Wallace B. Mendelson, MD

Many modern psychiatric medicines share a single, and surprising, origin story. They stem from a 19th-century attempt to deal with the problem of malaria, and its unexpected consequence, the development of the synthetic fabric dye industry. To see how medicines as seemingly diverse as chlorpromazine, imipramine, clozapine, and diazepam evolved from this unlikely source, let us step back in time to the 1850s.

At that point in time, malaria was taking a tremendous toll on the British effort to build and maintain an empire, and its devastation among the troops in the Crimean War was widely publicized. The only effective treatment was quinine, derived from the bark of the 

 tree in South America and Polynesia. There was an impetus to find a way to synthesize it at home, and a professor at the Royal College of Chemistry, August Wilhelm von Hofmann, believed that this could be done using the raw material of coal tar, in effect industrial waste from the manufacture of coke and illuminating gas. He challenged his students to do it, and one of them, 18-year-old 

During Easter vacation in 1856, Perkin attempted the synthesis in the attic of his home in east London. This was a risky project; not too long before, another student had burned to death while trying to obtain benzene from coal tar. Perkin tried to combine the coal tar derivative aniline, an oily, fishy-smelling liquid, with orange-red potassium dichromate powder. The result was a dark-colored sludge lodged in the bottom of his glassware, which is not usually considered a desirable outcome. When trying to dislodge the mess, he added alcohol, and found that it turned a vivid purple. When it imparted this color to his cleaning cloth, Perkin, who had a longstanding interest in painting and photography, wondered if it might be useful as a fabric dye. At the time, purple dye was obtained laboriously from the mucous secretions of mollusks and, hence, it was very expensive. A synthetic product from coal could in principle be made very cheaply.

Perkin took his idea to professor Hofmann, who at first scoffed at it as trivial and recommended that he turn his attention back to quinine. Undeterred, Perkin, along with his brother and a friend, built a laboratory in his backyard garden. After testing its ability to color silk, they applied for a patent and founded a company. Although he had not synthesized quinine (this would not happen for another 90 years), he had inadvertently opened the new field of synthetic organic chemistry.

Initially there was little interest in aniline purple, or mauveine, but after the Spanish-born Empress Eugenie de Montijo favored the new color and Queen Elizabeth wore a mauveine dress to the Great Exhibition of 1862, there was great public enthusiasm. Soon a variety of other dye companies, including Bayer, Ciba, Geigy, and Sandoz were using these newfound techniques to make fabric dyes, and later expanded into paints, food colorings, agricultural chemicals, explosives, and medicines. And here our story of synthetic dyes evolving into psychiatric drugs begins. (The depiction of these discoveries is presented in summary form; more detailed accounts can be found elsewhere.

A cascade of discoveries began with methylene blue

In 1876, Heinrich Caro, a German calico printer and chemist who would later co-discover indigo, synthesized the azo dye methylene blue, subsequently determined to be a tricyclic phenothiazine. It might have remained a footnote to the history of fabric production, but for 2 events. Fifteen years later, the pharmacologist 

 was using methylene blue to stain microscopic organisms when he noticed that it seemed to immobilize the Plasmodium parasites that cause malaria when transmitted by Anopheles mosquitos. He wondered whether it might become a clinical treatment and gave it to patients. Their condition improved.

Methylene blue went on to be widely used, notably for treating malaria in Allied troops in the Pacific during World War II. Although subsequently replaced by synthetic drugs such as quinacrine, chloroquine, and hydroxychloroquine (much in the news in this past year in another context), methylene blue was important because it was the first fully synthetic drug in medical practice. As an aside, Ehrlich also noted that it might have antidepressant or sedative effects, although that was not actively pursued at the time.

The second development based on methylene blue came some 70 years later. With the success of antihistamines such as diphenhydramine in 1945, pharmaceutical houses looked for other similar agents. 

, a chemist at Rhône-Poulenc, developed chlorpromazine, a derivative of methylene blue. Charpentier had been making antihistamines for Dr Henri Laborit, a French surgeon who believed that histamine release contributed to surgical shock. He recalled that chlorpromazine, which had been unsuccessfully tested as an antimalarial, had significant antihistaminic properties, and sent it on to Laborit. It was soon noticed that chlorpromazine quieted surgical patients, who seemed to develop a state of indifference, and Laborit wondered if it might be useful in psychiatry. He and colleagues at Val de Grâce hospital in Paris gave it to a 24-year-old patient with bipolar disorder, who improved and was ultimately discharged. The encouraging results were reported at a medical meeting, but they were met with indifference.

Things might have remained had not an anesthetist colleague of Laborit’s mentioned that his brother-in-law was Dr Pierre Deniker, a psychiatrist at the prestigious St. Anne’s Hospital in Paris. They contacted Deniker, who, along with his director Jean Delay, tested chlorpromazine, and soon publicized its success in improving the conditions of patients with psychosis. As more and more reports of efficacy came in from around the world, chlorpromazine was first marketed in Europe as Largactil (“large in action”) in 1953. The result was a transformation in the treatment of psychoses. Many patients no longer requiring inpatient care and were transferred to communities that were not always equipped to receive them.

The effect of chlorpromazine on the medical community was so great that soon other companies began modifying the molecule in the hopes of developing a related drug. Among them was Geigy, which provided compounds for testing to various psychiatrists, including 

 in Münsterlingen, a lakeside community in northern Switzerland. One compound, G22355, was similar to chlorpromazine, with 3 ring-like structures attached to a side chain. When it offered little benefit to patients with schizophrenia, Kuhn decided to try it on patients with depression. Why he did this is not completely clear. One possibility is that the experiment came from a desire for completeness; alternatively, the Münsterlingen facility was unusual in that it had a large outpatient clinic with patients with depression, and Kuhn may have been particularly sensitive to depression because of his work there. He gave it to a woman who seemed improved after 6 days, and went on to study additional patients. He reported his findings in a Swiss journal and at an international meeting, but he too met with little interest. Undeterred, he later gave a lecture at Galesburg State Hospital in the United States and published his findings in the 

. This time he found a more enthusiastic audience, and imipramine, the first of the 

, was released in Switzerland in 1957 and in the United States in 1959.

