W. Vaughn McCall, MD, MS

The battle against suicide took a step backward between 2011 and 2012. 

, while 8 of the 10 most common causes of death in the US showed statistically significant reductions in the death rate over the span of merely 1 year, one cause of death among the top 10 showed a significant increase-suicide.

 More than 40,000 Americans will complete suicide this year. Clearly more needs to be understood and done to reverse these trends.

All psychiatrists know the risk factors for suicide. Some are unmodifiable, such as advancing age, male sex, and being white. Others are potentially modifiable, such as depression, drug abuse, hopelessness, and social isolation. Among the newest modifiable risk factors to join the list are insomnia and nightmares.

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 of an association between insomnia and suicide death appeared about 25 years ago.

 The passage of time has produced a voluminous literature of more than 60 original research reports that show a statistical association between sleep disturbance and suicidal thinking, suicidal behavior, and suicide death. These reports come from North America, Europe, and Asia, and encompass children and adolescents, young adults, and the elderly.

The clever skeptic would guess that the association between sleep disturbance and suicide is spurious and is better explained by the well-known association of sleeping problems with depression; therefore, it must actually be the depression that is driving the association with suicide. And yet, when the presence and intensity of depression are controlled for within the statistical analysis, the relationship between sleep problems and suicide still stands. The odds ratio between insomnia and suicidal ideation is approximately 2.0. Moreover, the intensity of suicidal ideation co-varies with the intensity of insomnia during the course of clinical treatment for depression.

While much of the relevant literature has been about insomnia and suicide, there are reports that more specifically link nightmares with suicide. The association between nightmares and suicide (as judged by the size of the odds ratio) may be greater than the association between insomnia and suicide, per se. The odds ratio for insomnia and suicidal behavior has been reported as 7.0, while the odds ratio for nightmares and subsequent suicidal behavior is as high as 8.2.

What explains these associations, especially when 2 seemingly opposite phenomena such as insomnia and hypersomnia are linked to suicide? One explanation is the simple concept of “burden of illness.” It is well known that a chronic medical illness is a risk factor for suicide, so perhaps the burden of living with insomnia or hypersomnia becomes the “straw that breaks the camel’s back.”

The strength of the association between sleep disturbance and suicide would suggest that many suicide deaths happen at night, yet the opposite seems to be the case. Very few suicide deaths occur during the nighttime hours, followed by a sharp rise in suicide death rates through the morning hours and a decline again toward evening.6 Therefore, if sleep disturbance is related to suicide, it may be through the effects of sleep disturbance on daytime psychological or physiological function.

Both insomnia and hypersomnia are associated with impairments in cognitive functioning.

 Patients with insomnia have trouble in problem solving, and deficits in problem solving have been described in persons who have survived suicide attempts.

 In this scenario, the person who is dealt a major setback, such as a broken relationship or job loss, is unable to produce a solution to the problem if he or she has insomnia; this leads to the worst possible solution. Hypersomnia, like insomnia, is also associated with deficits in cognition.

A different possibility is that living with insomnia compounds any tendency toward hopelessness. Hopelessness is one of the most consistently replicated psychological findings in suicidal persons. In the field of sleep medicine, it is well know that persons living with chronic insomnia develop cognitive distortions about their sleep, in much the same way that suicidal persons might develop cognitive distortions regarding their future. Insomniacs can fall prey to the belief that they can do nothing to help themselves, that insomnia will ruin their life, and that whether they will sleep well or poorly on a given night is a total crapshoot.

The Dysfunctional Beliefs and Attitudes about Sleep (DBAS) scale has been used to catalogue distorted views about sleep. Although the word “hopeless” never appears in the DBAS scale, many of the items in the scale imply a certain degree of hopelessness or futility regarding the sleep of the person with insomnia. It had initially occurred to me that the DBAS scale was merely a reframing of the concept of hopelessness that was so well described in suicidology.

Our research team began to evaluate some of these ideas by examining the intensity of suicidal ideation (as measured by the Scale for Suicide Ideation [SSI]) in a sample of well-characterized depressed outpatients.

 We found that the intensity of suicidal ideation closely tracked the intensity of insomnia over the course of treatment for depression.

