remain large deficits in the recognition of the entire spectrum of sleep disorders in all age categories. People with untreated sleep disorders suffer impairments in their waking functions and society suffers with a significant economic burden. Even when sleep disorders are identified and properly diagnosed, their treatment is not necessarily optimal. An important part of the solution will be increasing the awareness of sleep disorders and sleep deprivation in the general public and in a wide range of educational settings. PP

References

1.    National Institutes of Health. National Institutes of Health State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
2.    Colten HR, Altevogt BM, eds. Institute of Medicine Report. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: The National Academic Press; 2006.