Dr. Kornstein is professor of Psychiatry and Obstetrics/Gynecology, executive director of the Institute for Women’s Health, and executive director of the Mood Disorders Institute at Virginia Commonwealth University in Richmond. Dr. Culpepper is professor and chairman in the Department of Family Medicine at Boston University Medical Center in Massachusetts.

Disclosures: Dr. Kornstein is on the advisory boards of or receives honoraria from Biovail, Bristol-Myers Squibb, Eli Lilly, Forest, Neurocrine, Pfizer, Sepracor, and Wyeth; and receives research support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health,  Novartis, Sanofi-Synthelabo, Sepracor, and Wyeth. Dr. Culpepper is a consultant to Eli Lilly, Forest, Pfizer, and Wyeth; and on the speaker’s bureaus of Forest, Pfizer, and Wyeth.

Acknowledgments: The authors would like to thank Grant Steen, PhD, for his assistance.

Please direct all correspondence to: Susan G. Kornstein, MD, Dept of Psychiatry, Virginia Commonwealth University, PO Box 980710, Richmond, VA 23298-0710; Tel: 804-828-5637; Fax: 804-828-5644; E-mail: skornste@vcu.edu.

 

 

Abstract

 

According to recent data, women are at increased risk for depression during the menopausal transition, even in the absence of a psychiatric history. As a result, it is important to identify biologic, psychiatric, and social risk factors for depression. An English language electronic literature search using the PubMed database (1986–2006) was conducted using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references were extracted and summarized. The authors of this article identified risk factors for menopausal depression reported in at least two primary references. It was found that a variety of biologic, psychiatric, and psychosocial factors interact to increase vulnerability to depression during the menopausal transition. These findings are consistent with a biopsychosocial model for perimenopausal depression. Depression in the context of the menopausal transition may be difficult to recognize. Thus, physicians should be aware of the various factors that can increase an individual patient’s risk for illness during this time period.

 

Introduction

Currently, 21.5 million women 45–54 years of age live in the United States1 and virtually all of these women will have entered menopause within the next decade. Crude calculation suggests that nearly 2 million American women per year will go through the menopausal transition. The life expectancy of women is now approximately 80 years, so many women will live 33% of their lives after menopause.2 Successful transition into menopause enhances health-related quality of life3,4 and may increase satisfaction in the postmenopausal phase.4

This article will summarize relevant evidence regarding the risk of depression during the menopausal transition and discuss contributing factors that can assist clinicians in diagnosing and treating depression in midlife women. The authors conducted an electronic literature search using the PubMed database (1986–2006; English language) using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references (and cross-references) were extracted and summarized. Risk factors for menopausal depression reported in at least two primary references were identified.

 

The Menopausal Transition

The Stages of Reproductive Aging Workshop (STRAW) standardized terminology relating to menstruation and menopause.5 The final menstrual period typically occurs when women are 42–58 years of age (mean age=52), and this event is the zero point for the STRAW staging system. Menarche marks entry into the reproductive phase of a woman’s life (Stage –5, relative to the zero point), after which it can take several years for a regular menstrual cycle to become established. Reproductive maturity is associated with menstrual periods that occur every 21–35 days (Stages –4 and –3), with the late reproductive stage (Stage –3) characterized by a gradual increase in levels of follicle-stimulating hormone (FSH). The early menopausal transition (Stage –2) begins when rising FSH levels lead to variability in menstrual cycle length, with cycles varying by >1 week from the normal cycle length. The late phase of the menopausal transition (Stage –1) is associated with higher levels of FSH and greater variability of the cycle, with ≥2 skipped cycles and an interval of amenorrhea lasting at least 60 days (Figure 1).5

 

Female reproductive senescence is defined by the depletion of oocytes in the ovary,5 and reproductive aging thus consists of a progressive loss of oocytes through atresia or ovulation. Menopause begins at the final menstrual period, but this point cannot be recognized with surety until after 12 months of amenorrhea. The early postmenopause (Stage +1) lasts 5 years and includes the 12-month period of amenorrhea that defines the beginning of the menopause. The late postmenopause (Stage +2) lasts for the rest of a woman’s life. Many menopausal symptoms, especially vasomotor symptoms such as hot flashes, are most severe during Stage –1 or Stage +1, in what has been called the “perimenopause.”5

The transition to menopause is a normal facet of aging, and most women do not become clinically depressed during this phase.6 However, for some women it may be associated with mood changes, including depressive symptoms—similar to other reproductive life events associated with hormonal fluctuations, including the premenstrual phase of the cycle,7-10 pregnancy,11-13 and the postpartum period.8,12,14-17 Understanding and recognizing physical, psychosocial, and psychiatric factors that increase the risk for depression during the menopausal transition and how these factors interact to modulate the risk imparted by the menopausal transition itself is important, particularly for primary care physicians (PCPs) who are likely to be confronted by these issues frequently as increasing numbers of women approach menopause.

 

Risk of Depression During the Menopausal Transition

The menopausal transition is often associated with an increase in depressive symptoms,18-22 and recent evidence suggests that the transition to menopause is a risk factor for depression in and of itself.17,23 In fact, the menopausal transition has been associated with an increased risk of depression in women with or without a previous history of depression.

A prospective study following 29 asymptomatic premenopausal women through the transition to menopause examined the relationship between the onset of depressive symptoms and perimenopause.24 The study found that the risk of depression during the 2-year period centered at the final menstrual period was 14-fold higher than risk during a 31-year premenopausal phase, and that a psychiatric history was not necessary for women to experience depression during this time.

More recently, two studies examined the risk for perimenopausal depression in women with no prior history of mood disturbance, with consistent findings. One study included 460 premenopausal women, who were followed prospectively for 3 years; menopausal status was determined every 6 months based on menstrual cycle changes ascertained through patient interviews.17 Among women who entered the menopausal transition, 32.5% had a new onset of depressive symptoms, whereas 20.0% of women who remained premenopausal became depressed. The adjusted odds ratio (OR) for depression among women who entered the perimenopause was 1.8, compared with premenopausal women.17 Findings were similar when a more stringent definition of depression was applied. The adjusted OR for severe first onset of depression (defined as women who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]25 criteria for major depressive disorder (MDD), self-reported depression most of the day nearly every day plus symptoms of anhedonia, or had a Center for Epidemiologic Studies Depression Scale score >24) in perimenopausal women compared with premenopausal women was 1.9, with incidence rates of 16.6% versus 9.5%, respectively.

The other study, an 8-year longitudinal study of 436 women, found that high depression scores were 4-fold more likely to occur during the menopausal transition (again determined based on menstrual cycle changes), relative to the premenopausal phase (P<.001).23,26 Increased levels of FSH and luteinizing hormone (LH) as well as increased variability of estradiol, FSH, and LH were all correlated with depressive symptoms. In a multivariate model, depressed women were 4.6-fold more likely to have elevated FSH levels and 3.0-fold more likely to have elevated LH levels (P<.002, for both).23 These relationships remained significant after adjusting for smoking, vasomotor symptoms, poor sleep, health status, employment, and marital status.

Studies that have included women with prior psychiatric diagnoses have found that those with a history of MDD prior to menopause are at particularly high risk for development of depression in the perimenopausal period.26-28 In addition, a history of prior depression related to the reproductive cycle, including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), ovarian cancer-related dysphoria, and/or postpartum MDD is associated with depression during the menopausal transition.29-31

Taken together, these findings suggest that the changing hormonal milieu during the menopausal transition is associated with onset of depression, even among women with no history of mood disturbance. Furthermore, some women may be particularly vulnerable to developing depression during times of hormonal flux. However, the risk for depression during the menopausal transition is influenced by multiple factors, which will be discussed in more detail below.

 

Risk Factors for Depression During the Menopausal Transition

Women at midlife face a unique set of circumstances including physical changes related to aging in general and to the menopause in particular, psychosocial adjustments related to changing roles and responsibilities within the family, and a variety of potential life stressors.32 These issues, in addition to psychiatric considerations (eg, history of or current mood or anxiety disorder), have an impact on the likelihood of depression in women as they transition to menopause.33

 

Physical Context of the Menopausal Transition

Hormonal changes, such as the widely fluctuating hormone levels that are the hallmark of the menopausal transition,32 may be associated with mood changes. Hormonal fluctuations may have direct effects on mood. Although the mechanism is poorly understood, preclinical studies suggest that estrogen has effects on areas of the brain involved in regulation of mood including the prefrontal/frontal cortex, hippocampus, amygdala, hypothalamus, dorsal raphe, and locus coeruleus.34-36 Specifically, estrogens have been reported to influence monoamine systems via modulation of the firing rate, synthesis, release rate, and elimination pathways.37-44 There may also be indirect effects; for example, physical symptoms related to menopause, including hot flashes and insomnia, may be problematic enough to affect mood in a kind of “domino effect” of menopause-related depression.31 Alternatively, complications in the management of chronic medical conditions or comorbidities may also contribute to the risk of depression during the menopausal transition.