This relationship was then examined in stable outpatients as well as in suicidal patients in the emergency department. We were surprised to find that the traditional notion of hopelessness as measured by the Beck Hopelessness Scale did not track along with the DBAS scale (Pearson’s r = 0.2; NS). It seems that regular hopelessness and sleep hopelessness are 2 different things! This finding must be viewed as preliminary and bears replication.

We also found that after taking into account the effects seen on the DBAS and the effects of nightmares, insomnia no longer made a contribution to the intensity of suicidal ideation, thus verifying the importance of understanding the role of nightmares in suicide risk. Preliminary data from a different sample of patients with depression, insomnia, and suicidal ideation suggest that both insomnia and hypersomnia independently contribute to the intensity of suicidal ideation. Thus, we are finding that a wide array of sleep-related concepts may contribute to suicidal ideation, including insomnia, hypersomnia, dysfunctional beliefs about sleep, and nightmares.

Apart from psychologically based hypotheses to explain the relationship between insomnia and suicide, there are also biological considerations. Abnormally low serotonin function in the brain is among the best-replicated findings in human suicide, and animal data suggest that sleep loss desensitizes 

 The psychobiology of insomnia strongly suggests that insomnia is a disorder of hyperarousal. That is, the sleeplessness of insomnia is better understood as an alerting system in overdrive, rather than a sleeping system that is broken.

 This conceptualization is supported by brain PET imaging, EEG data both awake and asleep, and metabolic studies of whole-body oxygen consumption.

Understanding insomnia as a state of hyperarousal is consistent with the clinical view that there is a greater risk of suicide in patients who are agitated or becoming more active. This concept is also consistent with activation syndrome, which has been applied to the feelings of psychomotor restlessness that some patients feel with the initiation of treatment with an SSRI; this may be a period of acute risk for suicide.

Hypervigilence (and perhaps hyperarousal) is also a key feature in patients with PTSD. It has been hypothesized that 

 So hypervigilence and hyperarousal are common features of insomnia and PTSD-related nightmares, and both insomnia and nightmares are, in turn, related to suicide. The psychological aspects of nightmares may also contribute to suicide because the patient cannot find relief either during the day or during the night.

The rapid growth of observational studies on the topic of sleep disturbance and suicide has not been translated into an intervention. There are, in fact, very few randomized controlled trials (RCTs) of any intervention in patients with active suicidal ideation. There are some studies on the risk for suicide on the basis of prior suicide attempts or behavior, and these have found support for clozapine and lithium because of their specific antisuicidal effect.

 In addition, open-label studies of electroconvulsive therapy (ECT) have suggested that suicidal ideation 

 But there are few RCTs that specifically recruit an enriched sample of patients with active suicidal ideation.

Indeed, active suicidal ideation is a routine exclusion criterion in most psychiatric RCTs that are supported by pharmaceutical companies, because companies try to avoid the occurrence of serious adverse events. For that matter, university institutional review boards may be reluctant to approve RCTs that specifically recruit suicidal patients for fear that a series of serious adverse events could reflect badly on the university. As a result, there is scant information regarding the efficacy of most pharmaceuticals to treat active suicidal ideation. This recruitment discrimination is not much different from the practice 40 years ago of primarily recruiting white men for cardiovascular RCTs, resulting in a disenfranchisement of women and minorities from the generalizability of the RCT results.

Our research team is moving forward with an RCT for adults with MDD, with the requirement that they simultaneously have insomnia and active suicidal ideation. The study, Reducing Suicidal Ideation Through Treatment of Insomnia (REST-IT), is supported by the NIMH. The design includes the provision of open-label fluoxetine for 8 weeks, coupled with blinded randomization to zolpidem controlled-release or placebo at bedtime. While the study is still in progress and results are not yet available, early efforts have emphasized processes to enhance safety.

 Other investigators are looking at the utility of psychotherapeutic techniques to treat sleep problems, such as cognitive-behavioral therapy for insomnia or imagery rehearsal therapy for nightmares, as a means to reduce suicidal ideation.

Regardless of the results of the REST-IT study, there is sufficient evidence to recommend that the emergence or worsening of insomnia or nightmares be viewed as a sign of suicide risk, at least in patients with depression. Both new patients and established patients who complain of a new or escalating problem with insomnia or nightmares should be queried regarding the presence of suicidal ideation.

