Possible trazodone potentiation of fluoxetine: a case series.

BACKGROUND: Fluoxetine is an effective serotonin reuptake inhibitor antidepressant that can fail to alleviate either insomnia or major depression in a substantial minority of depressed patients. Trazodone has been reported to be both an effective nonbenzodiazepine hypnotic for antidepressant-associated insomnia and a possible serotonergic antidepressant adjunct. We present a case series of patients with variable responses when trazodone was added to fluoxetine. METHOD: Eight consecutive depressed (DSM-III-R) patients taking fluoxetine were given trazodone either for sleep or as a possible antidepressant potentiator. RESULTS: Three (37.5%) of the eight patients (confidence interval = 4.0%-71.0%) had improvements in both sleep and depression. The remaining five patients either were unaffected by the addition of trazodone to fluoxetine or had intolerable adverse drug reactions. CONCLUSION: Trazodone may be an effective hypnotic and antidepressant potentiator when combined with fluoxetine for some patients, but its use may be limited by adverse effects.     

The effects of trazodone on sleep in patients treated with stimulant antidepressants

BACKGROUND AND PURPOSE: To evaluate the effects of trazodone on subjective and objective measures of sleep in depressed insomnia patients treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs can exacerbate or cause new insomnia while alleviating other symptoms of depression. Trazodone has been reported to be an effective hypnotic for patients with antidepressant-associated insomnia. PATIENTS AND METHODS: Twelve female patients were given either 100 mg trazodone or placebo for 7 days in a double-blind crossover design with a 7-day washout period. Polysomnographic recordings were repeated on the 3rd, 9th and 17th, 23rd nights after treatment with trazodone or placebo. Sleep was assessed by Pittsburgh sleep quality index (PSQI) at the beginning and end of the study. Psychological evaluation was done by Hamilton depression rating scale (HDRS). RESULTS: Trazodone significantly increased total sleep time, percentage of stages 3+4, sleep efficiency index, sleep continuity index and decreased percentage of stage 1, number of awakenings, stage shifts compared to the baseline. This improvement was also obtained after 7 days of treatment. The PSQI score was reduced to 5+/-1.6 at the end of the study. HDRS was reduced to 11.5+/-4.5 with trazodone and to 12.2+/-3 with placebo. CONCLUSION: Trazodone is effective in the treatment of antidepressant-associated insomnia.     

The effects of trazodone on sleep disturbances induced by brofaromine.

The effects of trazodone on subjective and objective sleep parameters were compared to those of placebo in a double-blind design in seven patients who developed insomnia during treatment with the selective and reversible MAO-A inhibitor, brofaromine. Trazodone significantly increased deep sleep and altered the architecture of sleep in these patients. Subjectively, patients reported a better and deeper sleep. No negative interactions between brofaromine and trazodone were observed and side-effects were minimal. A low dose of trazodone may be a safe and effective agent in the treatment of MAO-I induced insomnia.     

Diagnosis and treatment of chronic insomnia: a review

OBJECTIVE: Insomnia has high prevalence rates and is associated with significant personal and socioeconomic burden, yet it remains largely underrecognized and inadequately treated. METHODS: A PubMed search for English-language articles covering randomized controlled trials published between 1970 and 2004 was conducted. Search terms used were "insomnia," "behavioral therapy," and the generic names of agents commonly used to treat insomnia (the Food and Drug Administration-approved benzodiazepines and nonbenzodiazepines, trazodone, and over-the-counter agents). RESULTS: Evidence from epidemiologic studies, physician surveys, and clinical studies suggests that numerous patient and physician factors contribute to the fact that the needs of patients with insomnia remain unmet, including low reporting of insomnia by patients, limited physician training, and office-based time constraints, as well as misconceptions about the seriousness of insomnia, the advantages of treatment, and the risks associated with hypnotic use. Nonpharmacologic therapies produce long-lasting and reliable changes among people with chronic insomnia and have minimal side effects. Pharmacologic therapies have proven effective with improving wake time after sleep onset and sleep maintenance and reducing the number of nighttime awakenings. However, pharmacologic therapy has a greater chance of producing side effects. No conclusive evidence exists to favor either pharmacologic therapy or behavioral therapy. CONCLUSIONS: Insomnia is particularly challenging for clinicians because of the lack of guidelines and the small number of studies conducted in patient populations with behavioral and pharmacologic therapies. Current treatment options do not address the needs of difficult-to-treat patients with chronic insomnia, such as the elderly, and those with comorbid medical and psychiatric conditions. More research is necessary to determine the long-term effects of insomnia treatments.     