Just as the success of chlorpromazine ultimately resulted in imipramine, the enthusiasm for imipramine led other companies to seek similar agents. In the process, the Swiss firm Wander AG (which also made Ovaltine) came across what were known as “neuroleptic tricyclics.” During animal screening, an agent seemed of particular interest. It caused less sedation, and unexpectedly seemed to reduce sensitivity to pain. They selected this one for further study, and although it turned out that the analgesia finding had been an error due to deteriorated electrodes, it was a potent antipsychotic. After developing elaborate protocols to monitor its hematologic effects, 

 came on the market in the United States in 1989, and it remains the gold standard for treatment resistant schizophrenia.

How failed fabric dyes evolved into tranquilizers

 also have a background in fabric dyes. The rising popularity of meprobamate in 1955 inspired other companies to find antianxiety agents. 

 a chemist at Hoffman LaRoche, was asked to do so, but because other companies were already looking at variants on the meprobamate molecule, his task was to look for something with a completely different molecular structure. When thinking about possible chemical building blocks, he chose some azo dyes and derivatives that he had worked with at the University of Krakow in the 1930s. At the time, they had not been effective for coloring fabrics, so he had published a paper and moved on to other things. This time, he made about 40 variants of these molecules and gave them to colleagues for behavioral testing. Most of them were not successful, and Sternbach was told to let the project go and begin work on antibiotics.

A few years later, while cleaning out the laboratory, an assistant came across an old bottle from that previous work. He showed it to Sternbach; although he had moved on to other projects, Sternbach chose to test it. This last compound, chlordiazepoxide, came onto the market in 1960 as Librium (from “equilibrium”), the first of the benzodiazepine tranquilizers. It was followed 3 years later by diazepam and later others, and they rapidly became very popular, largely because of perceived advantages over barbiturates. They were less toxic in overdose when taken alone by healthy individuals (although indeed very toxic when combined with a number of other substances), had less respiratory depression, and did not stimulate hepatic enzymes to increase metabolism of other drugs. Their potential for misuse and abuse was not well recognized in those early years, but became more evident by 1975 when they were scheduled as Drug Enforcement Agency Class IV controlled substances, and again more recently with FDA Black Box warnings in 2016 and 2020.

The history of dyes leading to drug development is not confined to psychiatry. In 1931, a yellow acridine dye derived from methylene blue became quinacrine, a treatment for malaria. Another dye, prontosil red, became the first sulfonamide antibacterial agent. Sometime later its developer, 

, went on to modify related sulfa compounds and laid the groundwork for 1 of the routes to the antituberculosis drug isoniazid. In the early 1950s, iproniazid, closely related to isoniazid (which in this case came from a different source), was noted to elevate the mood of patients with tuberculosis, and ultimately came to market in 1958 as Marsilid, the first 

In the modern world, dyes continue to be explored as drugs. Derivatives of indigo (as in blue jeans), known as indigoid dyes, are being developed to act as photo switches that could turn antibacterial or anticancer drugs on and off when exposed to light.

 Methylene blue is still used as a treatment for the blood disease methemoglobinemia. Its effects on tau proteins have led to current studies of its possible utility in mild cognitive impairment

, and a derivative, hydromethylthionine, is under investigation for Alzheimer disease and frontotemporal dementia.

In summary, psychopharmacology as a field continues to grow rapidly and fruitfully, but it is good to remember its curious beginnings. Who could have guessed 150 years ago that a fabric printer, building on the lessons from a student’s failed chemistry project, would stumble upon a new coloring agent for calico and inadvertently set the stage for psychiatric pharmacology?

is a professor of psychiatry and clinical pharmacology (ret) at the University of Chicago. His recent books include

Molecules, Madness, and Malaria: How Victorian Fabric Dyes Evolved into Modern Medicines for Mental Illness

Nepenthe’s Children: The History of the Discoveries of Medicines for Sleep and Anesthesia

The Curious History of Medicines in Psychiatry.

2. Mendelson WB. Molecules, Madness, and Malaria: How Victorian Fabric Dyes Evolved into Modern Medicines for Mental Illness and Infectious Disease. Pythagoras Press; 2020.  

3. Petermayer C, Dube H. Indigoid Photoswitches: Visible Light Responsive Molecular Tools. Acc Chem Res. 2018;51(5):1153-1163. 

4. Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer Disease (MB2). Clinical Trials.gov. Accessed October 2, 2020. 

https://clinicaltrials.gov/ct2/show/NCT02380573

5. Shiells H, Schelter BO, Bentham P. Concentration-dependent activity of hydromethylthionine on clinical decline and brain atrophy in a randomized controlled trial in behavioral variant frontotemporal dementia. 

Articles

Weaving the story of modern psychopharmacology’s birth leads us to a most surprising origin.

Never Say Dye: the Roots of Modern Psychiatric Medicines in Nineteenth-Century Fabric Colorings

[[{"type":"media","view_mode":"media_crop","fid":"23130","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8740964767071","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1768","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right; margin: 10px;","title":" ","typeof":"foaf:Image"}}]]Anyone who has spent a sleepless night needs no convincing about the subjective discomfort associated with lying in bed awake and unable to sleep. In addition to nighttime discomfort, insomnia is associated with a wide assortment of daytime impairments, some intuitive and some startling. A number of studies have found decreased scores on quality-of-life scales in persons with insomnia. On the Short Form (SF-36) Health Survey, persons with insomnia score lower than good sleepers on measures such as emotional role, mental health, and vitality. They also have lower scores on the Medical Outcomes Study Cognitive Scale and higher rates of absenteeism from work and lower productivity.