The vast majority of the research on the link between sleep disturbance and suicide has been derived from population studies or samples of depressed patients. There is a small but growing body of work showing that sleep disturbance is also linked to suicidal ideation in persons experiencing alcohol use disorders. Less is known about the relationship between sleep problems and suicide in persons with schizophrenia. Extension of the finding of a link between sleep and suicide to persons with schizophrenia would pose the possibility that the association between sleep and suicide is a universal feature of psychiatric illness.

Dr McCall is Case Distinguished Chair in the department of psychiatry and health behavior at the Medical College of Georgia, Georgia Regents University in Augusta. He reports that he has received research support from the NIMH and the American Foundation for Suicide Prevention; he is Scientific Advisor for Merck and Luitpold; he has received CME honoraria from Global Medical Inc; and he receives royalties from Wolters Kluwer Publishing.

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Articles

All psychiatrists know the risk factors for suicide. Among the newest modifiable risk factors to join the list are insomnia and nightmares.

The Correlation Between Sleep Disturbance and Suicide

Neurostimulation has shown promising benefits in the treatment of schizophrenia over the years. Here we review the evidence for the use of ECT and other novel neurostimulation techniques in the treatment of schizophrenia.

Schizophrenia and schizoaffective disorder are indications for use of ECT, according to the FDA executive summary for the Neurological Devices Panel Meeting.

 In the US, ECT is predominantly used in the treatment of mood disorders, whereas in Asian countries, it is commonly used in the treatment of schizophrenia despite the relatively modest evidence for efficacy.

Randomized controlled trials (RCTs) that compare ECT with sham treatment for schizophrenia have yielded mixed results. Trials conducted before the 1980s consistently reported nonsignificant differences in efficacy between groups; however, later reports indicate that there may be significant benefits. This discrepancy may be due to the fact that the patient population in the older studies had a chronic, unremitting course and there was no concomitant use of antipsychotics.

The combined use of antipsychotics with ECT has proved to be beneficial in antipsychotic nonresponders. One study showed that a combination of high-dosage bilateral ECT and flupenthixol in patients with schizophrenia speeds the clinical response and lessens the number of treatments and days to remission.

 Another RCT indicates that the adjuvant use of ECT with olanzapine was more effective than its use with sulpride or risperidone.

A prospective open trial of adjuvant ECT with risperidone or olanzapine in patients with treatmentresistant schizophrenia (TRS) reported significant improvement in global assessment of functioning and clinical global impression.

 Conversely, ECT with concomitant haloperidol in patients with first-episode psychosis showed no difference in efficacy compared with sham treatment, but this may have been due to methodological limitations.

An 8-week single-blind study of 39 patients with TRS showed a 50% response in the clozapine plus ECT group, versus 0% in the clozapine group.

 There are safety concerns in combining ECT with clozapine because the latter is a proconvulsant, but the researchers reported no safety issues-the only adverse effect was mild confusion that required postponement of the ECT.

Patients with schizophrenia and prominent depression, positive symptoms, and recent-onset catatonia may be the best candidates for ECT. Suzuki and colleagues

 reported remarkable improvement in symptoms in patients with catatonia. However, relapse rates after completion of acute ECT were high, and combined use of continuation or maintenance ECT with neuroleptics was important to prevent relapse.

ECT is safe and effective as an adjuvant for treatment of schizophrenia, and it should be considered in patients who do not respond to adequate trials of antipsychotics. It can improve positive, negative, affective, and vegetative symptoms as well as quality of life in patients with schizophrenia. There is adequate evidence for use of ECT in schizophrenia, although the mechanisms of antipsychotic effect of ECT are still unclear.

Repetitive transcranial magnetic stimulation (rTMS) is a nonconvulsive brain stimulation technique that has gained popularity in the past 2 decades. There is ongoing exploration of the use of rTMS in schizophrenia and other neuropsychiatric disorders as well as in stroke and movement disorders.

rTMS has the potential to alter the excitability of the underlying cortex with persisting after effects. The reports of beneficial effects of rTMS in the treatment of schizophrenia symptoms, such as auditory hallucinations and catatonia, have led to additional studies.

 Low-frequency stimulation (less than 5 Hz) was found to diminish excitability of the underlying cortex, and the changes resembled long-term depression; high-frequency stimulation (10 Hz) excited the underlying cortex and caused long-term potentiation.