A review of the evidence for the efficacy and safety of trazodone in insomnia

OBJECTIVE: Trazodone, a triazolopyridine antidepressant, is currently the second most commonly prescribed agent for the treatment of insomnia due to its sedating qualities. Given trazodone's widespread use, a careful review of the literature was conducted to assess its efficacy and side effects when given for treatment of insomnia. DATA SOURCES: In April 2003, a MEDLINE search was conducted using the search terms trazodone and insomnia and trazodone and sleep and restricted to 1980-2003, human subjects, and English language. As trazodone has been implicated in cardiac disorders, a further search was conducted using the term cardiac and trazodone. STUDY SELECTION: All clinical trials that measured any endpoint for insomnia efficacy were included in the assessment. A total of 18 studies were identified from the literature search. In addition, commonly used texts were consulted for information regarding adverse effects related to trazodone. DATA EXTRACTION: Because so few studies were identified by the literature search, all were evaluated and described. DATA SYNTHESIS: Evidence for the efficacy of trazodone in treating insomnia is very limited; most studies are small, conducted in populations of depressed patients, raise issues of design, and often lack objective efficacy measures. Side effects associated with trazodone are not inconsequential, with a high incidence of discontinuation due to side effects, such as sedation, dizziness, and psychomotor impairment, which raise particular concern regarding its use in the elderly. There is also some evidence of tolerance related to use of trazodone. CONCLUSION: Given the relative absence of efficacy data in patients with insomnia and the adverse events associated with trazodone's use in general, it is uncertain whether the risk/benefit ratio warrants trazodone's use in nondepressed patients with insomnia.     

Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares

BACKGROUND: Trazodone is commonly used in the treatment of insonmia and nightmares in patients with PTSD. There is little evidence in the literature for this practice. METHOD: Seventy-four patients from the Palo Alto Veterans Affairs Health Care System in California who were admitted to a specialized 8 week inpatient treatment program for PTSD were surveyed regarding their use of trazodone in the treatment of insomnia or nightmares. Patients were asked to complete a questionnaire regarding trazodone's effectiveness, side effects, and optimal doses. RESULTS: Of 74 patients surveyed, 60 patients were able to maintain an effective dose of trazodone. The other 14 patients were unable to tolerate the medication. Seventy-two percent of the 60 patients assessed found trazodone helpful in decreasing nightmares, from an average of 3.3 to 1.3 nights per week (p<.005). Ninety-two percent found it helped with sleep onset, and 78% reported improvement with sleep maintenance. There was a significant correlation between the effectiveness in decreasing nightmares and improving sleep (r= .57, p < .005). The effective dose range of trazodone for 70% of patients was 50 to 200 mg nightly. Of the 74 patients surveyed, 9 (12%) reported priapism. CONCLUSION: Trazodone appears effective for the treatment of insomnia and nightmares associated with chronic PTSD. However, controlled trials are needed before any definite conclusions can be drawn. The higher than expected occurrence of priapism warrants clinicians asking directly about this side effect.     

The use of trazodone as a hypnotic: a critical review

BACKGROUND: The last few years have seen a remarkable rise in the off-label use of trazodone for inducing sleep in nondepressed patients, to a degree that it is prescribed for this purpose as commonly as the leading hypnotic. In view of this widespread popularity, it seems prudent to review what is known of the safety and efficacy of trazodone when used in this context. DATA SOURCES AND SELECTION: A MEDLINE search of the literature published in English between 1975 and 2003 that included the keywords sleep, trazodone, Desyrel, depression, sleeping pill, and sedative-hypnotics was conducted. DATA SYNTHESIS: From this review, it is concluded that there are very few data to suggest that trazodone improves sleep in patients without mood disorder, though it does increase total sleep in patients with major depressive disorder. There are virtually no dose-response data for trazodone vis-à-vis sleep and, similarly, no available data on tolerance to its possible hypnotic effects. Areas of concern with its use include reports of significant dropout rates and induction of arrhythmias, primarily in patients with histories of cardiac disease, as well as the development of priapism. CONCLUSION: In summary, there are few data to support the use of trazodone in nondepressed subjects. When the risk-benefit ratio of trazodone is assessed, its side effect profile, which is much more significant than that of conventional hypnotics, should be considered.     

The challenge of chronic insomnia: is non-nightly hypnotic treatment a feasible alternative?