 Some years ago I examined the possibility that sleep disturbance might be a predictor of employment longevity. A questionnaire about sleep was given to newly hired employees at a large international bank in New York. Two years later, we examined how many of the responders were still employed by the bank. Among officers, those no longer working at the bank were more than twice as likely to have reported difficulty in sleeping as were those still employed there.

These findings are similar to those of an earlier study of military personnel. Navy recruits who reported sleep disturbance at the time of induction had higher attrition rates and were less likely to be promoted or to be asked to reenlist.

 They also had more sick days, which is of some significance because later studies showed that persons with insomnia use the health care system substantially more often than those who do not have insomnia.

In a study of 1100 primary care patients, those who described sleep disturbance on initial intake were more likely to make phone calls to the doctor, visit the doctor's office or emergency department, undergo blood tests, or receive prescriptions in the next 8 weeks.

 The reasons for this higher rate of health care use are unclear. There is also a higher rate of falls in community-dwelling older adults with sleep disturbances, particularly women.

 Although most of us are familiar with the caution about the dangers of falls for nursing home patients who take hypnotics, one study of more than 34,000 nursing home residents found that having insomnia raised the risk of falls (odds ratio, 1.52; 95% confidence interval [CI], 1.38 to 1.66), while the use of hypnotics did not.

 Although this does not rule out the possibility that certain therapies may be associated with falls, it indicates that insomnia itself is an independent risk factor.

 Insomnia also appears to be a complicating factor in patients with depression. The coexistence of insomnia and depression is of course very common, but when severe, it is associated with higher rates of suicide as well as poorer response to cognitive-behavioral therapy.

 Given the many difficulties associated with insomnia, a review of new ways of thinking may be timely. This article looks at new data on the underlying physiology of insomnia, evidence that suggests that insomnia is a risk factor for other disorders, and the interaction between insomnia and coexisting conditions.

Not surprisingly, most research has been oriented to examining possible physiological counterparts to the clinical impression that persons with insomnia have excessive arousal. Early work focused on elevated heart rate and core temperature at the time of sleep onset.

 Later studies have suggested that those persons who have insomnia with sleep disruption documented on the polysomnogram have elevated nighttime circulating concentrations of cortisol and adrenocorticotropic hormone.

 This does not appear to be a result of sleep deprivation per se, since most studies of sleep deprivation do not report increased hypothalamic-pituitary-adrenal axis (HPA) activity. Persons with insomnia have an elevated whole-body metabolic rate, which is not seen in study participants who do not have insomnia but whose sleep has been experimentally disrupted.

 Perhaps most intriguing are positron emission tomography (PET) scan studies that indicate that persons with insomnia have increased overall cerebral glucose metabolic rates both when asleep and awake. In the study by Nofzinger and colleagues,

 findings indicate that although overall cerebral metabolism was elevated by day, there was a relatively lower metabolic rate in the prefrontal areas, which has been speculated to be associated with complaints of fatigue.

Persons with insomnia appear to be excessively physiologically aroused, although a number of questions remain. Most of these changes have been observed primarily in patients who have objective sleep disturbance seen on the polysomnogram, as opposed to the very interesting group who complain of sleep disturbance but who manifest minimal objective sleep changes. Whether this is a difference of degree (as has been suggested by the whole-body metabolic rate studies) or represents some fundamental difference in kind is not yet known. Similarly, whether these physiological changes have health consequences (and hence might be related to the higher rate of health care use) is uncertain. Perhaps the strongest case for the latter comes from the HPA studies, insofar as elevated cortisol has been reported to be a risk factor for coronary artery atherosclerosis.

 Finally, there remain questions of causality-are elevated circulating cortisol or cerebral glucose metabolism causes or correlates of insomnia?

Insomnia has been shown to be a risk factor for depression and anxiety disorders. In terms of temporal sequence, the most common presen- tation for sleep disturbance and depression is for insomnia to appear first, rather than at the same time or after depressive symptoms.19 As an example of studies showing increased later risk of depression, Breslau and colleagues

 monitored 1200 young adults for 3 years and found that those with insomnia at baseline had about a 4-fold increased likelihood of a new major depression developing (95% CI, 2.2 to 7.0). A recent formal analysis suggests that insomnia is a state marker of depression and anxiety, and a trait marker of anxiety disorders.

A study of more than 2000 persons found that those who had a sleep complaint "on most nights" were substantially more likely to complain of anxiety, depression, or widespread pain (in 4 or more areas) a year later.

 There are also studies that link insomnia to hypertension even when possible confounding variables such as age and weight are held constant, as well as with increased risk of death from atherosclerotic heart disease.

 Often, sleep disturbance persists in the presence of the various illnesses.

Findings from several recent studies indicate that treatment of insomnia can ameliorate the symptoms of some coexisting illnesses. These studies are not fully consistent and can be difficult to interpret because of variations in methodology, duration of treatment, and choice of drug. (The interested reader may wish to look at more detailed reviews.

) In a study of 545 patients with depression, Fava and colleagues

 compared fluoxetine and eszopiclone 3 mg daily with fluoxetine and placebo. Significant improvement was seen at weeks 4 (P = .01) and 8 (P = .002) in the group treated with fluoxetine and eszopiclone on the 

Hamilton Rating Scale for Depression (HAM-D)

, and in weeks 2 through 8 on the Clinical Global Impression Severity scale, compared with those who received only fluoxetine and placebo. There were significantly (P = .009) more responders in the combination therapy group than in the monotherapy group (59% vs 48%). This suggests that adjunctive treatment of the accompanying sleep disturbance may result in more effective antidepressant response.