 The rTMS stimulus parameters and electrode montage used depend on the target symptoms.

Low-frequency stimulation has shown benefits in the treatment of auditory hallucinations of schizophrenia, and it significantly reduced the number of positive symptoms.

 In addition, rTMS could be used to prevent relapse of antipsychoticrefractory auditory hallucinations.

Auditory hallucinations may be associated with cortical activation in the perisylvian language areas.

 This activation in language areas is reversed by the stimulation of temporoparietal rTMS.

 The dominant and nondominant temporoparietal areas are sites for intervention for auditory hallucinations.

 Hallucinations can vary between the left and right side of the brain; thus, it is important to locate the area of abnormality before stimulation. High-frequency stimulation of the prefrontal cortex was found to significantly improve the negative and cognitive symptoms of schizophrenia.

Although there are studies of rTMS with negative results, the evidence in support of its use is promising. More research is needed to explore its potential in acute and maintenance phases as monotherapy and as an adjunctive treatment. Future research should also explore neuronavigation guidance to further individualize treatment in patients with schizophrenia.

Transcranial direct current stimulation (tDCS) is another novel, nonconvulsive brain stimulation technique that has gained popularity in the treatment of schizophrenia in the past 3 years; however, it is not FDA-approved. tDCS involves stimulation of the brain with low-amplitude direct current via 2 scalp electrodes (anode and cathode). It can be used to either stimulate or inhibit the underlying cortex, similar to rTMS. The anodal stimulation of the motor cortex enhances cortical excitability, whereas the cathodal stimulation reduces excitability.

The first case report for schizophrenia was the use of cathodal tDCS over the left temporoparietal cortex in a patient with medication-refractory auditory hallucinations. Symptom improvement was seen at 6-week follow-up.

 A randomized sham-controlled trial reaffirmed the benefits of tDCS in patients with medication-refractory auditory hallucinations. The study indicated that benefits lasted for 3 months.

Symptom improvement may be attributable to the neuroplasticity effects of tDCS.

 In 2 cases, tDCS was used successfully as an adjunct to antipsychotics in TRS. In one of the cases, it was safely used for more than 3 years and resulted in improvement from vegetative state to near-normal functioning.

 In the other case, improvement in positive and negative symptoms was also seen.

Anodal tDCS over the left dorsolateral prefrontal cortex improved negative symptoms of schizophrenia.

 Symptom improvement was also seen in a patient with catatonic schizophrenia refractory to treatment with a combination of clozapine and ECT.

 Moreover, tDCS may have the potential to be used as monotherapy.

 The results from studies of tDCS use for the treatment of schizophrenia are promising and research is ongoing. The tDCS device is less expensive than other brain stimulation devices and it has the potential to be an economical treatment.

Dr Surya is Chief Resident, Dr Miller is Associate Professor, Dr Rosenquist is Professor and Vice Chair, and Dr McCall is Case Distinguished University Chairman in the department of psychiatry and health behavior at the Medical College of Georgia of Georgia Regents University in Augusta. Drs Surya, Miller, and McCall report no conflicts concerning the subject matter of this article; Dr Rosenquist reports that he has received research support from the NIMH, Neuronetics, Cyberonics, and NeoSync.

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The authors review the evidence for the use of ECT and other novel neurostimulation techniques in the treatment of schizophrenia.

Therapeutic Neurostimulation and Schizophrenia

Health-related quality of life (HRQOL) can be defined as a broad array of outcomes that go beyond syndrome-specific symptoms or mortality and can include satisfaction and competence in primary life role (e.g., student, homemaker or breadwinner), satisfaction and competence in relationships, freedom from pain and mental anguish, energy, and other broad and subjective psychosocial constructs affected by one's health. Health-related quality of life is part of the larger concept of QOL, which includes some aspects of living that, while important, do not necessarily directly reflect health per se, such as spiritual satisfaction, lack of crowding and availability of a stimulating environment. Of necessity, HRQOL must be defined with reference to the patient's values (Asadi-Lari et al., 2004) and cannot always be subjected to external validation, in contrast to more objective measures of function such as activities of daily living, which can be validated by direct observation (McCall et al., 2002).