Ovarian hormones or fluctuations in hormone levels have been implicated in the regulation of mood and behavior.44 For example, women have about twice the risk of depression as men,15,27 and analysis of the age at onset of depression shows that the risk difference between females and males arises in early adolescence and persists through the mid-50s,27 roughly the ages that correspond to menarche and menopause. Furthermore, psychiatric illnesses—including depression, anxiety, bipolar disorder, schizophrenia, bulimia nervosa, and substance abuse—can undergo cyclic fluctuations in symptom severity, with worsening of symptoms during the premenstrual period.8 These exacerbations may reflect the intensification of an underlying psychiatric disorder and/or the onset of symptoms that occur only during the premenstrual phase of the cycle. In addition, hormonal fluctuations during the postpartum period can also lead to mood disturbance.45 During the menopausal transition, acute hormonal changes that occur during a normal menstrual cycle are superimposed upon gradual menopause-related changes in hormones.46 This hormonal unpredictability can potentially intensify the emotional lability that is a natural part of the menstrual cycle.

As previously mentioned, there is an increased risk of clinical depression associated with the menopausal transition.19,21,26,32,47-51 Yet, the heightened risk of depression related to menopause is transitory19 and changes over time, concurrent with the hormonal changes characteristic of each stage of the menopausal transition. Recent results suggest that the risk of depression increases during early to late perimenopause, but decreases afterward.26,52 The likelihood of depressive symptoms is lower for women with a rapidly increasing FSH profile.26 Since rapid changes in FSH are associated with a relatively short duration of the menopausal transition, this evidence is consistent with the finding that depression is less of a problem if the menopausal transition takes no longer than 27 months.19

In some women of reproductive age there is a cyclic exacerbation of chronic medical conditions during the menstrual cycle, including migraine, epilepsy, asthma, diabetes, rheumatoid arthritis, and irritable bowel syndrome, that is thought to be related to rapid changes in concentrations of circulating ovarian steroids.9,53,54 Likewise, the hormonal fluctuations associated with the menopausal transition may exacerbate symptoms or complicate management of some chronic medical conditions.54-57 Such challenges may have a negative impact on mood for some women.

Approximately 40% of women seek medical attention to alleviate symptoms of the menopausal transition.58 Physical complaints associated with the hormonal fluctuations of the perimenopause include headache, insomnia, vasomotor symptoms (eg, hot flashes and night sweats), and genital atrophy. Hot flashes are the core symptom that reflect the brain’s response to the changing hormonal milieu, particularly fluctuating levels of estrogen.59 Evidence shows that vasomotor symptoms are strongly associated with depression during the menopausal transition. In a cohort of 309 women followed prospectively for 3 years, hot flashes and night sweats increased the odds of depression 1.8-fold and insomnia increased the odds of depression 4.0-fold.18 In another study, perimenopausal women with vasomotor symptoms were 4.4-fold more likely to be depressed than were women without vasomotor symptoms.21

 

Psychosocial Context of the Menopausal Transition

Depression at the menopausal transition may not necessarily be precipitated only by changes in hormones. Many women have a subjective experience of loss or “exit events” at this time, as children mature and leave the home, living circumstances change, elderly parents become ill or pass away, and marriages evolve or end.32 Race and ethnicity appear to influence the risk for depression in middle-aged women until adjustment is made for psychosocial factors such as poverty, at which point racial and ethnic differences are no longer significant.60 In general, having a social support network is protective from depression, whereas a sense of loss of control is a risk factor.61 In some studies, the importance of social factors such as inadequate income was greater than menopausal status in causing depression.20 Although the number of women living alone increases with age, many women report an improvement in mood after the last child leaves the home.62

Adverse life events can have a powerful impact on the risk of depression during the menopausal transition.17,31,63,64 Stressful life events, especially those of a chronic nature, generally increase the risk of depression.33 In addition, women with high levels of trait anxiety or a pessimistic outlook are more prone to depression and more vulnerable to stressful life events.63 Women with negative life events, low self-esteem, a troubled relationship with a life partner or children, or a weak social support network are at greater risk for depression.64 Presence of adverse life events increases the risk of depression during the menopausal transition by approximately 26% compared with women without such events, and the risk is even greater if the life events occur against a background of vasomotor symptoms.17 In short, life stressors such as aging, general health problems, caring for elderly parents, marital problems, career changes, children leaving home, and other life losses may contribute to depression, completely apart from other biologic and psychiatric risk factors.

A prospective cohort study investigated the determinants of depression in Dutch women going through the menopausal transition, after excluding women who used hormone therapy or who were status post hysterectomy or oophorectomy.50 Self-reported depressive symptoms from 2,103 women were analyzed to determine which social factors correlated with depression. A range of social factors was found to increase the risk of depression significantly. The OR for depression was higher in the context of job loss or unemployment (OR=3.1), inability to work (OR=1.7), financial difficulties (OR=2.9), death of a life partner (OR=2.6), death of a child (OR=5.9), or having a previous episode of depression (OR=2.0). It is important to note that because history of MDD was via self-report in this study, some women may have had earlier depressive episodes that remained undiagnosed (and thus were not reported); in addition, recall of social factors (eg, divorce, job loss) was likely to be stronger. Other studies, which will be reviewed in more detail in the next section, have shown stronger associations between psychiatric history and risk during the menopausal transition. Nevertheless, these data provide a clear demonstration of the importance of social factors in depression during menopausal transition.

Another important factor that contributes to the risk of depression is a woman’s attitude toward menopause. While research in the United States tends to focus on the negative aspects of menopause, some cultures are more attuned to the positive outcomes of the menopausal transition.46 For example, in certain African tribes, women are said to relish the increase in freedom and social influence that is attained after menopause.46 Menopause frees women from the burden of childbirth, the worries of contraception, and the cultural restrictions that may apply to women who still menstruate. Many reports suggest that the psychological reaction of women to menopause reflects the values of the society in which they live, and the social status assigned to aging women.46

 

Psychiatric Risk Factors for Depression During the Menopausal Transition

Psychiatric History
The most significant risk factor for developing depression during the menopausal transition is a history of depression.19 A 5-year longitudinal study tracked 2,565 women and found that prior depression is the single best predictor of depression during the menopausal transition, with an adjusted OR of 9.6 (P<.0001).19 Prior depression was a better predictor than was use of hormone replacement therapy (OR=1.0), stage of menopause (OR<2.1), or menopausal symptom severity (OR=3.6). In addition, women who became depressed during a prior reproductive event are at greater risk of menopause-related depression.28-31 For example, women with a history of severe PMS or PMDD appear to be more likely to suffer from depression during the menopausal transition.30,31,51 Interestingly, women with a lifetime history of MDD may be more likely to show an early decline in ovarian function,17,22 suggesting that the relationship between mood and the reproductive system is bi-directional (ie, hormonal changes associated with reproductive life events can influence mood and the presence of mood disorder can influence reproductive life events).


Genetic Factors

Although there has been no research specifically focused on a potential genetic risk for depression during the menopausal transition, genetic factors have been shown to interact with stress to influence the risk for depression. A study of 549 male and female twins found an interaction between stressful life events and a genetic liability for depression.65 Twins with one specific form of the serotonin transporter gene were at significantly greater risk of depression following common life stressors. Twins having alternative forms of the serotonin transporter gene were at lower risk.65 These results replicate an earlier prospective longitudinal analysis of a birth cohort which also found a functional polymorphism in the promoter region of the serotonin transporter gene that varies in a way that moderates the effect of stress on depression.66 People with one specific allele of the serotonin promoter were more likely to show depressive symptoms in relation to stressful life events. This vulnerability revealed a gene-by-environment interaction (ie, an individual’s response to the environment is moderated by their genetic makeup).66 A third analysis of the association between functional variation in the serotonin protein and depression confirmed that people with one particular variant of this gene are at increased risk of depression following relatively mild stressors.65

A second possible genetic component is a potential genetic vulnerability related to the menopausal transition. Although there is not yet direct evidence of a genetic risk specific to menopause, there is evidence demonstrating a genetic component related to premenstrual symptoms that is largely independent of the risk for MDD. Studies investigating the heritability of menstrual and premenstrual symptoms found that the environmental and genetic risk factors for premenstrual symptoms were not closely related to those associated with lifetime MDD.67,68 A similar phenomenon may be associated with other reproductive events including the menopause, ie, there may be a genetic predisposition to depressive symptoms during the menopausal transition.

Neuroendocrine Effects of Estrogen
Estrogen is known to have very powerful neuroendocrine effects in the brain. Acute increases in estrogen can blunt the response to stress, whereas chronic increases in estrogen downregulate serotonin receptors and increase the risk of depression and anxiety.69 Estrogens exert an agonistic effect on serotonergic activity by increasing the number of serotonergic receptors and by increasing the transport and uptake of serotonin. Estrogens also increase synthesis of serotonin, upregulate serotonin receptors, downregulate serotonin receptors, and decrease the activity of an enzyme (monoamine oxidase) involved in serotonin metabolism.70 The cumulative effect of estrogen on the serotonin system is thus to enhance serotonergic activity.

Estrogens appear to also increase noradrenergic activity by increasing receptor turnover, decreasing noradrenergic reuptake, and decreasing both the number and the sensitivity of dopamine-2 receptors.71 Animal studies suggest that there are potent behavioral effects associated with estrogen withdrawal or fluctuations in estrogen; bilateral ovariectomy of mice increases the duration of immobility—which is often taken as a measure of behavioral depression—while estrogen replacement decreases depressive-like behavior.72

 

The Transition Triad: A Biopsychosocial Model of Depression

Women experience depression during the menopausal transition because of a wide range of factors. It is only by understanding biologic, psychiatric, and social risk factors that we can begin to evaluate depression in midlife women.