On the other hand, a smaller (N = 190), shorter duration (4-week) study with a different hypnotic (zolpidem 10 mg) and antidepressant (any of 3 SSRIs) found improvements in sleep, alertness, and the SF-36 Vitality subscale but not in the HAM-D.27

It is also possible that benefits for depression that result from adjunctive treatment of coexisting insomnia might not be confined to pharmacological approaches. Manber and colleagues

 recently reported that cognitive-behavioral therapy for insomnia, when given as adjunctive therapy to depressed patients receiving escitalopram, resulted in a higher rate of remission of depression at the end of the 12-week study period.

 randomly selected 595 patients with generalized anxiety disorder who had a sleep disturbance into groups that received escitalopram 10 mg/d plus eszopiclone 3 mg/d and those who received escitalopram plus placebo for 8 weeks. Scores on the Hamilton Rating Scale for Anxiety were reduced by half or more at week 8 significantly (P < .01) more often in the eszopiclone than in the placebo group (62% vs 49%). Remission of both insomnia and anxiety symptoms occurred significantly (P < .05) more often in the eszopiclone group as well.

Similar types of findings (again, with some inconsistencies) have been found in the adjunctive treatment of sleep disturbance in patients with rheumatoid arthritis.

 There are also data that indicate that in the first 6 months of pharmacological treatment of insomnia, there is a relative decline in general health care costs compared with untreated patients with insomnia.

 A recent review of nonpharmacological and pharmacological treatment for insomnia found that 14 of 20 studies showed improvement in health, function, or quality of life.

The studies outlined in this article have led to a number of changes in the way sleep researchers approach insomnia. The growing recognition that insomnia is associated with changes in quality of life and a wide range of daytime impairments has led to interest in including these types of variables, as well as traditional measures of sleep, in treatment efficacy studies. In other words, we need to examine not only how treatments affect sleep but how they affect waking life as well.

The growing evidence that insomnia is a risk factor for a variety of other illnesses, and the finding that the treatment of insomnia may improve the therapy of some coexisting illnesses have also contributed to a change in thinking. This found expression in the 2005 NIH state-of- the-science statement on chronic insomnia.

One result has been that most sleep researchers now refer to insomnia in the context of another illness as "comorbid insomnia," rather than "secondary insomnia." This is much more than a change in phraseology, because it emphasizes that insomnia is a process that can interact with a coexisting illness and is not merely a consequence of the other disorder. Of course, there are a number of ways in which a risk factor might be associated with a second illness: insomnia, for instance, might be an early manifestation of another condition; alternatively, sleep disturbance might make a person more susceptible to another illness, or both might be consequences of a more fundamental disorder. In a recent article, I outlined these various possibilities, using the interrelationship of insomnia and depression as a model.

If these studies continue to support the comorbid model, this would suggest a very specific change in the way many of us treat insomnia. For sev- eral decades, most sleep researchers emphasized that when insomnia is found accompanying another illness, the best strategy was to treat the underlying illness (for instance, major depression or arthritis), and the insomnia would then "take care of itself." The new data raise the possibility that adjunctive nonpharmacolog-ical or pharmacological management of the sleep disturbance may make it easier to treat the accompanying illness.

This is not an industry-supported project. The author serves as a consultant or member of the speakers' bureau for the following companies: Neurocrine Biosciences, Neurogen, Sanofi-Aventis, Sepracor, and Takeda. He is also a consultant to the nonphar-maceutical companies Abiant, VivoMetrics, and ScienceFirst.

1. Zammit GK, Weiner J, Damato N, et al. Quality of life in people with insomnia. Sleep. 1999;22(suppl 2): S379-S385.

2. Daley ME, Leblanc M, Morin CM. The direct and indirect costs associated with insomnia. Sleep. 2004; 27:A281.

3. Mendelson WB, Donnellan M, Schneider WJ. Sleep disturbance as a predictor of employment duration. Sleep Res. 1995;24:295.

4. Johnson LC, Spinweber CL. Quality of sleep and performance in the navy: a longitudinal study of good and poor sleepers. In: Guilleminault C, Lugaresi E, eds. Sleep/WakeDisorders: Natural History, Epidemiology, and Long-Term Evolution. New York: Raven Press; 1983:13-28.

5. Hatoum HT, Kong SX, Kania CM, et al. Insomnia, health-related quality of life, and healthcare consumption: a study of managed-care organisation enrollees. Pharmacoeconomics. 1998;14:629-637.

6. Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64-99 years. J Am Geriatr Soc. 2000;48:1234-1240.

7. Avidan AY, Fries BE, James ML, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc. 2005;53:955-962.

8. Wang PS, Bohn RL, Glynn RJ, et al. Zolpidem use and hip fractures in older people. J Am Geriatr Soc. 2001;49:1685-1690.

9. Agargun MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. J Clin Psychiatry. 1997;58:249-251.

10. Thase ME, Simons AD, Reynolds CF III. Abnormal electroencephalographic sleep profiles in major depression: association with response to cognitive behavior therapy. Arch Gen Psychiatry. 1996;53:99-108.

11. Monroe LJ. Psychological and physiological differences between good and poor sleepers. J Abnormal Psychol. 1967;72:255-264.

12. Rodenbeck A, Huether G, Ruther E, Hajak G. Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia. Neurosci Lett. 2002;324: 159-163.

13. Vgontzas AN, Bixler EO, Lin HM, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. 2001;86:3787-3794.

14. Vgontzas AN, Zoumakis M, Bixler EO, et al. Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. J Clin Endocrinol Metab. 2003;88:2087-2095.