The adverse effects of insomnia on health and quality of life are matters receiving increasing attention. Yet, surveys have consistently shown that most people suffering from insomnia do not seek medical help, perhaps, in part, because of a concern of becoming dependent on hypnotic medication. The treatment of chronic insomnia poses a particular dilemma in that continuous hypnotic treatment is restricted in many countries to a maximum of 4 weeks, and behavioural treatment is not readily available. Non-nightly hypnotic treatment of chronic insomnia offers a promising alternative option for the many patients whose symptoms do not necessitate nightly drug intake, allaying fears of psychological dependence on medication and respecting regulatory constraints on hypnotic use while providing patients with adequate symptom relief. The practical feasibility and efficacy of this approach has been demonstrated with zolpidem using various treatment regimens and study designs. So far, six clinical trials have been completed on over 4000 patients. Published results show effective treatment of insomnia without any evidence of either adverse event associated with a discontinuous regimen or increased hypnotic use over the treatment period.     

Electroconvulsive therapy and cardiovascular complications in patients taking trazodone for insomnia

BACKGROUND: Trazodone has been used widely to treat insomnia in depressed patients. When used in combination with electroconvulsive therapy (ECT), trazodone has been suspected to cause cardiovascular side effects. METHOD: A retrospective study was done of 100 patients who received ECT with concurrent trazodone. One patient was excluded because permission to review the patient's records had not been given. The remaining 99 patients were matched with control ECT patients. RESULTS: No statistically significant between-group differences were identified in cardiovascular side effects, although a trend toward more orthostatic hypotension was observed in patients taking trazodone. CONCLUSION: Administering low-dose trazodone for insomnia in conjunction with ECT does not appear to increase cardiovascular complications. The true incidence of adverse cardiac events was not higher than 3.66% at a 95% confidence level.     

Cognitive behavioural therapy with behavioural analysis for pharmacological treatment-resistant chronic insomnia

This study aimed to determine whether (1) cognitive behavioural therapy with behavioural analysis for insomnia (CBTi-BA) is more effective for insomnia and co-morbid depressive symptoms than treatment as usual (TAU) and (2) whether CBTi-BA promotes earlier reduction of the daily dose of hypnotic medication in chronic insomnia resistant to pharmacological treatment. A total of 63 patients with chronic insomnia aged 20–77 years who already received hypnotic medication regularly were assigned to two interventions: combined therapy or TAU alone. The subjects provided demographic information and completed self-rating scales for insomnia and depressive symptoms. After treatment, the combined therapy group showed significant decreases in the symptoms of both insomnia and depression and significant reductions in the daily dose of hypnotic medication compared with the group receiving TAU alone. In the combined therapy group, 71% of the participants reported a reduction in insomnia to normal levels and 79% succeeded in decreasing the daily dose of hypnotics to 50% or less of the baseline dose. These results revealed that CBTi-BA can reduce insomnia and depressive symptoms as well as the daily dose of hypnotic medication in patients with chronic insomnia resistant to pharmacological treatment.     

The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium

This paper summarizes a group of presentations and panel discussions on chronic insomnia at the 2001 NCDEU meeting. The presentations and discussions focused on the twin issues of efficacy and concerns of abuse liability with long-term hypnotic therapy. The panel concluded that insomnia may be an epidemiological marker for a variety of difficulties including accidents, increased health care utilization and subsequent development of major depression. Whether or not treatment of insomnia will prevent these long-term problems has not yet been determined. Since the mid-1980s there has been a rapid rise in the off-label use of antidepressants, particularly trazodone, for treating insomnia. Some participants expressed concern at the lack of data for this practice, particularly the absence of dose-response and tolerance information, and noted that the small amount of efficacy data available is not encouraging. Similarly, there are minimal data to support the use of antihistamines as sleep aids; moreover, their side effect profile and interactions with other drugs may be under appreciated. The limited data available on nightly long-term usage of the newer non-benzodiazepine hypnotics, primarily of six-months' duration, suggest an absence of tolerance, but more data for both nightly and non-nightly administration are needed. Insomniacs tend to show therapy-seeking, rather than drug-seeking behavior, and patients without histories of drug abuse are unlikely to self-escalate dosage of currently available hypnotics. There is fairly good agreement on the characteristics of an ideal hypnotic. All currently available agents, while effective and safe, do not achieve this ideal. The next few years are likely to see the appearance of a variety of agents with new and promising mechanisms of action.     