The morbidity associated with mood disorders during midlife may be quite significant; as life expectancy continues to increase, it will become increasingly important to prevent, recognize, and treat depression during the menopausal transition in order to reduce the possibility of long-term sequelae.31 Women report symptoms of physical illness at higher rates, visit physicians more often, and make greater use of healthcare services than do men.54 This gives PCPs the opportunity to intervene in the lives of women who may not realize that they have a treatable problem. Awareness of the biopsychosocial factors that can impact depression during the menopausal transition may assist clinicians in the challenge of distinguishing symptoms of MDD from menopausal symptoms, and may help in the diagnosis and treatment of women with new-onset depression.

 

Evaluating Depression During the Menopausal Transition

Recognizing depression in the context of the menopausal transition can be challenging. First, there is considerable overlap between menopause-related symptoms and symptoms of MDD, including diminished energy level, poor concentration, sleep disturbance, weight change, and decreased libido (Figure 2).59,73 In addition, it may be difficult to differentiate whether mood symptoms are simply reactions to the myriad life stressors that can affect midlife women or are indicative of a psychiatric diagnosis.

 

 

Screening for depression in primary care can be done relatively quickly and easily by asking just two questions: “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the past month, have you been bothered by little interest or pleasure in doing things?”74 When 421 patients were given a psychiatric interview and a screening questionnaire comprised of 27 items, these two questions were clinically most useful, offering 97% sensitivity and 67% specificity for a diagnosis of clinical depression.73 If these questions are answered in the affirmative, a more thorough evaluation for depression is needed. Although the study sample included women and men of all ages and this was not a menopause-specific study, this screening tool for depression, used in conjunction with a clinical interview (which should include an assessment of reproductive status and history, current menopausal status, a review of changes in menstrual pattern, and a history of reproductive-related mood disturbance) and an evaluation of the presence and severity of somatic symptoms (which should include vasomotor symptoms, sleep disturbances, and changes in sexual function) provides an efficient and effective means of identifying depression during the menopausal transition in clinical practice.

 

Treating Depression During the Menopausal Transition

Management of depression during the menopausal transition should be part of a comprehensive treatment strategy designed to address the needs of the patient as a whole. As with depression at other times in a woman’s life, antidepressant therapy may be indicated. When selecting a therapy, it is important to consider whether treatment outcomes are affected by factors such as age, sex, and menopausal status.

As discussed previously, the neuroendocrine effects of estrogen are mediated at least in part by serotonergic activity in the brain.71,75 This mechanism could suggest that one therapeutic approach to menopausal depression would be to use antidepressants that modulate serotonin at the synapse.14 Alternatively, if estrogen serves to augment the serotonin system, it is possible that loss of this effect could result in a dampening of the efficacy of purely serotonergic agents in postmenopausal women compared with their use in premenopausal women.44 Unfortunately, relatively few studies have tested these hypotheses in a clinical setting. Of those that have evaluated the effect of gender and/or menopausal status on outcomes76-85 the evidence has not been entirely consistent, though differences could be attributable to small sample sizes and lack of statistical power to detect such interactions in some studies rather than discrepant findings.

In general, several studies have shown that compared with men, women may respond differently to some antidepressants,77,79,81,82 and postmenopausal women may respond differently than premenopausal women.76-83 For example, when the efficacy of sertraline, a selective serotonin reuptake inhibitor (SSRI), was compared to imipramine, a tricyclic antidepressant (TCA), gender- and menopause-related differences in response rates were found. Women were significantly more likely to show a favorable response to the SSRI, whereas men were more likely to benefit from the TCA; among the women, the difference between the two agents was found only in premenopausal women.82 More recently, a study in primary care patients found that menopause negatively affected response to SSRIs in depressed women.79 Specifically, the likelihood of responding to SSRIs was two times greater in premenopausal women compared with postmenopausal women. Other studies evaluating age as a proxy for menopausal status have found that antidepressant response in younger and older women differs, with younger women generally more treatment-responsive to SSRIs.76,80,83 Martenyi and colleagues81 reported that women in their reproductive years (defined in this study as <44 years of age) tended to be more responsive to SSRI treatment than to the predominantly noradrenergic tetracyclic antidepressant maprotiline. A meta-analysis of eight double-blind clinical trials of 2,045 patients randomized to treatment with the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine, SSRIs, or placebo76 found poorer response in the older women compared with the younger women taking SSRIs, with no such difference observed among women taking the SNRI. However, older women taking SSRIs and concomitant hormone therapy had a comparable response to younger women taking SSRIs alone.76

These results are controversial, as some studies have failed to replicate the finding of gender and/or menopausal status differences in antidepressant response.78,80,84 For example, a re-analysis of data from two clinical studies found no evidence that women have a preferential response to SSRIs or that men have a better TCA response.80 Another analysis of data from nine clinical trials found that women and men in all age groups had comparable response rates to TCAs and to the SSRI fluoxetine, although older women did show a superior response to TCAs compared with younger women.78 Finally, a post-hoc analysis of a study in 184 depressed women treated with fluoxetine failed to find a significant difference in response or remission rates among the pre-, peri-, and postmenopausal groups.84 Postmenopausal women did have significantly more residual symptoms following acute-phase treatment, though this difference was no longer significant when adjusted for baseline severity. It is important to note that the lack of statistical differences in this study might have been a function of the small sample sizes in the peri- (N=28) and postmenopausal (N=35) groups and hence low statistical power to detect differences in outcomes.84

It also remains unclear if the potentially diminished antidepressant efficacy in older or postmenopausal women is limited to SSRIs. Available studies suggest that the response to SNRI treatment is comparable in older and younger women.76,85 Prospective studies designed to specifically address the issue of a treatment-by-menopausal-status interaction are warranted to confirm the preliminary data described above.

 

Use of Estrogen in Treatment of Menopausal Depression

Hormone therapy has been used for many years to treat menopausal symptoms, and in more recent years tested as an option for peri- and postmenopausal mood disturbance.16,44,48,59,86 The value of hormone therapy as augmentation for antidepressant response has been evaluated in a handful of studies, with mixed results. In a double-blind study of fluoxetine in elderly depressed patients,87 fluoxetine treatment was significantly more effective than placebo in women who were taking concomitant estrogen therapy but not among those women who were not taking estrogen. A similar analysis in a study of sertraline demonstrated that older depressed women (>60 years of age) taking estrogen had significantly greater global improvement and quality of life than those not receiving estrogen.88 In contrast to these results, a reanalysis of data from a relapse prevention study found similar efficacy in fluoxetine-treated women ≥45 years of age with and without estrogen therapy.89 Finally, a small recently published pilot trial in postmenopausal women found that hormone therapy did not alter the response rate to treatment with sertraline, though hormone therapy may accelerate the treatment effect.90

The efficacy of estrogen as a monotherapy for depression also has been assessed in peri- and postmenopausal women. Preliminary data by Schmidt and colleagues86 suggested a role for estradiol in a double-blind, placebo-controlled, randomized clinical trial of 34 perimenopausal women with predominantly minor depression. These preliminary findings have since been replicated in a somewhat larger group of perimenopausal women91 with MDD, dysthymic disorder, or minor depressive disorder randomized to treatment with transdermal estradiol or placebo. Results were consistent regardless of DSM-IV diagnosis. However, evidence does not support the efficacy of estrogen as monotherapy for postmenopausal depression. In a randomized controlled trial of mild-to-moderate depression in postmenopausal women92 there was no difference between estrogen and placebo after 8 weeks of treatment. The authors concluded that estradiol cannot be considered effective treatment for postmenopausal depression.92

In summary, available evidence suggests a possible role for hormone therapy as monotherapy in perimenopausal women. The use of hormone therapy as an augmenting agent for antidepressant therapy is interesting but remains to be demonstrated prospectively in a randomized controlled trial. A careful consideration of the risks and benefits of these options should be made in conjunction with the patient, particularly in light of the widely publicized potential risks associated with hormone therapy for some patients.93 Although hormone therapy has been the mainstay of treatment for menopausal symptoms for many years, women are now increasingly likely to treat menopausal symptoms with nonhormonal treatments (eg, antidepressants; gabapentin; and alternative therapies, including exercise, herbal products, dietary supplements, and mind-body techniques).94 As such, there may be similar reluctance among some patients to consider estrogen as a therapeutic option for depression. Recently published data from the Women’s Health Initiative trial suggest there is a differential risk-benefit profile depending on years since menopause.95,96 These data should be taken into consideration when assessing options for short-term treatment during the menopausal transition.97  

 

Conclusion

Although we now have a clearer understanding of the risk for depression during the menopausal transition, many unanswered questions remain regarding the approach to treatment in peri- and postmenopausal women. Whether estrogen can be prescribed safely for a brief period of time at the menopausal transition warrants continued study. Some of the larger, prospective clinical trials of antidepressants such as fluoxetine, sertraline, venlafaxine, and duloxetine should be replicated with a larger sample size before recommendations for one treatment class over another can be made with confidence. We must also continue to search for antidepressants that work by different mechanisms, which may prove more effective for perimenopausal women. Finally, management of depression during the menopausal transition should be part of a comprehensive treatment strategy that addresses the needs of the patient as a whole. PP

 