15. Bonnet MH, Arand DL. Insomnia, metabolic rate, and sleep restoration. J Intern Med. 2003;254:23-31.

16. Bonnet MH, Arand DL. The consequences of a week of insomnia. Sleep. 1996;19:453-461.

17. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161:2126-2128.

18. Troxler RG, Sprague EA, Albanese RA, et al. The association of elevated plasma cortisol and early atherosclerosis as demonstrated by coronary angiography. Atherosclerosis. 1977;26:151-162.

19. Ohayon M, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003;37:9-15.

20. 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.

21. Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep. 2007;30:873-880.

22. Morphy H, Dunn KM, Lewis M, et al. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep. 2007;30:274-280.

23. Mallon L, Broman JE, Hetta J. Sleep complaints predict coronary artery disease mortality in males: a 12-year follow-up study of a middle-aged Swedish population. J Intern Med. 2002;251:207-216

24. Mendelson W. Impact of insomnia: wide-reaching burden and a conceptual framework for comorbidity. Int J Sleep Wakefulness. 2008;1:118-123.

25. Krystal AD. Treating the health, quality of life, and functional impairments in insomnia. J Clin Sleep Med. 2007;3:63-72.

26. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59:1052-1060.

27. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60:668-676.

28. Manber R, Edinger JD, Gress JL, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep. 2008;31:489-495.

29. Pollack M, Amato DA, Schaefer K, et al. Effects of eszopiclone/escitalopram co-therapy on the percentage of patients experiencing coincident resolution of both insomnia and anxiety in patients with insomnia coexisting with generalized anxiety disorder. Presented at: the American Psychiatry Association 160th Annual Meeting; May 19-24, 2007; San Diego.

30. Hawkins K, Treglia M, Healey P, et al. An analysis of the health and productivity burden of insomnia and its treatment. ISPOR 12th Annual International Meeting; May 19-23, 2007; Arlington, VA.

31. NIH state of the science conference statement on manifestations and management of chronic insomnia in adults statement. J Clin Sleep Med. 2005;1:412-421.

A number of studies have found decreased scores on quality-of-life scales in persons with insomnia, which is associated with a wide assortment of daytime impairments, some intuitive and some startling.

New Research on Insomnia

The "time has come to accept bright light treatment into our therapeutic armamentarium," urged Daniel F. Kripke, M.D., professor of psychiatry at the University of California San Diego. Kripke has studied the relationship between biological rhythms and depression since the early 1970s. In an interview with 

, Kripke discussed two theories of phototherapy.

"We know that seasonal responses in many mammals are controlled by the photoperiod...We know that the lethargy, changes in appetite and loss of sexual interest seen in many small mammals in the winter are, in fact, controlled by the reduced daylight...Such mammals increase their activity, sexuality and aggressiveness in the summer, because the days are longer. From that knowledge, it seemed that depression might be analogous to winter responses and that light might be an effective treatment. That is one plausible theory.

"There also is a theory based on the finding that there are some timing abnormalities of circadian rhythms in many depressed patients, and that because light can correct timing abnormalities, it might work," he added. "As of today, there is evidence for both theories and evidence against both theories. I don't believe the theoretical basis is yet established. Nevertheless, the treatment [has been] tried and it works."

Numerous trials from Europe, Japan and the United States indicate that bright light is beneficial in treating nonseasonal as well as seasonal depression (Dietzel et al., 1986; Kjellman et al., 1993; Levitt et al., 1991; Peter, 1986; Yamada et al., 1995), Kripke pointed out.

"The response [to light therapy] is quite rapid, often within a week or two, which is more rapid than the response to antidepressant drugs or psychotherapy," he said.

(Other studies have found modest or no clear benefit to bright light therapy for nonseasonal depression [Mackert et al., 1990; Szadoczky et al., 1991; Thalen et al., 1995]-Ed.)

Kripke and his colleagues also have conducted clinical studies of bright light. As early as 1981, he reported that bright light had an antidepressant effect among patients with nonseasonal major depressive disorders. Although a single hour of light treatment produced only about a 12% reduction in depression ratings as compared to placebo, the result was statistically significant in the first seven patients.

In 1992, Kripke and colleagues reported on their one-week study of veterans with depression who were hospitalized in a Veterans Affairs Medical Center. The veterans had nonseasonal major depressive disorders or depressed forms of bipolar disorder. Additionally, the majority of the patients had comorbidities, such as substance use disorders. Twenty-five patients were randomly assigned to bright white light treatment (2,000 to 3,000 lux) and 26 patients were randomized to dim red light placebo-control treatment.

"Within one week of bright light treatment, the 25 patients reduced their depression scores about 18%, whereas the 26 placebo patients didn't improve at all," Kripke said.

Currently, a study is being conducted by Kripke's colleague, Richard Loving, Ph.D., R.N., in the department of psychiatry, University of California San Diego. Loving has been studying unipolar nonseasonally depressed outpatients who are being treated with antidepressants along with a half-night of sleep deprivation followed by administration of bright light therapy.

"There is evidence that a half-night of sleep deprivation may augment the bright light response," Kripke said. "Indeed, Loving has found that with this triple combination, the patients given the bright light had a 30% improvement within a week as compared to the group treated with placebo light and otherwise the same medication and sleep deprivation. That is a very dramatic response of a similar or greater magnitude than one might obtain with Prozac [fluoxetine] in 12 to 16 weeks. That study is very small and still going on, but it resembles the study done by Neumeister [1996] at the University of Vienna on inpatients with about the same results."