Why is HRQOL important to psychiatry and, more specifically, to the practice of electroconvulsive therapy? The Institute of Medicine quality improvement blueprint calls for care that is both evidence-based and customized based upon patient needs and values (Committee on Quality Health Care in America, 2001). In a world with limited resources for the treatment of disease, HRQOL is a useful means of contrasting the overall impact of different diseases on patients' lives. For example, HRQOL creates a common language that allows a comparison of the impact of problems as disparate as orthopedic problems and cancers. Similarly, treatments of different diseases can be contrasted for their relative value in improving HRQOL. Going further, the relative cost of a unit of improvement in HRQOL for different treatments of different diseases can be compared, facilitating optimal allocation of scarce health resources.

Health-related quality of life can also assist in determining the relative health benefits of treatments that have both high efficacy and significant side effects. In the example of cancer, HRQOL can simultaneously take into account the therapeutic action of chemotherapy and its adverse effects, giving some sense of the overall net impact of chemotherapy on health.

In the same vein, HRQOL can provide a simultaneous and net assessment of the therapeutic and adverse effects of psychiatric treatments. Major depressive disorder (MDD) has been identified as the candidate for the second leading cause of poor HRQOL in the world by the year 2020 (Murray and Lopez, 1996). This phenomenon is predicted by both the high world prevalence of MDD as well as the greater negative impact of MDD on HRQOL as compared with the impact of other common conditions, such as arthritis, diabetes or coronary disease (Wells et al., 1989). Within samples of patients with depression, severity of depression is related to the extent of HRQOL deficits, and the type of deficit depends in part upon the age of the patient with depression (McCall et al., 1999a).

Therefore, antidepressant treatments, including ECT, would be expected to have the potential for producing large improvements in HRQOL that would be of relevance to public health. Indeed, successful treatment of depression is associated with improvements in HRQOL (McCall et al., 2001). Conversely, partial antidepressant response and failure to achieve a complete remission, leaving the patient with ongoing residual symptoms, is associated with worse HRQOL (Zimmerman et al., 2004).

While antidepressant medications have side effects that could potentially offset some of the HRQOL gains that come with successful medication treatment of depression, the issue of side effects offsetting antidepressant effects is of even greater interest with ECT. The cognitive side effects of ECT, specifically amnesia, might be predicted to be a limiting factor on HRQOL gains resulting from ECT's antidepressant effect. It is well established that depressed mood and cognitive deficits have additive negative effects on functional capacity. For example, secondary depression limits functional capacity in people with primary dementia (Espiritu et al., 2001; Pearson et al., 1989) and, conversely, secondary cognitive deficits are associated with limitations of functional capacity in people with primary MDD (McCall and Dunn, 2003). For these reasons, it is reasonable to take a hard look at ECT and the potential for simultaneous and offsetting effects of change in mood and memory on HRQOL.

A few nonprofessional organizations have a taken a vocal and consistently negative attitude toward ECT. The directors of these organizations do not deny the acute antidepressant efficacy of ECT; instead, they argue that the cognitive side effects of ECT are so severe and persistent that patients' lives can be nearly ruined (Andre, 2005a). These organizations may not specifically use the terms 

, but the charges they lay against ECT are nevertheless within these domains. These charges are usually supported by a biased selection of individuals who were unhappy with their own outcome as ECT patients. Despite a lack of systematic, unbiased information on the effects of ECT on HRQOL, these organizations occasionally make incursions into mainstream psychiatric journals (Andre, 2005b; McCall, 2005).

Very recently, governmental health regulatory agencies have expressed concern over a perceived lack of sufficient data on the effects of ECT on HRQOL. This concern, among others, led to the recommendation to restrict ECT, including a recommendation against ECT in non-life-threatening circumstances unless the patient fails multiple trials of antidepressant medications during each new episode of MDD (National Institute for Clinical Excellence, 2003).

Quantitative assessment of HRQOL using established assessment tools is a relatively new development in the area of ECT. Thienhaus et al. (1990) were among the first to apply established quantitative assessments of HRQOL in ECT, looking at change in the Global Assessment of Functioning (GAF) scale. In their case series of six older patients (mean age=71±5) who received a course of ECT followed by continuation ECT, they found that GAF scores increased from 53±11 to 68±11. Statistical testing was not reported for the change in GAF scores.