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27. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29(2-3):85-96.
28. Hay AG, Bancroft J, Johnstone EC. Affective symptoms in women attending a menopause clinic. Br J Psychiatry. 1994;164(4):513-516.
29. Stewart DE, Boydell KM. Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med. 1993;23(2):157-162.
30. Gregory RJ, Masand PS, Yohai NH. Depression across the reproductive life cycle: correlations between events. Prim Care Companion J Clin Psychiatry. 2000;2(4):127-129.
31. Feld J, Halbreich U, Karkun S. The association of perimenopausal mood disorders with other reproductive-related disorders. CNS Spectr. 2005;10(6):461-470.
32. Rasgon N, Shelton S, Halbreich U. Perimenopausal mental disorders: epidemiology and phenomenology. CNS Spectr. 2005;10(6):471-478.
33. Bromberger JT, Matthews KA, Schott LL, et al. Depressive symptoms during the menopausal transition: The Study of Women’s Health Across the Nation (SWAN). J Affect Disord. Feb 27, 2007 [Epub ahead of print].
34. Gundlah C, Kohama SG, Mirkes SJ, Garyfallou VT, Urbanski HF, Bethea CL. Distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamus, midbrain and temporal lobe of spayed macaque: continued expression with hormone replacement. Brain Res Mol Brain Res. 2000;76(2):191-204.
35. McEwen BS. Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol. 2001;91(6):2785-2801.
36. Pau CY, Pau KY, Spies HG. Putative estrogen receptor beta and alpha mRNA expression in male and female rhesus macaques. Mol Cell Endocrinol. 1998;146(1-2):59-68.
37. Gonzales GF, Carrillo C. Blood serotonin levels in postmenopausal women: effects of age and serum oestradiol levels. Maturitas. 1993;17(1):23-29.
38. Gundlah C, Lu NZ, Bethea CL. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei. Psychopharmacology (Berl). 2002;160(3):271-282.
39. Karkanias GB, Etgen AM. Estradiol attenuates alpha 2-adrenoceptor-mediated inhibition of hypothalamic norepinephrine release. J Neurosci. 1993;13(8):3448-3455.
40. Pau KY, Hess DL, Kohama S, Bao J, Pau CY, Spies HG. Oestrogen upregulates noradrenaline release in the mediobasal hypothalamus and tyrosine hydroxylase gene expression in the brainstem of ovariectomized rhesus macaques. J Neuroendocrinol. 2000;12(9):899-909.
41. Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosci. 1996;16(21):7021-7029.
42. Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience. 1999;89(1):267-277.
43. Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques. Neuropsychopharmacology. 2004;29(11):2035-2045.
44. Halbreich U, Kahn LS. Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs. 2001;15(10):797-817.
45. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157(6):924-930.
46. World Health Organization. WHO Technical Report Series: Research on the Menopause in the 1990s. Geneva, Switzerland: World Health Organization; 1996. Series #866.
47. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health. 2001;91(9):1435-1442.
48. Burt VK, Altshuler LL, Rasgon N. Depressive symptoms in the perimenopause: prevalence, assessment, and guidelines for treatment. Harv Rev Psychiatry. 1998;6(3):121-132.
49. Hunter MS. Psychological and somatic experience of the menopause: a prospective study [corrected]. Psychosom Med. 1990;52(3):357-367. Erratum in: Psychosom Med. 1990;52(4):410.
50. Maartens LW, Knottnerus JA, Pop VJ. Menopausal transition and increased depressive symptomatology: a community based prospective study. Maturitas. 2002;42(3):195-200.
51. Novaes C, Almeida OP, de Melo NR. Mental health among perimenopausal women attending a menopause clinic: possible association with premenstrual syndrome? Climacteric. 1998;1(4):264-270.
52. Bosworth HB. Depression increases in women during early to late menopause but decreases after menopause. Evid Based Ment Health. 2004;7(3):90.
53. Case AM, Reid RL. Menstrual cycle effects on common medical conditions. Compr Ther. 2001;27(1):65-71.
54. Ensom MH. Gender-based differences and menstrual cycle-related changes in specific diseases: implications for pharmacotherapy. Pharmacotherapy. 2000;20(5):523-539.
55. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 1999;40(10):1402-1407.
56. Keck M, Romero-Aleshire MJ, Cai Q, Hoyer PB, Brooks HL. Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause. Am J Physiol Renal Physiol. 2007;293(1):F193-F199.
57. Szoeke CE, Cicuttini F, Guthrie J, Dennerstein L. Self-reported arthritis and the menopause. Climacteric. 2005;8(1):49-55.
58. McMillan TL, Mark S. Complementary and alternative medicine and physical activity for menopausal symptoms. J Am Med Womens Assoc. 2004;59(4):270-277.
59. Joffe H, Soares CN, Cohen LS. Assessment and treatment of hot flushes and menopausal mood disturbance. Psychiatr Clin North Am. 2003;26(3):563-580.
60. Bromberger JT, Harlow S, Avis N, Kravitz HM, Cordal A. Racial/ethnic differences in the prevalence of depressive symptoms among middle-aged women: the Study of Women’s Health Across the Nation (SWAN). Am J Public Health. 2004;94(8):1378-1385.
61. Voils CI, Steffens DC, Flint EP, Bosworth HB. Social support and locus of control as predictors of adherence to antidepressant medication in an elderly population. Am J Geriatr Psychiatry. 2005;13(2):157-165.
62. Dennerstein L, Dudley E, Guthrie J. Empty nest or revolving door? A prospective study of women’s quality of life in midlife during the phase of children leaving and re-entering the home. Psychol Med. 2002;32(3):545-550.
63. Bromberger JT, Matthews KA. A longitudinal study of the effects of pessimism, trait anxiety, and life stress on depressive symptoms in middle-aged women. Psychol Aging. 1996;11(2):207-213.
64. Deeks AA. Psychological aspects of menopause management. Best Pract Res Clin Endocrinol Metab. 2003;17(1):17-31.
65. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry. 2005;62(5):529-535.
66. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
67. Kendler KS, Karkowski LM, Corey LA, Neale MC. Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry. 1998;155(9):1234-1240.
68. Kendler KS, Silberg JL, Neale MC, Kessler RC, Heath AC, Eaves LJ. Genetic and environmental factors in the aetiology of menstrual, premenstrual and neurotic symptoms: a population-based twin study. Psychol Med. 1992;22(1):85-100.
69. Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry. 2004;161(2):195-216.
70. McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev. 1999;20(3):279-307.
71. Garlow S, Musselman D, Nemeroff C. The neurochemistry of mood disorders: clinical studies. In: Charney D, Nestler E, Bunney B, eds. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 1999:348-364.
72. Bekku N, Yoshimura H. Animal model of menopausal depressive-like state in female mice: prolongation of immobility time in the forced swimming test following ovariectomy. Psychopharmacology (Berl). 2005;183(3):300-307.
73. Soares CN, Cohen LS. Perimenopause and mood disturbance: an update. CNS Spectr. 2001;6:167-174.
74. Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally asked questions: cross sectional study. BMJ. 2003;327(7424):1144-1146.
75. Soares CN, Prouty J, Born L, Steiner M. Treatment of menopause-related mood disturbances. CNS Spectr. 2005;10(6):489-497.
76. Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005;14(7):609-616.
77. Raskin A. Age-sex differences in response to antidepressant drugs. J Nerv Ment Dis. 1974;159(2):120-130.
78. Quitkin FM, Stewart JW, McGrath PJ, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159(11):1848-1854.
79. Pinto-Meza A, Usall J, Serrano-Blanco A, Suarez D, Haro JM. Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference? J Affect Disord. 2006;93(1-3):53-60.
80. Parker G, Parker K, Austin MP, Mitchell P, Brotchie H. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med. 2003;33(8):1473-1477.
81. Martenyi F, Dossenbach M, Mraz K, Metcalfe S. Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile. Eur Neuropsychopharmacol. 2001;11(3):227-232.
82. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
83. Grigoriadis S, Kennedy SH, Bagby RM. A comparison of antidepressant response in younger and older women. J Clin Psychopharmacol. 2003;23(4):405-407.
84. Cassano P, Soares CN, Cusin C, Mascarini A, Cohen LS, Fava M. Antidepressant response and well-being in pre-, peri- and postmenopausal women with major depressive disorder treated with fluoxetine. Psychother Psychosom. 2005;74(6):362-365.
85. Burt VK, Wohlreich MM, Mallinckrodt CH, Detke MJ, Watkin JG, Stewart DE. Duloxetine for the treatment of major depressive disorder in women ages 40 to 55 years. Psychosomatics. 2005;46(4):345-354.
86. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000;183(2):414-420.
87. Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemeroff CB, Meyers BS. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry. 1997;5(2):97-106.
88. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393-399.
89. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11-17.
90. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):338-343.
91. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529-534.
92. Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55(4):406-412.
93. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
94. Ma J, Drieling R, Stafford RS. US women desire greater professional guidance on hormone and alternative therapies for menopause symptom management. Menopause. 2006;13(3):506-516.
95. Manson JE, Allison MA, Rossouw JE et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591-2602.
96. Rossouw JE, Prentice RL, Manson JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477.
97. Burger HG. WHI risks: any relevance to menopause management? Maturitas. 2007;57(1):6-10.

 

Dr. Ginsberg is vice-chair of clinical affairs in the Department of Psychiatry at New York University Medical Center in New York City.