Confirmation of the neurophysiologically predicted therapeutic effects of trazodone on its target symptoms depression, anxiety and insomnia by postmarketing clinical studies with a controlled-release formulation in depressed outpatients

Early human pharmaco-EEG and subsequent sleep laboratory studies identified trazodone, a 5-HT(2) antagonist and 5-HT reuptake inhibitor (SARI), as an antidepressant with therapeutic effects on its target symptoms depressed mood, anxiety and insomnia. On the occasion of the introduction of a controlled-release (CR) formulation (Trittico 150 mg retard, marketed in Austria by CSC Pharmaceuticals Handels GmbH, Vienna, Austria) in Austria in July 2000, a multi-center, open, clinical post-marketing study on the therapeutic effects, safety and target symptoms of trazodone CR in depression was carried out at 80 offices of Austrian neuropsychiatrists. 549 outpatients (63% females) of all age groups suffering from five different subtypes of depression were enrolled in the study. After a 2-week fixed dose-titration regimen up to 150 mg and a 4-week adjustment period to the optimum dose, 66% of the patients remained on 150 mg, 20% increased the dose and 11% decreased it. Only 3.7% discontinued treatment. Rating by the neuropsychiatrists based on the Clinical Global Impression showed very much to much improvement in 78.3% of the patients, and no change or a deterioration in only 3.6%. In the Hamilton Depression Scale (HAMD) a statistically significant improvement from a baseline score of 21 to a score of 14 after 2 weeks was found, and a normalization to a score of 8 after 6 weeks. Therapeutic effects were similar in the five groups suffering from different subtypes of depression and in patients with and without comedication. Self-rating by the patients based on the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS) also showed a significant improvement in the 2nd and 6th week of therapy. Evaluation of the target symptoms of trazodone by ranking the most improved symptoms identified insomnia as the most improved psychopathological item in all three scales. While in the observer ratings also suicidal tendencies and weight loss were found much improved, in the self-rated Zung SDS sadness and loss of drive came second and third in the improvement ranking, in the self-rated Zung SAS anxiety and the feeling of falling apart. Tolerability was very good. In the 2nd week only 16.9% and in the 6th week only 7.6% of the patients reported side effects, mostly characterized by tiredness and rarely by nausea and vertigo. The present clinical study is in agreement with previous studies identifying trazodone as a safe and effective antidepressant, specifically regarding its target symptoms insomnia, depression and anxiety. It also confirms our own early predictions based on neurophysiological investigations concerning the mode of action of the drug.     

Pharmacologic and nonpharmacologic treatments of insomnia

Insomnia in its chronic form is present in high numbers of patients presenting to physicians. As older women who have medical problems have the highest rates of chronic insomnia, physicians must have a high index of suspicion and be prepared to explore various etiologic factors that might be operative. Treatment should focus on setting specific goals, with patients using strategies that combine lifestyle changes, behavioral interventions, and appropriate medications. OTC agents, sedating antidepressants at low dosages (trazodone, doxepin, amitriptyline, and others), and nonhypnotic benzodiazepines are insufficiently studied to provide evidence-based support for their use to treat chronic insomnia. Particularly in the elderly, close monitoring is needed to prevent falls, accidents, and cognitive impairment from these agents. FDA-labeled hypnotic agents are efficacious, but long-term studies have not been available until the recent release of eszopiclone in the United States. Recent work encourages the use of CBT even in patients who have used sleeping pills for several years, although the success of CBT has been less encouraging when applied to chronic insomnia sufferers who have concurrent psychiatric disorders and who have taken hypnotics for years.     

Cognitive-behavioral treatment of insomnia and its use during withdrawal of hypnotic medication

Insomnia is a widespread health problem that often leads to the use of hypnotic medication. Among the available pharmacological agents to treat insomnia, benzodiazepines (BZD) present some undesirable effects, entailing risks of tolerance and dependence, and increased risk of automobile accidents, falls and fractures in the elderly. Cognitive-behavioral treatment (CBT) of insomnia, which focuses on psychological and behavioral factors that play a role in maintaining sleep-related problems, is efficient to improve sleep in the elderly who suffer from primary insomnia. This treatment may represent an alternative to pharmacotherapy or again be complementary during discontinuation of hypnotic medication. The CBT of insomnia may include different components such as stimulus control, sleep restriction, relaxation, cognitive restructuring and sleep hygiene. For people who are dependent to BZD or other hypnotic medication, a supervised tapering based on attaining successive objectives is generally added to the CBT of insomnia.     