For patients with major depressive disorder, Neumeister and colleagues studied whether light therapy beginning in the morning after a partial-sleep deprivation is able to prevent a relapse after sleep deprivation. (In some patients with major depressive disorder, partial-sleep deprivation results in a pronounced decrease of depressive symptoms. However, the beneficial effect is usually lost after one night of recovery sleep.) In the study, all patients received an antidepressant medication, which was kept constant before and during the study period. Neumeister and colleagues found that bright light prolonged the antidepressant effects of partial-sleep deprivation for up to seven days.

Based on these studies, Kripke believes "a clinician would be wise to go ahead with standard therapy and add bright light." He added, "I would only recommend using bright light alone for the patient who for some reason didn't want to accept or couldn't tolerate standard treatment. Pregnant women, young children whose parents are nervous about starting them on a drug regimen, or patients who had allergic reactions or other side effects with antidepressants would be common examples."

Another candidate group might be depressed individuals not currently receiving treatment, Kripke suggested.

"We know that the majority of Americans who are depressed are not asking for [or] receiving treatment. So there is a very large portion of the depressed population that, for philosophic reasons, doesn't want to avail themselves of standard treatment, but they might be more willing to use bright light."

For his own patients who are suffering from a newly diagnosed seasonal or nonseasonal depressive disorder, Kripke said he would provide standard treatment (antidepressant drug and some psychotherapy) as well as bright light therapy.

"If the situation was rather severe and the need for response urgent, I might suggest that the patient get up in the middle of the night on the day before the first light treatment," he said. While acknowledging that "the sleep deprivation part of it needs more study," Kripke said, "the addition of light to standard treatment is ready for clinicians to use.

"There is now plenty of evidence that adding light will help the patient at least in the first week or two of treatment when the antidepressant drugs don't actually do that much," he said.

Kripke is not aware of any controlled data in seasonal affective disorder or nonseasonal depressed populations showing that adding bright light therapy to standard treatment improves outcome, although he said each modality "works alone." Many clinicians, he added, using light therapy to treat patients with seasonal affective disorder do eventually include medications.

Bright light therapy must be consistent with the patient's habits, according to Kripke.

"The most important decisions are whether to give the patient bright light through going outdoors, through changes in room lighting or through buying a light box," he said.

Advising patients to spend more time outdoors can work well in Southern California but not in areas with harsher climates, Kripke said. In many circumstances, it also is possible to increase ordinary room lighting, and sometimes that will be of considerable benefit.

To clarify, Kripke pointed out that on a sunny day outdoors, illumination might be about 10,000 lux looking towards the horizon. However, people spend most of their time indoors in environments with lighting between 50 and 500 lux. In the evening, the average living room might be lit at about 15 lux, but some people watch television in rooms as dim as 1 lux, which is about the same as the light of the full moon.

"We have evidence that people who are outdoors at least one hour a day are less depressed and report fewer sleep complaints in the general population. Such a study doesn't prove causality, but since we have shown beneficial effects in  experimental studies, it is reasonable to think that a large segment of the population, which isn't in daylight even an hour per day, is causing themselves problems."

In a book chapter, "The Uses of Bright Light in an Office Practice," Kripke pointed out that there is a trend for people who experienced less bright lighting to report more depression (Kripke, 1998b). Therefore, he prescribes a special light box that is available through a number of manufacturers for approximately $200 to $400 (Table). Generally, the light boxes contain fluorescent bulbs, which use less electricity and radiate less heat than incandescent lights.

"Because the fluorescent light boxes produce quite diffuse light, you can look at them directly, whereas with very bright incandescent light such as that produced by halogen bulbs, the light comes from a very small point, which is really too bright to look at directly with safety," he said.

In general, 200 to 300 watts of fluorescent light illuminating a bright diffuser about one yard from the eyes will give about 2,000 to 3,000 lux. Some bigger higher wattage light boxes placed 12 to 18 inches from the patient's eyes will give off 10,000 lux.

Kripke also addressed dosage strategies in the chapter. "Just like with any medical treatment, [depressed patients] vary in the dose they need," he said. The amounts of light needed are somewhere in the range required to bring a depressed person above the average for daily light exposure, Kripke wrote. That can be achieved with as little as 15 to 30 minutes of very bright light (approaching 10,000 lux) or with a few hours of light of 2,000 to 3,000 lux (like a cloudy day in the shade).

For mild depression accompanying advanced sleep-phase in the elderly, modest amounts of lighting may be sufficient, he wrote. But for cases of severe depression, light much dimmer than 2,000 lux is not likely to be effective without many hours of daily exposure.

For many patients, bright light at any time of day helps depression, according to Kripke, but there is some evidence that seasonal affective disorder (SAD) patients may do a bit better with morning light (Ruhrmann et al., 1998). This may be due in part to SAD patients' tendency to sleep late rather than the seasonality of their depression, Kripke wrote.

It is the sleep pattern that provides the most useful clue to optimal timing, he added. Patients whose depression is linked to hypersomnia tend to do best with light in the morning. For such patients, the hour immediately after awakening is the most effective time to use bright light. For the patient who nods off early in the evening and cannot stay awake for prime-time television, Kripke recommended evening bright light.

If the physician has a patient who may be bipolar, Kripke said it might be safer to use evening light, because the risk of mania appears to be less with evening rather than morning light. "I don't recommend using bright light for depressed bipolar patients unless they are receiving a mood stabilizer, because in 1% or 2% of cases, bright light will trigger serious mania in a bipolar patient," he noted. "The duration of bright light treatment in a depressed bipolar patient must be individualized."

In studies of light box therapy, Kripke said some minor side effects (e.g., nausea, headache and eye irritation) have been reported, but they "generally involve no permanent risk and usually not enough discomfort to require discontinuation."

(When adjunct light therapy was used with trimipramine [Surmontil], Muller et al. [1997] did report some side effects, such as aggravated sedation and decreased appetite-Ed.)