 


Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

 

 
 

Lithium-Induced Brugada Syndrome

The July 2007 “Psychopharmacology Reviews”1 discussed a report of second-degree, type 2 sinoatrial block that resulted from toxic lithium levels.2 Other possible electrocardiogram (ECG) manifestations of lithium toxicity include prolonged QT interval, T-wave flattening and inversion, first-degree atrioventricular conduction delay, and, rarely, ventricular tachycardia and ventricular fibrillation resulting in death.3-6

Even at therapeutic levels, there are other potential cardiac consequences of chronic lithium therapy, such as sinus node suppression.7-9 The mechanism of action underlying this effect may be related to lithium’s competitive inhibition of calcium in the sodium-calcium exchange in cardiac cells.10

In an ion channel disease known as Brugada syndrome, transmural dispersion of repolarization is accentuated as a result of preferential abbreviation of the right ventricular epicardial action potential. Brugada syndrome is characterized by syncopes and sudden cardiac death due to polymorphic ventricular tachyarrhythmia. In approximately 20% of cases, it is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the a-subunit of the cardiac sodium channel.11

In a healthy population, the point prevalence of the Brugada syndrome ECG pattern has been estimated at 1–5 per 10,000 individuals wordwide.12 Such a pattern has a QRS morphology similar to right bundle branch block, with ST-segment elevation in leads V1-V3. In addition, some Brugada syndrome patients display QT prolongation, though when it does occur it is usually limited to the right precordial leads V1-V3. The following is a published report of a patient who developed Brugada syndrome in association with use of lithium.13

A 42-year-old male with schizoaffective disorder experienced a syncopal episode. He had been receiving lithium for 8 years and had a history of recurrent syncopes during this period. His ECG showed typical signs of Brugada syndrome, with ST-segment elevation in the precordial leads V1-V3. Serum lithium level was within therapeutic range (0.75 mmoL/L), but lithium was discontinued after the diagnosis of Brugada syndrome.

Three weeks after lithium withdrawal, the patient developed a manic episode and was admitted to a hospital in Germany. Physical examination was normal. Family medical and psychiatric histories were normal. Treatment with olanzapine 30 mg/day resulted in complete symptom remission after 4 weeks. ECG showed resolution of ST abnormalities. Programmed electrical stimulation from the right ventricular outflow tract induced only nonsustained ventricular tachycardia. However, a provocation test with ajmaline demonstrated ST-segment elevations typical for Brugada syndrome. Subsequently, an automatic defibrillator was implanted to prevent future syncopes and sudden cardiac death.

The case described here is consistent with Brugada syndrome precipitated by lithium, which has been previously reported.14 It is also known that sodium channel blockers, such as carbamazepine, oxcarbazepine, valproate, lamotrigine, phenothiazines, clozapine, selective serotonin reuptake inhibitors, and tricyclic antidepressants may also increase the risk of developing symptomatic Brugada syndrome.11 Whether the risk increases when lithium is combined with any of these other agents has not been reported but, given the number of patients receiving such combinations, deserves further study. PP

 

References

1. Ginsberg DL. Lithium-induced sinoatrial block. Primary Psychiatry. 2007;14(7):37-38.
2. Goldberger ZD. Sinoatrial block in lithium toxicity. Am J Psychiatry. 2007;164(5):831-832.
3. Brady HR, Horgan JH. Lithium and the heart: unanswered questions. Chest. 1988;93(1):166-169.
4. Mitchell JE, Mackenzie TB. Cardiac effects of lithium therapy in man: a review. J Clin Psychiatry. 1982;43(2):47-51.
5. Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN. The cardiovascular effects of lithium in man. A review of the literature. Am J Med. 1976;61(5):665-670.
6. Montalescot G, Levy Y, Farge D, et al. Lithium causing a serious sinus-node dysfunction at therapeutic doses. Clin Cardiol. 1984;7(11):617-620.
7. Wellens HJ, Cats VM, Duren DR. Symptomatic sinus node abnormalities following lithium carbonate therapy. Am J Med. 1975;59(2):285-287.
8. Wilson JR, Kraus ES, Bailas MM, Rakita L. Reversible sinus-node abnormalities due to lithium carbonate therapy. N Engl J Med. 1976;294(22):1223-1224.
9. Terao T, Abe H, Abe K. Irreversible sinus node dysfunction induced by resumption of lithium therapy. Acta Psychiatr Scand. 1996;93(5):407-408.
10. Lai CL, Chen WJ, Huang CH, et al. Sinus node dysfunction in a patient with lithium intoxication. J Formos Med Assoc. 2000;99(1):66-68.
11. Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. 2000;101(5):510-515.
12. Hermida JS, Lemoine JL, Aoun FB, Jarry G, Rey JL, Quiret JC. Prevalence of the brugada syndrome in an apparently healthy population. Am J Cardiol. 2000;86(1):91-94.
13. Laske C, Soekadar SR, Laszlo R, Plewnia C. Brugada syndrome in a patient treated with lithium. Am J Psychiatry. 2007;164(9):1440-1441.
14. Darbar D, Yang T, Churchwell K, Wilde AA, Roden DM. Unmasking of brugada syndrome by lithium. Circulation. 2005;112(11):1527-1531.

 

Neonatal Brain Infarcts Possibly Due to Electroconvulsive Therapy During Pregnancy

Electroconvulsive therapy (ECT) has been in use since the 1940s and is primarily indicated for the treatment of depression, acute mania, schizophrenia, and catatonia. The American Psychiatric Association (APA)-published text regarding recommendations related to ECT1 states that ECT is a treatment with low risk and high efficacy in the management of specific disorders in all three trimesters of pregnancy. The following is a report of a young woman who received ECT for bipolar depression every 2 weeks throughout her pregnancy and who subsequently delivered an infant with neurologic abnormalities associated with several brain infarcts.2

A 22-year-old primigravida with a long history of bipolar depression received bifrontal ECT every 2 weeks during her entire pregnancy. No complications from the ECT were reported. Prior to becoming pregnant, the patient had received maintenance ECT with good effect. After becoming pregnant, the patient continued to receive ECT to treat ongoing severe depression that in the past had only been partially responsive to medication treatment. Between 20 and 34 weeks of gestational age, seven documented ECT treatments occurred. Fetal heart rates were recorded after each treatment with no reported abnormalities. There is no evidence of a nonstress test having been performed. Further specifics about the maternal ECT were not recorded.

At 36.1 weeks of gestation, just prior to her scheduled ECT, the patient was noted to have an elevated blood pressure of 162/100 mm Hg. Twenty four-hour urinalysis showed mildly elevated protein. All other laboratory values were normal. The patient underwent induction of labor for preeclampsia and vaginally delivered a male infant weighing 2,550 grams (5.61 lbs) with 1- and 5-minute Apgar scores of 4 and 7, without complications. Throughout labor and delivery, the fetal heart rate tracing was unremarkable. Anatomic survey at 20 weeks was normal.

The infant was stimulated with no response, and his upper extremities were tonic with extension posturing. An umbilical cord blood gas analysis showed a pH of 7.24, PCO2 of 42, HCO3 of 18, and PO2 of 27. The infant’s infectious disease workup, toxicity screens, and other blood tests were all negative. Brain computed tomography and magnetic resonance imaging scans performed on the second and third day of life showed a small left cerebellar, bihemispheric deep white matter, and cortical infarcts. The infant was discharged home at age 12 days. A neurology consultant who evaluated the infant concluded that the prognosis was guarded with expected long-term motor control issues. Further follow-up was not available.

As pointed out by the authors of this report, whether ECT in this case led to titanic uterine contractions causing a fetal bradycardia or other type arrhythmia that then resulted in fetal brain injury is a possibility but unproven. There are no prospective or controlled studies of ECT in pregnancy. The APA ECT Practice Guidelines Recommendations1 derive principally from reviews of case reports. The largest such review evaluated 300 reports of ECT in pregnancy from 1942–1991.3 Twenty-eight cases (9.3%) were noted to have complications, including fetal cardiac arrhythmias (five), vaginal bleeding (five), uterine contractions (two), abdominal pain (three), premature labor (four), miscarriage (five), stillbirth and neonatal death (three), neonatal respiratory distress (one), and teratogenicity (five). Of note, 25 of these 28 patients were >30 years of age at the time of publication of the review. There have been an additional six cases in the literature with obstetric outcomes reported.4-7 Included among these are reports of fetal heart rate decelerations in three of six cases, one requiring tocolytic medication, and one case of first trimester bleeding with subsequent miscarriage. Among these reports, there is a good deal of heterogeneity in regard to details of diagnosis, treatments, pregnancy trimester, other potential contributing factors, and outcomes reported.

The APA Practice Guidelines1 for ECT include recommendations for managing a pregnant patient undergoing ECT. These recommendations are designed to minimize potential complications such as aspiration and altered uteroplacental blood flow. Even with their implementation however, serious neonatal complications may result. The exact incidence of such complications, and the attribution of them to ECT, is difficult to determine in the absence of controlled studies. Risk-benefit assessments, both of the mother and the neonate, need to account for the severity of the underlying psychiatric condition and the safety and efficacy not only of ECT, but of alternate medication therapies as well. PP

 

References

1. Committee on Electroconvulsive Therapy. The Practice of Electroconvulsive Therapy, Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association. 2nd ed. Washington, DC: American Psychiatric Association; 2001.
2. Pinette MG, Santarpio C, Wax JR, Blackstone J. Electroconvulsive therapy in pregnancy. Obstet Gynecol. 2007;110(2 Pt 2):465-466.
3. DeBattista C, Cochran M, Barry JJ, Brock-Utne JG. Fetal heart rate decelerations during ECT-induced seizures: is it important? Acta Anaesthesiol Scand. 2003;47(1):101-103.
4. Bhatia SC, Baldwin SA, Bhatia SK. Electroconvulsive therapy during the third trimester of pregnancy. J ECT. 1999;15(4):270-274.
5. Polster DS, Wisner KL. ECT-induced premature labor: a case report. J Clin Psychiatry. 1999;60(1):53-54.
6. Echevarria Moreno M, Martin Munoz J, Sanchez Valderrabanos J, Vazquez Gutierrez T. Electroconvulsive therapy in the first trimester of pregnancy. J ECT. 1998;14(4):251-254.
7. Livingston JC, Johnstone WM Jr, Hadi HA. Electroconvulsive therapy in a twin pregnancy: a case report. Am J Perinatol. 1994;11(2):116-118.