We later found a similar magnitude of effect following an acute course of ECT (Dew et al., 2005). Change of this size would be best viewed as indicative of a moderate positive effect of ECT on function, but leaving the patients with residual global impairment. A limitation of the GAF is that it attempts to parse the limitations in the individual's functional capacity to separate bins pertaining to mental-health-related disability versus disability due to other causes. Making the distinction between mental-health-related disability and medical disability becomes an impossible task in patients with multiple concurrent psychiatric and medical problems, as may be seen in the older patient treated with ECT.

In a later paper, the change in social functioning after a course of ECT was followed in 40 patients using the Social Functioning Schedule (SFS) (Casey et al., 1996). The SFS scale includes measures of employment, household chores, finance, self care, relationships and recreation. The researchers tracked SFS scores prior to onset of ECT and every six weeks up to six months. Again, statistical testing on the difference between pre- and post-ECT SFS scores was not presented, but the numerical change in scores is impressive, showing an approximately 80% improvement in SFS scores from baseline to six months post-ECT.

We subsequently began a series of studies examining the effect of ECT on HRQOL and function. In the first study, we contrasted 31 depressed inpatients treated with ECT with 59 depressed inpatients treated with medications (McCall et al., 1999b). Assignment to medications versus ECT was nonrandom and was at the discretion of the attending psychiatrist. Health-related quality of life was assessed with the daily-living/role functioning (DLRF) and relationship to self/others (RSO) subscales of the Behavior and Symptom Identification Scale (BASIS-32), while functional capacity was assessed with an instrumental activities of daily living (IADL) scale. The ECT-treated patients were older than the medication-treated patients, but the two groups were not different in overall depression severity. Instead, the older ECT-treated patients reported a lesser scope of activities on the IADL scale and more problems on the DLRF scale. These patients were then followed for 12 months, revealing that the degree of improvement in depression scores, DLRF improvement and IADL improvement were significantly greater in the ECT group than the medication group after one year (McCall et al., 2001). This finding must be tempered by the nonrandom assignment to medications versus ECT.

We then studied a new series of depressed, ECT-treated patients with the BASIS-32 and IADL scales before ECT and at two and four weeks after ECT, but this time including comprehensive measurement of memory in addition to standard assessment of mood (McCall et al., 2004). Significant improvement in the IADL scale and the DLRF subscale of the BASIS-32 were seen at two and four weeks, with greater than or equal to 80% of patients reporting improvement on each HRQOL and function measure.

Most recently, we have used the Medical Outcomes Study Short Form-36 (SF-36) as a generic measure of HRQOL (unpublished data). In this study, 283 patients were tested before ECT, immediately after and again at six months. Eighty-seven percent of patients had improvement in the SF-36 score immediately after ECT, and 78% still showed positive change at six months. Importantly, patients who did not respond to ECT or who subsequently relapsed overall still showed improved SF-36 scores compared to baseline. Similar effects of ECT on the SF-36 were reported by Fisher et al. (2004).

There is accumulating evidence that ECT is associated with improvements in HRQOL and function and that this improvement is seen soon after ECT and is maintained for up to one year. The degree of change in HRQOL and function in patients with depression is greater with ECT than with medication. These effects are seen with a variety of different assessment tools (

). Improvement in mood explains most of the improvement in HRQOL and function, and the majority of ECT-treated patients experience an improvement in these measures over the first few months.

Overall, these findings support the idea that ECT is a helpful experience for most patients and are convergent with other data sources showing that ECT does not cause structural change in the brain or persistent effects on whole brain metabolism. In general, ECT is followed by a net improvement in health for most patients with depression. However, our findings do not discount the minority of patients who have worse HRQOL after ECT or that a small number of individuals may find the side effects of ECT disabling.

Dr. McCall is chairperson and professor in the department of psychiatry and behavioral medicine at Wake Forest University Health Sciences.

Dr. Rosenquist is professor in the department of psychiatry and behavioral medicine at Wake Forest University Health Sciences.

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Health-related quality of life can provide a simultaneous and net assessment of the therapeutic and adverse affects of psychiatric treatments for depression. While the cognitive side effects of ECT might be thought of as a limiting factor in HRQOL gains, they have not been systematically studied until recently. Find out what quantitative assessment of HRQOL following ECT for major depressive disorder shows.

W. Vaughn McCall, MD, MS

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