With regards to duration of bright light therapy, Kripke wrote that many people who benefit from it need to use it for years.

"If they discontinue using light, after a few weeks, they may relapse into depression again. Some people find they need less time with their light box to avoid relapse than they did to make the depression go away at the beginning," he wrote. "Therefore, after at least two to three months of remission, it could be reasonable to try slowly reducing the light dose, to see if symptoms recur."

To help guide clinicians in the use of light therapy, Kripke recommended the following resources: the book 

 edited by Poceta and Mitler, in which Kripke has a chapter; his 1998 article in the 

; a chapter on light therapy by Norman Rosenthal, M.D., who is with the Clinical Psychobiology Branch at the National Institute of Mental Health, in 

 (Rosenthal, 1995); and several articles published in the 

 (Campbell et al., 1995; Dijk et al., 1995; Terman et al., 1995); and the Society for Light Treatment and Biological Rhythms, New Haven, Conn.,.<

Based on his extensive work with bright light therapy, Kripke believes it is an effective and cost-efficient addition to modern health care:

"It is a wonderful thing to be able to offer patients this simple and safe treatment and see them become happier faster."

Campbell SS, Dijk DJ, Boulos Z et al. (1995), Light treatment for sleep disorders: consensus report. III. Alerting and activating effects. J Biol Rhythms 10(2):129-132.


Depression Guideline Panel (1993), Depression in Primary Care: Volume 2. Treatment of Major Depression. Washington, D.C.: Agency for Health Care Policy and Research, AHCPR Publication No. 93-0551, U.S. Government Printing Office.


Dietzel M, Saletu B, Lesch OM et al. (1986), Light treatment in depressive illness. Polysomnographic, psychometric and neuroendocrinological findings. Eur Neurol 25(suppl 2):93-103.


Dijk DJ, Boulos Z, Eastman CI et al. (1995), Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation. J Biol Rhythms 10(2):113-125.


Kjellman BF, Thalen BE, Wetterberg L (1993), Light treatment of depressive states: Swedish experiences in latitude 59 north. In: Light and Biological Rhythms in Man (Wenner-Gren International), Wetterberg L, ed. Stockholm: Pergamon Press, pp 351-370.


Kripke DF (1998a), Light treatment for nonseasonal depression: speed, efficacy and combined treatment. J Affect Disord 49(2):109-117.


Kripke DF (1998b), The uses of bright light in an office practice. How to brighten up your patients. In: Sleep Disorders: Diagnoses and Treatment, Poceta JS, Mitler MM, eds. Totowa, N.J.: Humana Press.


Kripke DF (1981), Photoperiodic mechanisms for depression and its treatment. In Biological Psychiatry 1981: Proceedings of the IIIrd World Congress of Biological Psychiatry Held From June 28th to July 3rd, 1981 in Stockholm, Sweden. Perris C, Struwe G, Jansson B, eds. New York: Elsevier-North Holland Biomedical Press, pp 1249-1252.


Kripke DF, Mullaney DJ, Klauber MR et al. (1992), Controlled trial of bright light for nonseasonal major depressive disorders. Biol Psychiatry 31(2):119-134.


Levitt AJ, Joffe RT, Kennedy SH (1991), Bright light augmentation in antidepressant nonresponders. J Clin Psychiatry 52(8):336-337.


Mackert A, Volz HP, Stieglitz RD et al. (1990), Effect of bright white light on nonseasonal depressive disorder. Pharmacopsychiatry 23(3):151-154.


Muller MJ, Seifritz E, Hatzinger M et al. (1997), Side effects of adjunct light therapy in patients with major depression. Eur Arch Psychiatry Clin Neurosci 247(5):252-258.


Neumeister A, Goessler R, Lucht M et al. (1996), Bright light therapy stabilizes the antidepressant effect of partial sleep deprivation. Biol Psychiatry 39(1):16-21.


Peter K, Rabiger U, Kowalik A (1986), [Initial results with bright light (phototherapy) in affective psychosis]. Psychiatr Neurol Med Psychol (Leipz) 38(7):384-390.


Rosenthal NE (1995), Light Therapy. In Treatment of Psychiatric Disorders, Gabbard GO, ed. Washington, D.C.: American Psychiatric Press Inc., pp 1263-1273.


Ruhrmann S, Kasper S, Haweliek B et al. (1998), Effects of fluoxetine versus bright light in the treatment of seasonal affective disorder. Psychol Med 28(4):923-933.


Szadoczky E, Falus A, Nemeth A et al. (1991), Effect of phototherapy on 3H-imipramine binding sites in patients with SAD, non-SAD and in healthy controls. J Affect Disord 22(4):179-184.


Terman M, Lewy AJ, Dijk DJ et al. (1995), Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances. J Biol Rhythms 10(2):135-147.


Thalen BE, Kjellman BF, Morkrid L et al. (1995), Light treatment in seasonal and nonseasonal depression. Acta Psychiatr Scand 91(5):352-360.


Yamada N, Martin-Iverson MT, Daimon K et al. (1995), Clinical and chronological effects of light on nonseasonal affective disorders. Biol Psychiatry 37(12):866-873.

Daniel F. Kripke, M.D. has studied the relationship between biological rhythms and depression since the early 1970s. He states that seasonal responses in many mammals are controlled by the photoperiod. Therefore, it seemed that depression might be analogous to winter responses and that light might be an effective treatment.

Light Treatment for Nonseasonal Depression

Insomnia, the subjective sense of having inadequate quantity orquality of sleep, may result from a variety of causes. In itschronic form, such etiologies may include psychiatric disorderssuch as depression or anxiety, medical illnesses, medications,substance abuse, circadian dysrhythmias and pathophysiologiesintrinsic to sleep such as sleep apnea or periodic movement disorder.When these conditions have been ruled out, however, there remaintwo very interesting groups that at this time are best understoodin psychophysiological terms.