 

Gabapentin-Induced Rhabdomyolysis

Rhabdomyolysis is characterized by a 5-fold increase in the upper normal limit of blood creatine kinase (CK) levels, which usually is associated with acute renal failure.1 Accumulation of intracellular calcium, activation of proteases and lipases, production of free radicals, and infiltration by inflammatory cells are some of the mechanisms responsible for muscular necrosis. The diagnosis of rhabdomyolysis relies on the elevation of CK and myoglobin blood levels. The main therapeutic goals focus on removal of precipitating factors, correction of biochemical alterations, and treatment of acute renal failure by hemodialysis when necessary. Conservative interventions, such as early and vigorous hydration associated with forced alkaline diuresis, can improve the prognosis of this adverse event.

Rhabdomyolysis usually occurs following traumatic injuries, excessive physical activity, seizures, infections, and adverse drug reactions.1 Besides statins, recognized as the drugs most commonly associated with severe myopathy, neuroleptics—typically in the setting of neuroleptic malignant syndrome2,3—and proton pump inhibitors4 have been suggested as other possible causative agents of somatic muscular alterations.

Gabapentin is a γ-aminobutyric acid (GABA)ergic anticonvulsant indicated for adjunctive therapy in the treatment of partial seizures with and without secondary generalization, in adults with epilepsy. Despite the lack of placebo-controlled trials affirming its use, in recent years gabapentin has been used to treat numerous other neuropsychiatric conditions including bipolar disorder,5 anxiety disorders,6-9 somatization disorder,10 behavioral dyscontrol,11-13 cocaine and alcohol withdrawal,14,15 antipsychotic-induced movement disorders,16 neuropathic pain,17,18 ciguatera poisoning,19 nicotine20 and benzodiazepine dependence,21 tinnitus,22 and hot flashes in postmenopausal women and in men taking hormone therapy for prostate cancer.23,24 Gabapentin is well absorbed, renally excreted, does not bind to plasma proteins, and has few, if any, drug interactions. The most frequent adverse effects are drowsiness, dizziness, ataxia, and gastrointestinal upset.25 Postmarketing reports of gabapentin-associated sexual dysfunction in both men and women have also appeared,26-31 as well as a report of gabapentin-associated worsening renal function in two patients previously treated with lithium.32 The following is a report of gabapentin-induced rhabdomyolysis.33

An 85-year-old diabetic female was hospitalized for severe pain in her lower limbs and difficulty in walking, compromising her daily activities. On admission, the woman’s laboratory parameters, including CK and myoglobin, were in the normal range. Neurologic evaluation suggested a diagnosis of diabetic neuropathic pain, and therapy with gabapentin 150 mg TID was started. On the same day, the patient developed psychomotor agitation and gastric pain, which were treated with haloperidol 10 mg and lansoprazole 30 mg, respectively. Over the next few hours, the severity of muscular pain increased, with the patient developing myopathy with acute renal failure. Laboratory values were as follows: CK 459 U/L (normal 24–190 U/L), myoglobin 11,437 ng/mL (normal 10–90 ng/mL), and creatinine 4.59 mg/dL (normal 0.30–1.10 mg/dL). During the next 2 days, despite supportive treatment and discontinuation of haloperidol and lansoprazole, the patient’s condition progressively worsened as manifested by the following laboratory indices: CK 3095 U/L, myoglobin 17,000 mg/dL, and creatinine 4.77 mg/dL. No signs of trauma or edema were detected; consequently, compartmental or crush syndrome was excluded as a possibility. Gabapentin was then withdrawn. The patient’s condition rapidly improved, with a reduction in pain; progressive normalization of CK, myoglobin, and creatinine; and overall complete recovery after approximately 10 days.

The temporal sequence of events described above, with worsening of the clinical picture despite discontinuation of haloperidol and lansoprazole but rapid improvement after withdrawal of gabapentin, strongly suggests an association between gabapentin and rhabdomyolysis. On the Naranjo probability scale, the association is rated as probable.34 Gabapentin-associated myopathy has been previously reported in two patients, both of whom had end-stage renal disease.35

The mechanism of action underlying this association is not known, but may involve the action of gabapentin on voltage-gated calcium and sodium channels in muscle cells. Regardless of the pathophysiology, the appearance of the syndrome soon after the initiation of gabapentin at therapeutic doses is compatible with an idiosyncratic adverse event. Given the widespread use of gabapentin, including for off-label uses, clinical caution is advised. PP

 

References

1. Singh D, Chander V, Chopra K. Rhabdomyolysis. Methods Find Exp Clin Pharmacol. 2005;27(1):39-48.
2. Yoshikawa H, Watanabe T, Abe T, Oda Y, Ozawa K. Haloperidol-induced rhabdomyolysis without neuroleptic malignant syndrome in a handicapped child. Brain Dev. 2000;22(4):256-258.
3. Marinella MA. Rhabdomyolysis associated with haloperidol without evidence of NMS. Ann Pharmacother. 1997;31(7-8):927-928.
4. Clark DW, Strandell J. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur J Clin Pharmacol. 2006;62(6):473-479.
5. Stanton SP, Keck PE Jr, McElroy SL. Treatment of acute mania with gabapentin. Am J Psychiatry. 1997;154(2):287.
6. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry. 1998;43(3):305.
7. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry. 1998;155(7):992-993.
8. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: A placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
9. Brannon N, Labbate L, Huber M. Gabapentin treatment for posttraumatic stress disorder. Can J Psychiatry. 2000;45(1):84.
10. Garcia-Campayo J, Sanz-Carrillo C. Gabapentin for the treatment of patients with somatization disorder. J Clin Psychiatry. 2001;62(6):474.
11. Ryback R, Ryback L. Gabapentin for behavioral dyscontrol. Am J Psychiatry. 1995;152(9):1399.
12. Herrmann N, Lanctot K, Myszak M. Effectiveness of gabapentin for the treatment of behavioral disorders in dementia. J Clin Psychopharmacol. 2000;20(1):90-93.
13. Low RA Jr, Brandes M. Gabapentin for the management of agitation. J Clin Psychopharmacol. 1999;19(5):482-483.
14. Markowitz JS, Finkenbine R, Myrick H, King L, Carson WH. Gabapentin abuse in a cocaine user: implications for treatment ? J Clin Psychopharmacol. 1997;17(5):423-424.
15. Myrick H, Malcolm R, Brady KT. Gabapentin treatment of alcohol withdrawal (letter). Am J Psychiatry. 1998;155(11):1632.
16. Hardoy MC, Hardoy MJ, Carta MG, Cabras PL. Gabapentin as a promising treatment for antipsychotic-induced movement disorders in schizoaffective and bipolar disorder patients. J Affect Disord. 1999;54(3):315-317.
17. Morris GL. Gabapentin. Epilepsia. 1999;40(suppl 5):S63-S70.
18. Laird MA, Gidal BE. Use of gabapentin in the treatment of neuropathic pain. Ann Pharmacother. 2000;34(6):802-807.
19. Perez CM, Vasquez PA, Perret CF. Treatment of ciguatera poisoning with gabapentin. N Engl J Med. 2001;344(9):692-693.
20. Myrick H, Malcolm R, Henderson S, McCormick K. Gabapentin for misuse of homemade nicotine nasal spray. Am J Psychiatry. 2001;158(3):498.
21. Crockford D, White WD, Campbell B. Gabapentin use in benzodiazepine dependence and detoxification. Can J Psychiatry. 2001;46(3):287.
22. Zapp JJ. Gabapentin for the treatment of tinnitus: a case report. Ear Nose Throat J. 2001;80(2):114-116.
23. Guttuso TJ Jr. Gabapentin’s effects on hot flashes and hypothermia. Neurology. 2000;54(11):2161-2163.
24. Jeffery SM, Pepe JJ, Popovich LM, Vitagliano G. Gabapentin for hot flashes in prostate cancer. Ann Pharmacother. 2002;36(3):433-436.
25. Dichter MA, Brodie J. New antiepileptic drugs. N Engl J Med. 1996;334(24):1583-1590.
26. Clark JD, Elliott J. Gabapentin-induced anorgasmia. Neurology. 1999;53(9):2209.
27. Labbate LA, Rubey RN. Gabapentin-induced ejaculatory failure and anorgasmia. Am J Psychiatry. 1999;156(6):972.
28. Brannon GE, Rolland PD. Anorgasmia in a patient with bipolar disorder type 1 treated with gabapentin. J Clin Psychopharmacol. 2000;20(3):379-381.
29. Husain AM, Carwile ST, Miller PP, Radtke RA. Improved sexual function in three men taking lamotrigine for epilepsy. South Med J. 2000;93(3):335-336.
30. Montes JM, Ferrando L. Gabapentin-induced anorgasmia as a cause of noncompliance in a bipolar patient. Bipolar Disord. 2001;3(1):52.
31. Grant AC, Oh H. Gabapentin-induced anorgasmia in women. Am J Psychiatry. 2002;159(7):1247.
32. Silvia RJ, Spitznas AL. Gabapentin-related changes in renal function: two case reports. J Clin Psychopharmacol. 2007;27(1):117-119.
33. Tuccori M, Lombardo G, Lapi F, Vannacci A, Blandizzi C, Del Tacca M. Gabapentin-induced severe myopathy. Ann Pharmacother. 2007;41(7):1301-1305.
34.  Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-245.
35. Lipson J, Lavoie S, Zimmerman D. Gabapentin-induced myopathy in 2 patients on short daily hemodialysis. Am J Kidney Dis. 2005;45(6):e100-e104.