A preliminary study of the effects of nighttime administration of the serotonin agonist, m-CPP, on sleep architecture and behavior in healthy volunteers

The effects of m-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) on sleep architecture and behavior were examined in six healthy volunteers following a single oral dose of the drug in a randomized, double-blind, placebo-controlled study. m-CPP reduced total sleep time (TST) and sleep efficiency in all subjects. Slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep were decreased and stage 1 sleep was prolonged in a majority of subjects. Prominent behavioral and psychological effects were reported in five out of six subjects following m-CPP (but not following placebo) that interfered with sleep. The sleep disruption and behavioral activation following nighttime administration of m-CPP contrasts with the sedative properties of its parent compound, trazodone, suggesting that the hypnotic effect of trazodone is not related to the agonist profile of its metabolite, m-CPP.     

Impetuous suicidality with zolpidem use: a case report and minireview

Zolpidem is a clinically effective hypnotic medication for treating chronic insomnia. In the last decade, there has been increasing documentation of altered consciousness and behavioral changes following zolpidem administration. This report presents a case of a probable zolpidem induced suicide attempt and highlights similar studies of suicidal thoughts and behaviors of other patients that have taken the drug. We examine zolpidem and other treatments for insomnia, including the FDA approved hypnotics and frequently prescribed off-label medications, in terms of prescribing practices and adverse effects, especially altered consciousness and risk of suicide. Parallels are identified between the untoward activating side effects of zolpidem and its off-label use for patients in persistent vegetative states. We hypothesize that similar to the proposed mechanism in which the wakefulness promoted by zolpidem in vegetative patients is mediated by disruption of GABAergic tone in neurodormant brain regions, there may occur in patients with parasomnias interference of GABA activity in brain regions that maintain a high level of inhibitory regulation. Dosing recommendations are offered together with the FDA Safety Announcement addressing dose reductions for women due to possible carry-over effects the morning after ingesting zolpidem.     

Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies.

BACKGROUND: Although insomnia is highly prevalent, sleep disturbances often go unrecognized and untreated. When insomnia is recognized, considerable emphasis has been placed on improving sleep onset; however, there is growing evidence that improving sleep maintenance is an equally important treatment goal. METHODS: A MEDLINE literature search was performed using the search parameters "insomnia," "zolpidem," "zaleplon," "flurazepam," "estazolam," "quazepam," "triazolam," and "temazepam," as these agents are FDA-approved for the treatment of insomnia. Per reviewer comments, the search criteria was later expanded to include lorazepam. A literature search using the terms "trazodone" and "insomnia" was also performed, as this is the second-most commonly prescribed agent for treating insomnia. Sleep efficacy endpoints from randomized, placebo-controlled clinical trials in adult populations and key review articles published between 1975 and 2004 were included in this review. As only one randomized placebo-controlled trial evaluated trazodone use in primary insomnia, the trazodone search was expanded to include all clinical trials that evaluated trazodone use in insomnia. Relevant texts and other articles that evaluated side effect profiles of these agents were also included, one of which was published in January of 2005. In all publications, impact of treatment on sleep maintenance parameters (wake time after sleep onset, number of awakenings) and measures of next-day functioning were evaluated, in addition to sleep onset parameters (sleep latency, time to sleep onset/induction) and sleep duration data (total sleep time). RESULTS: Many of the currently available agents used to treat insomnia, including the antidepressant trazodone, the non-benzodiazepine hypnotics zolpidem and zaleplon, and some of the benzodiazepines, have not consistently demonstrated effectiveness in promoting sleep maintenance. Furthermore, the benzodiazepines with established sleep maintenance efficacy are associated with next-day sedation, the risk of tolerance and dependence, or both. CONCLUSIONS: New agents that offer relief of sleep maintenance insomnia without residual next day impairment while improving next day function are needed. Several compounds currently under development may offer clinicians a more effective and safer treatment for this common disorder.     

Pathophysiology and Management of Insomnia During Depression

Depressed patients often report problems sleeping, and epidemiologic evidence suggests that insomnia may precede the onset of depression. Insomnia is associated with marked impairment in quality of life and ability to function effectively. Many studies have indicated that patients with chronic sleep problems have impaired mood and that effective management of insomnia in depressed patients can markedly improve their depression. Diagnosis of insomnia is challenging because there can be many different causes and the clinical picture can be blurred by the presence of other psychiatric illnesses. Pharmacotherapy provides reliable and rapid relief from insomnia, whereas behavioral therapies help produce long-term improvement. For many years, benzodiazepines have been the mainstay of drug treatment for insomnia. However, these drugs have significant side effects, and tolerance and dependence have discouraged use. Many doctors use sedating antidepressants in low doses to treat chronic insomnia. However, there is little evidence supporting the efficacy of these agents, and many have adverse side effects, including impairment of sleep. The newer selective hypnotic drugs, including the imidazopyridines, may offer patients a better short-term alternative to benzodiazepines or sedating antidepressants.