In the first form, conditioned insomnia ("chronic psychophysiologicinsomnia"), sleep is disrupted because the act of going tosleep has become associated with anxiety-related behaviors incompatiblewith sleep, and excessive efforts are made to try to fall asleepthat are counterproductive (Mendelson, 1987).

The second form is subjective insomnia, characterized by a disparitybetween the degree of sleep disturbance reported by the patientand that seen by a sleep study (polysomnography). Typically, sucha patient will come to the clinic complaining of taking an hourto fall asleep and then sleeping only three hours. The sleep study,however, might reveal that in physiologic terms he or she fellasleep in 30 minutes and slept six hours.

If the unwary physician should later meet with the patient andreport that he or she "in fact" did sleep adequately,the patient is unlikely to believe such report. Also, the patientmay feel that the doctor doesn't believe him or her. Such intriguingand difficult patients are the subject of this paper, and forshorthand they will be referred to as "insomniacs."

One of the first insights into subjective insomnia came from theclassic study by Rechtschaffen (1968), in which he reported thatwhen poor sleepers were awakened 10 minutes after the first sleepspindle, they were more likely to report that they had been awake;in contrast, good sleepers were more likely to report that theyhad been asleep. 

Moore and colleagues, Coates and colleagues, and Mendelson andcolleagues subsequently described a similar phenomenon. The modelwhich we used involved awakening the subject with a 500 Hz electronictone of progressively increasing amplitude (two dB every threeseconds) at five time points across the night:

5 minutes after "lights out," at which time subjectshave empirically been found to be awake;

10 minutes after the first sleep spindle (in all studies subjectshave been in Stage 2 sleep at that point);

10 minutes after the onset of Stage 4 sleep;

5 minutes after the onset of rapid eye movement (REM) sleep;

during the first period of spontaneous waking time after thefirst REM period.

During these events, which we shall refer to as "forced arousals,"an investigator enters the room and asks each subject a seriesof questions, including whether he or she was awake or asleepand whether the subject had been dreaming. The investigator alsoadministers a brief rating scale, the Dream Complexity Scale (Foulkesand Vogel), which helps determine the subject's perception ofstate of consciousness. These data, combined with the polygraphicsleep stage and a measure of the amplitude of the electronic tone,provide the basic observations which we shall discuss.

In our 1986 study that contrasted insomniacs and age- and sex-matchedcontrols, the amplitude of the electronic tone needed to awakenthe insomniacs and good sleepers was similar, suggesting thatsubjectively poor sleep may not necessarily be the same as "light"sleep (as determined by the amplitude of a stimulus needed toinduce an arousal). It was found, though, that insomniacs reportedhaving been awake in 71 percent of the forced arousals acrossall time points; this was significantly (p<0.05) more oftenthan the 44.6 percent found in the normal controls. The consistencyof this observation suggests its incorporation into any theoryof the mechanism of insomnia, and the implication to us has beenthat insomniacs may suffer from a dissociation between the perceptionof being awake or asleep and the physiologic measures of wakingand sleep, at least as we know how to assess them at this point.

A second insight into insomnia may come by studying medicationsused to treat it: clinically used hypnotics such as thebenzodiazepines and newer nonbenzodiazepine hypnotics such aszolpidem (Ambien). There seems little doubt that in a short-termsense, i.e., measured in terms of a few nights, they provide substantialrelief from insomnia, as measured by the patient's report in themorning (although in chronic nightly use their benefits are lessclear due to issues of tolerance). Indeed their acceptance bypatients is striking. Although hypnotics are substantially lesswidely used than antidepressants, nonetheless approximately 2percent to 3 percent of the population has taken them sometimein the past year, according to Mellinger and Balter. Shader andcolleagues found that approximately 20 million prescriptions arewritten annually for this purpose.

One interpretation would seem to be that many patients get relieffrom these agents. Such a view would be supported by the observationof Balter and Uhlenhuth that approximately 70 percent to 80 percentof people who have taken the most common benzodiazepine hypnoticsin the past year say that they would want to take the medicationagain should the need arise.

In contrast to this relatively high rate of acceptance of clinicalhypnotics, at least for short-term use, is what I believe to berelatively modest improvement in polygraphic measures of sleep.To give but a few examples:

In one of the major studies of the efficacy of flurazepam (Dalmane),a 30 mg dose led to an increase in total sleep of only 6 percentto 8 percent during one month of administration; sleep onset timewas improved only on nights 11 through 13 (Kales and associates,1975).

When 30 mg flurazepam was given to insomniacs for five weeks,total sleep rose by only 21 minutes (Mitler et al., 1984).

A one-week trial of 15 mg flurazepam given to insomniacs forone week increased sleep by a mean of only 29 minutes (Roehrsand colleagues, 1982).

Patients on chronic low doses of benzodiazepines have similarsleep to nonmedicated insomniacs in terms of total sleep, sleeponset time and waking time after initial sleep onset (Schneider-Helmert,1988).

A multicenter study of 99 insomniacs receiving 15 or 30 mg flurazepamor 15 mg midazolam (Versed) for two weeks found no polygraphicimprovement of sleep on the first night with flurazepam, althoughpatients reported in the morning that they believed that theyhad slept longer (Kripke et al., 1990). The few significant polygraphicimprovements in sleep with either drug were only on the firsttwo nights.

Wallace B. Mendelson, MD

Articles

Never Say Dye: the Roots of Modern Psychiatric Medicines in Nineteenth-Century Fabric Colorings

New Research on Insomnia

Light Treatment for Nonseasonal Depression

Hypnotics and the Perception of Wakefulness