Insomnia and Psychiatric Disorders
06/21/2004
David N. Neubauer, MD

During the past several years, the relationship between insomnia and psychiatric disorders has come to be viewed as circular and synergistic. Psychiatric illnesses, particularly anxiety and mood disorders, have long been recognized as a frequent cause of insomnia symptoms. In some instances, this association is even formalized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria. Clinical experience shows that almost all patients with mood and anxiety disorders have sleep disturbances either chronically or during exacerbations of their psychiatric illnesses. However, it has become clear that insomnia also increases the risk of future relapse or the development of new onset anxiety, mood, and substance abuse disorders. This relationship can promote a downward spiral of symptom severity and quality of life for patients that further complicates treatment efforts. On the other hand, the close association of insomnia, depression, and anxiety symptoms can be viewed as an opportunity for targeted therapies that may provide significant benefits for patients.

Epidemiology
An analysis of data from the large-scale Epidemiologic Catchment Area (ECA) project[1] demonstrates the relatively high percentage of individuals in the general population who suffer from significant insomnia symptoms and meet the criteria for mood, anxiety, or substance abuse disorders. In all, 10% of the sample met the stringent criteria for insomnia, and 40% of these insomnia sufferers met the criteria for at least 1 psychiatric disorder. Major depression or dysthymia was diagnosed in 23%; anxiety disorder was diagnosed in 24%; alcohol abuse was found in 7%; and drug abuse was discovered in 4%. Furthermore, if insomnia was present both at baseline and 1 year later, the risk of the individual having a new onset mood or anxiety disorder at the time of the follow-up interview increased significantly.

This general conclusion has been replicated in longitudinal studies with subjects ranging from adolescents to the elderly.[2,3] Indeed, any history of persistent insomnia augments the lifetime risk of major depression.[4] It is unclear whether the insomnia represents a prodrome, shared genetic vulnerability, or a causative process promoting depressive symptoms. Nevertheless, this association emphasizes the need for early recognition and treatment of insomnia, and an evaluation for potential psychiatric disorders.

Insomnia and Bipolar Disorder
In addition to major depression and dysthymic disorder, insomnia commonly occurs with bipolar disorder during depressive and manic episodes. Although some manic patients will describe a decreased need for sleep, others complain of being distressed by an inability to sleep. Sleep loss from any reason, including jet lag and work schedules, may contribute to the onset or progression of manic episodes in patients with bipolar disorder.[5,6] Early sleep-targeted interventions may prevent or limit exacerbations for these patients.

Anxiety Disorders
Among anxiety disorders, insomnia is particularly problematic for patients with panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Most patients with panic disorder at times will experience distressing panic episodes that awaken them from sleep. This may lead to considerable anticipatory anxiety about going to sleep, which may lead to sleep insufficiency and more anxiety.[7] Patients with posttraumatic stress disorder frequently experience poor sleep quality and vivid nightmares.[8] The chronic anxiety of patients with generalized anxiety disorder often affects these patients throughout the night with resulting difficulty falling asleep and repeated awakenings. Patients with social phobia report significantly worse sleep quality and difficulty falling asleep as compared with healthy controls.[9]

Management of Insomnia in Patients With Psychiatric Comorbidities
Managing the insomnia complaints of patients with concurrent psychiatric disorders is a 2-pronged approach. Specific therapeutic interventions should address the primary psychiatric condition. These interventions may include psychotherapeutic, behavioral, and pharmacologic strategies. Optimizing the treatment of the underlying disorder ultimately should improve sleep.

Medications for patients with mood and anxiety disorders include an assortment of antidepressants, anxiolytics, and mood stabilizers. The selective serotonin reuptake inhibitor (SSRI) antidepressants and venlafaxine (a combination SSRI and norepinephrine reuptake inhibitor) often are effective for these patients, although they rarely improve insomnia symptoms rapidly. Furthermore, some patients will develop insomnia as a side effect from these medications.

A sedating antidepressant, such as amitriptyline, trazodone, or mirtazapine, may help with sleep, but also may cause residual sedation the following day. If trazodone is prescribed, further caution is advised regarding hypotension, priapism (men and women), and the potential contribution to the serotonin syndrome when combined with other serotonergic medications. Although selected medications work well for certain patients, there currently is no antidepressant that reliably and rapidly promotes improved nighttime sleep and daytime alertness.

General approaches to insomnia are those applicable to a broad range of patients and include sleep hygiene and behavioral interventions, cognitive behavioral therapy, and hypnotic medications. These approaches may be used concurrently with specific treatment strategies for the psychiatric disorders. There are several advantages to this 2-pronged approach. First, there is greater choice in selecting medications for the psychiatric symptoms, rather than restricting the options to sedating agents. There also can be flexibility in the dosage, timing, and duration of use of medications targeting different symptoms. Second, hypnotic medications may provide immediate relief and, subsequently, decreased distress and improved quality of life. A hypnotic can offset the stimulating effect of some antidepressants. Third, these general insomnia treatment approaches can directly address the perpetuating factors that reinforce chronic insomnia.

Currently available hypnotic agents include 5 benzodiazepines (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 2, newer nonbenzodiazepine agents (zaleplon and zolpidem). All of these medications are positive allosteric modulators at the gamma-aminobutyric acid (GABA)-A receptor complex. The inhibitory GABA-A system functions through membrane hyperpolarization as negative chloride ions enter the cells. Benzodiazepine receptor agonists enhance this normal process. The traditional benzodiazepines appear to interact with most subunit configurations of the GABA-A receptor, whereas the newer agents are more selective for a particular configuration. This selectivity and the relatively short elimination half-lives of these nonbenzodiazepine hypnotics help explain the good efficacy, safety, and tolerance of these newer-generation agents.