 

Dr. Wu is associate director, Mr. Durkin is senior director of outcomes research, and Dr. Canuso is senior director of clinical development at Ortho-McNeil Janssen Scientific Affairs, LLC, in Titusville, New Jersey. Dr. Dickson is professor and past-chairman of the Pharmaceutical and Health Outcomes Sciences Department at the University of South Carolina in Columbia.

Disclosures: Drs. Wu and Canuso own stock in Johnson and Johnson and are employees of Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Dickson is consultant to Ortho-McNeil Janssen Scientific Affairs, LLC. Mr. Durkin is an employee of Ortho-McNeil Janssen Scientific Affairs, LLC.  This article was funded by Ortho-McNeil Janssen Scientific Affairs, LLC.

Acknowledgments: The authors thank Dr. Victor Navarro for his assistance. Data in this study were presented at the Annual Meeting of the American Psychiatric Association in San Diego, CA, May 19-24, 2007.

Please direct all correspondence to: Jasmanda H. Wu, MPH, PhD, Associate Director, Outcomes Research, Ortho-McNeil Janssen Scientific Affairs, LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ 08560-0200; Tel: 609-730-7718; Fax: 609-730-2411; E-mail: jwu2@omjus.jnj.com.

 


 

Focus Points

• There is a high occurrence of liver diseases observed in patients with mental illness.
• True prevalence of liver diseases may be even higher than that observed.
• Clinicians should consider hepatic issues when treating patients with mental illness. 


 

Abstract

Objective:  To evaluate the percentage of patients with treated liver diseases in patients with schizophrenia or bipolar disorder, compared to a comparison group without mental illness.
Methods: South Carolina State Medicaid program data were analyzed. Patients <65 years of age, with a schizophrenia or bipolar disorder diagnosis from 2002–2003 were identified. A 4–1 frequency-matching algorithm (4 without diagnosis to 1 with diagnosis) was applied. Treated liver diseases were assessed from ambulatory or hospital claims over the 24-month period and compared between the two groups. Direct standardization was used to account for the differences in demographics between the two groups.  
Results: A total of 5,211 patients with schizophrenia and 4,553 patients with bipolar disorder were identified. After standardizing for the differences in age, gender, and race, the percentages of patients with treated liver diseases in patients with schizophrenia (or bipolar disorder) was statistically significantly higher than the non-mentally ill comparison group (schizophrenia versus comparison=4.64% versus 4.14%,
P<.0001; bipolar disorder versus comparison=6.96% versus 2.66%, P<.0001). The percentages observed in the disease group were also higher than the reported prevalence of liver disease from the historic general population (1.3%).
Conclusion: Medicaid recipients with schizophrenia or bipolar disorder have higher percentages of patients with treated liver diseases than non-mentally ill Medicaid recipients. The percentages observed were also higher than the prevalence rate reported for the general population. Clinicians should consider hepatic issues in the management of their patients.

 

Introduction

Schizophrenia and bipolar disorder are severe disorders that usually manifest in late adolescence or early adulthood.1-5 Both conditions involve substantial direct healthcare burden due to early onset, chronicity, and frequent need for repeated hospitalizations.6,7 In addition, patients experience impairments in occupational and social functioning that can result in increased family and societal burden.8,9

It is common for patients with schizophrenia or bipolar disorder to exhibit comorbidities such as substance abuse and hepatic viral infection.10-12 According to the literature, up to 60% of patients with bipolar disorder meet diagnostic criteria for substance abuse.13 Comorbid substance abuse disorder is reported to occur in almost 50% of patients with schizophrenia.13 Patients with alcohol abuse are at particular risk for hepatic impairment.14,15 Increased rates of drug abuse, particularly injection drug use, are likely to contribute to increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with mental illness.16

It has been found that HBV and HCV occur more frequently in patients with severe mental illness than in the general population.17 A 2001 study revealed that the prevalence of HBV (23.4%) and HCV (19.6%), respectively, was 5 and 11 times higher for patients with severe mental illness than in the general population.16 A retrospective database study showed that 9.9% of patients with schizophrenia were infected with HCV.18 Both HBV and HCV are major causes of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.19,20

Patients with schizophrenia and bipolar disorder may be at higher risk for acquiring another spectrum of liver diseases known as non-alcoholic fatty liver disease (NAFLD).21 Among the most common risk factors associated with NAFLD21 are those observed in metabolic syndrome.22 According to the literature, prevalence of metabolic syndrome was 36% for males and 51% for females in patients with schizophrenia. These rates are higher than in the general population (20% males; 25% females).23

Patients with schizophrenia or bipolar disorder commonly receive antipsychotic polypharmacy and pharmacologic add-on therapy for various aspects of their illness.24-27 Unintended interactions between medications may be associated with liver damage. Previous studies have evaluated viral hepatitis in people with severe mental illness.16,17 However, few research articles have been published that address the issue of overall liver diseases in psychiatric patients.

In this study, the authors examined insurance claims data from a State Medicaid program to evaluate the percentages of patients with treated liver diseases in Medicaid recipients with a schizophrenia or bipolar disorder diagnosis, compared to those without mental illness.

 

Methods

Study Cohort

Claims data were analyzed from the South Carolina State Medicaid program database. Approximately 500,000 eligible beneficiaries were identified in 2004 and 2005. Patient identifiers were removed to ensure patient confidentiality. The South Carolina Medicaid Program Committee and the University of South Carolina Institutional Review Board approved the study and did not require informed consent.

Patients <65 years of age who had at least one hospital claim or two ambulatory claims with a diagnosis of schizophrenia or bipolar disorder (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM],28 codes 295.xx, 296.0, 296.1, and 296.4-296.8) during 2002 and 2003 were selected. This method has been used previously for selecting patients with schizophrenia, schizoaffective disorder, or bipolar disorder for examining comorbid conditions, adverse events, and medication compliance.29-32 Diagnosis of schizophrenia included schizoaffective disorder with schizophrenia-spectrum illnesses (ICD-9-CM codes 295.7x). Patients who had skilled nursing home claims during 2002 and 2003 were excluded due to the absence of pharmacy claims records. Those without continuous eligibility during 2004 and 2005 were excluded. The enrollment period (January 1, 2002 to December 31, 2003) differed from the follow-up period (January 1, 2004 to December 31, 2005) to allow focus on liver conditions for existing rather than new schizophrenia or bipolar patients. Temporal sequence between the occurrence of liver disease and schizophrenia/bipolar disorder diagnoses was difficult to establish using claims data and was not required for inclusion. 

The authors of this study separated patients into two cohorts, including those with schizophrenia and those with bipolar disorder. Patients with both conditions were excluded. For each patient in either cohort, four individuals were randomly selected using frequency matching on the age category (age groups of 1–20, 21–40, and 41–64 years) to create the comparison group without mental illness. The authors used medical and pharmacy claims to exclude comparison group subjects who exhibited a diagnosis of mental illness (ICD-9-CM codes 290.xx to 319.xx) or who had received antipsychotics between January 1, 2002 through December 31, 2005. National Drug Codes33 were used to identify the presence of antipsychotics within the comparison group cohort, including aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, promazine, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone.

The four cohorts (schizophrenia and bipolar disorder, and their corresponding comparison group without mental illness) were reviewed for new and existing liver diseases by searching claims for related ICD-9-CM codes occurring between January 1, 2004 and December 31, 2005.

 

Measurements

Liver Diseases
Individuals were identified as having liver diseases (acute and chronic), viral hepatitis, or chronic cirrhosis if they had at least one hospital claim or two ambulatory claims for the ICD-9-CM codes listed in Table 1.28 The method using two separate outpatient visits to help increase the diagnostic specificity has been used previously to examine medical comorbidities in patients with bipolar disorder.29 Patients were identified as having NALFD if they had at least one hospital claim or two ambulatory claims for the ICD-9-CM codes listed in Table 1 and had a diagnosis of diabetes (the ICD-9-CM codes 250.xx), obesity (278.0), hyperlipidemia (272.0, 272.1, 272.2, 272.3, and 272.4), or hypertension (401.xx–405.xx). NAFLD patient selection also required the absence of specific ICD-9-CM codes in their claim history, including 571.0, 571.1, 571.2, 571.3, 573.1, 070, and V02.6. Ascertaining diagnosis of NAFLD generally is to rule out co-existent or alternate liver diseases and to evaluate the presence of metabolic syndrome and insulin resistance in patients.21 Determination of specific ICD-9-CM codes was based on hepatologist consultation and published literature.34 Absence of clinical details in the claims forms and different coding practice in different clinics may have compromised classification of specific types of liver diseases from these claims. The authors of this study intended to focus on the overall liver diseases as the primary outcome of interest.