In clinical practice, hypnotics often are prescribed concurrently with antidepressants for patients with mood and anxiety disorders. Pharmacokinetic and pharmacodynamic studies of fluoxetine and sertraline combined with zolpidem have been performed in healthy, nondepressed women.[10,11] These studies found no clinically significant interactions. Another trial evaluated the sleep of patients prescribed an SSRI concurrently with zolpidem or a placebo.[12] The study population included individuals successfully treated for depression with an SSRI, but who were complaining of persistent insomnia. The hypnotic-treated patients reported significantly improved sleep and daytime functioning.

New Agents
A variety of pharmacologic agents is being evaluated in clinical trials for the treatment of insomnia. These include new nonbenzodiazepine medications and modified-release preparations as well as melatonin agonists, presynaptic and postsynaptic GABA-A modulators, and corticotropin-releasing factor antagonists.

On the near horizon is eszopiclone, a moderately short-acting, nonbenzodiazepine agent derived from zolpiclone, which has been available outside the United States for several years. The newest development with the nonbenzodiazepine hypnotics is the modified-release formulation. The rationale behind the development of this formulation is that the immediate-release component promotes rapid sleep onset, whereas the extended-release component helps maintain sleep through the night. Ideally, short medication half-lives will allow a rapid decline of the sedating effects to prevent residual daytime effects. Formulations of this type are being evaluated for zaleplon and zolpidem. Indiplon is a new, very short half-life nonbenzodiazepine hypnotic that likely will be available in both immediate- and modified-release formulations.

Looking for Other Causes of Sleeplessness
Although it is important to identify and treat the insomnia symptoms that may result from psychiatric illnesses, it is equally important to evaluate psychiatric patients for other possible contributing causes of their sleep disturbances. These may include stimulating effects of psychotropic and other medications, medical disorders and underlying primary sleep disorders, circadian rhythm disorders, irregular schedules, and maladaptive habits and routines. Patients with sleep apnea can present solely with insomnia complaints. Restless legs syndrome and periodic limb movements, which can be exacerbated by most antidepressants, can cause difficulty falling asleep and repeated awakenings. Withdrawn or agoraphobic patients may spend excessive time at home, sleep at irregular times, and be deprived of the photoperiod that normally reinforces the sleep-wake cycle.

Although the clinical history is the cornerstone of the evaluation of sleep disturbances, patients' descriptions of their sleep problems can be supplemented with a sleep log or diary maintained for at least several weeks. This may offer a more accurate representation of exactly when they are awake or sleeping (nighttime and daytime) as compared with their summary given at a clinic appointment. It also can be helpful when monitoring the effectiveness of treatment approaches. Consultation with a sleep medicine specialist and sleep laboratory testing may be appropriate for patients with excessive daytime sleepiness, when patients are suspected of having disorders, such as sleep apnea and narcolepsy, and when insomnia is persistent and not responsive to standard treatments.

The effective treatment of insomnia in patients with psychiatric disorders may require a constellation of strategies involving proper sleep habits, schedule manipulations, cognitive behavioral interventions, and adjustments of psychiatric medications. Hypnotic medications may play a valuable role for selected patients. Improving sleep can be an important catalyst to more general clinical recovery.

References
1. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989;262:1479-1484.
2. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39:411-418. Abstract
3. Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Sleep complaints and depression in an aging cohort: a prospective perspective. Am J Psychiatry. 2000;157:81-88. Abstract
4. Ford DE, Cooper-Patrick L. Sleep disturbances and mood disorders: an epidemiologic perspective. Depress Anxiety. 2001;14:3-6. Abstract
5. Leibenluft E, Albert PS, Rosenthal NE, Wehr TA. Relationship between sleep and mood in patients with rapid-cycling bipolar disorder. Psychiatry Res. 1996;63:161-168. Abstract
6. Young DM. Psychiatric morbidity in travelers to Honolulu, Hawaii. Compr Psychiatry. 1995;36:224-228. Abstract
7. Uhde TW. Anxiety disorders. In: Principles and Practice of Sleep Medicine. Kryger MH, Roth T, Dement WC, eds. WB Saunders: Philadelphia, Pa; 2000.
8. Green B. Post-traumatic stress disorder: symptom profiles in men and women. Curr Med Res Opin. 2003;19:200-204. Abstract
9. Stein MB, Kroft CDL, Walter JR. Sleep impairment in patients with social phobia. Psychiatry Res. 1993;49:251-256. Abstract
10. Allard S, Sainati SM, Roth-Schechter BF. Coadministration of short-term zolpidem with sertraline in healthy women. J Clin Pharmacol. 1999;39:184-191. Abstract
11. Allard S, Sainati SM, Roth-Schechter BF, MacIntyre J. Minimal interaction between fluoxetine and multiple-dose zolpidem in healthy women. Drug Metab Dispos. 1998;26:617-622. Abstract
12. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60:668-676. Abstract


David N. Neubauer, MD, is an Assistant Professor, Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Associate Director, Johns Hopkins Sleep Disorders Center, Baltimore, Maryland

Disclosure: David N. Neubauer, MD, has disclosed that he has served as an advisor or consultant for Pfizer/Neurocrine, Sanofi-Synthelabo, and Takeda. Dr. Neubauer has reported that he discusses the unlabeled uses of antidepressants for primary insomnia and the chronic use of hypnotics in this activity.

Medscape Neurology & Neurosurgery 6(1), 2004.