 

 

Comorbid Conditions
The four study cohorts were evaluated for comorbid conditions (January 1, 2002–December 2003), which included hypertension (ICD-9-CM codes 401.xx–405.xx), hyperlipidemia (272.0, 272.1, 272.2, 272.3, and 272.4), diabetes (250.xx), obesity (278.0), human immunodeficiency virus (HIV) infection (042, 795.71, and V08), and substance abuse (291.xx, 292.xx, 303.xx–304.xx, and 305.xx).

Percentage of Patients with Treated Liver Diseases
The percentage of patients with treated liver diseases for 2004–2005 were computed using the number of new and existing liver disease cases divided by the total number of individuals in the schizophrenia, bipolar disorder, and comparison (individuals without mental illness) groups.

Direct Standardization
The adjusted percentages of patients with treated liver diseases were computed using direct standardization to account for the differences in age, gender, and race between the schizophrenia (or bipolar disorder) and the comparison without mental illness groups. The adjusted percentages were computed for the comparison group based on the age, gender, and race distribution of the schizophrenia (or bipolar disorder) cohort. The detailed formula for the computation is displayed in Table 2. For illustration purpose, only the age group between 36 and 50 is included in Table 2.

 

 

 

Sub-Analysis on Schizoaffective Disorder

The study authors also performed a subgroup analysis to evaluate demographic characteristics and outcomes of interest for schizoaffective disorder patients with schizophrenia-spectrum illnesses (ICD-9-CM codes 295.7x). 

 

Statistical Methods

Statistical analyses were performed using Statistical Analysis System (version 9.1.3). Standard descriptive statistics summarized the data in the schizophrenia, bipolar disorder, schizoaffective disorder with schizophrenia-spectrum illnesses, and comparison groups. The mean, median, standard deviation, minimum, and maximum were provided for continuous variables. Frequency distributions were provided for categorical variables, including gender, race, and comobid conditions. The differences in the categorical variables between the schizophrenia (bipolar disorder or schizoaffective disorder with schizophrenia-spectrum illnesses) and the comparison groups were assessed using a Chi-square test for independent samples. The differences in the continuous variables were assessed using a t-test. A two-sided 5% significance level was used for all tests.

 

Results

Baseline Characteristics

Patients with schizophrenia were identified (n=5,211; n=20,844 comparison group without mental illness). Baseline characteristics (Table 3) indicated that age distribution was similar between the two groups as expected using frequency matching. There was a higher proportion of male patients in the schizophrenia group compared to the comparison group without mental illness. By race, black patients represented the highest proportion of patients in the schizophrenia cohort as compared to the comparison group.

 

For comorbid conditions, 19.2% of schizophrenia patients had substance abuse. Patients with schizophrenia were more likely to have HIV infection, hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness.

The mean age of patients with bipolar disorder was 33.0. By race, white patients represented the highest proportion of patients in the bipolar cohort as compared to the comparison group without mental illness. Approximately 29.3% of patients with bipolar disorder had substance abuse, and patients with bipolar disorder were more likely to have HIV infection, hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness.

 

Treated Liver Diseases

The percentage of patients with treated liver diseases in patients with schizophrenia were statistically significantly higher than the comparison group after standardizing the age, gender, and race distribution of the two groups (in schizophrenia versus comparison without mental illness, overall liver diseases was 4.64% versus 4.14%, P<.0001) (Table 4). The majority (80%) of these cases were coded using the liver disease-related ICD-9-CM codes other than abnormal liver function test (ICD-9-CM codes 790.4 and 794.8). Schizophrenia patients also had higher percentages of various liver diseases, except for NAFLD.

 

 

The differences in the percentages of patients with treated liver diseases were even greater between patients with bipolar disorder and the comparison group without mental illness after standardizing the age, gender, and race distribution of the two groups. In bipolar disorder versus comparison without mental illness, the percentage of overall liver diseases was 6.96% versus 2.66%, P<.0001; acute liver disease was 5.47% versus 2.00%, P<.0001; chronic liver disease was 6.94% versus 2.66%, P<.0001; viral hepatitis was 2.99% versus 0.73%, P<.0001; chronic cirrhosis was 2.09% versus 0.84%, P<.0001; and NAFLD was 1.89% versus 1.05%, P<.0001.

For various subgroup analyses, the percentage of patients with treated liver diseases were higher in females than males (eg, bipolar disorder, male [4.53%] versus female [8.21%], P<.0001). “Other” race had the highest prevalence of overall liver diseases, followed by white, then black (eg, bipolar disorder, white [7.59%] versus black [4.33%] versus “other” [8.67%], P=.0007). The group 31–50 years of age had the highest percentage of patients with treated liver diseases (eg, bipolar disorder, age <30 [2.97%] versus 31–50 years of age [10.76%], versus >50 [7.38%], P<.0001).

 

Schizoaffective Disorder Group

A total of 2,056 schizoaffective disorder patients with schizophrenia-spectrum illnesses were identified, along with 8,224 subjects in the comparison group without mental illness. The mean age was 42.1 years in these patients and a higher percentage of male patients in the schizoaffective disorder group were observed. In the schizoaffective versus comparison group, the male percentage was 42.7% versus 25.3%. Approximately 19% of schizoaffective disorder patients with schizophrenia-spectrum illnesses had substance abuse, and these patients were more likely to have hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness. In the schizoaffective versus comparison without mental illness, hypertension was 35.5% versus 32.8%, P=.0214; diabetes was 20.5% versus 18.6%, P=.0515; hyperlipidemia was 17.7% versus 15.4%, P=.0141; and obesity was 8.6% versus 6.0%, P<.0001.

Schizoaffective disorder patients with schizophrenia-spectrum illnesses had higher percentages of patients with various treated liver diseases, except for NAFLD, compared to the comparison group without mental illness after standardizing the age, gender, and race distribution of the two groups. In the schizoaffective versus comparison without mental illness, overall liver disease was 4.62% versus 4.12%, P<.0001; acute liver disease was 3.84% versus 3.37%, P<.0001; chronic liver disease was 4.57% versus 4.11%, P<.0001; viral hepatitis was 1.70% versus 1.27%, P<.0001; chronic cirrhosis was 1.12% versus 1.06%, P<.0001; and NAFLD was 1.31% versus 1.55%, P<.0001.

 

Discussion

In this study, claims data from the South Carolina State Medicaid program were used to evaluate the percentages of patients with treated liver diseases in Medicaid recipients with the diagnosis of schizophrenia (including schizoaffective disorder patients with schizophrenia-spectrum illnesses) or bipolar disorder as compared to those without diagnosis of mental illness. Results indicate that 4.64% of patients with schizophrenia and 6.96% with bipolar disorder had a diagnosis of liver disease, which is statistically significantly higher than Medicaid recipients without mental illness. Although the absolute difference in the prevalence rates observed between Medicaid recipients with schizophrenia and Medicaid recipients without mental illness is small, bias may be introduced when using Medicaid recipients without mental illness as the comparison group. The percentages of patients with treated liver diseases observed in Medicaid recipients with schizophrenia or bipolar disorder are approximately three to five times higher than the 1.3% reported prevalence of liver disease in the general population (National Health Interview Survey)35 and are more than 10 times higher than the 0.2% reported in the non-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,36 disorder control group in a study by Carney and Jones.29 The percentages of patients with treated liver diseases found in this study are slightly <7.4%, as reported from a claim-based study which evaluated comorbid conditions among patients with schizophrenia in the Veterans Health Administration database.30

The authors of this study also found that the differences in the percentages of patients with treated liver diseases between the disease group and the comparison group without mental illness were larger for patients with bipolar disorder than those with schizophrenia. Higher percentages of patients with substance abuse and viral hepatitis observed in patients with bipolar disorder may account for this finding. The percentages of patients with NAFLD were also higher in the bipolar disorder group than the comparison group. Most patients with NAFLD are female and obesity is present in >50% of these patients.21 The bipolar cohort reflected higher percentages of female patients and obesity and may partially explain the observation.

The percentages of patients with treated liver diseases found in the two different samples of the comparison groups without mental illness were different (eg, the adjusted percentages of patients with treated liver diseases were 4.14% versus 2.66%). Since the percentages in the comparison groups were adjusted based on the demographic distribution of the disease groups, the differences observed are likely related to the differences in demographic distribution of these two samples.

It is surprising that the percentages of patients with substance abuse in schizophrenia patients (19.2%) and bipolar disorder patients (29.3%) was much lower than those reported in the literature.13  However, substance abuse is often underreported and underdiagnosed and may not be fully represented in claims data since treatment may be bundled and not readily recognized in the claims history.

The authors of this study found a higher proportion of male and black patients in the schizophrenia group, and a higher proportion of female and white patients in the bipolar disorder group. Some evidence suggests that clinicians may have a tendency to overdiagnose schizophrenia in some ethnic groups.36 It is unknown whether the differences in the diagnosis of schizophrenia and bipolar disorder observed in our study represent true differences among gender and race groups or if it results from clinician bias or cultural insensitivity. In addition, since the Medicaid population has a higher proportion of minority groups compared to the general population, the differences observed among gender and race groups in this study may be larger than other studies due to overrepresentation of minority population.

The true prevalence of liver diseases may be higher due to failure of asymptomatic cases to present for care. For example, HBV and HCV do not have subjective symptoms in most instances and many people may be unaware that they are infected with HBV and HCV.37 Cases with symptoms may be under-recognized because common complaints are often nonspecific (eg, fatigue, muscle ache, headache, abdominal discomfort).38 Seroprevalence rates of HBV and HCV have been reported16 and the prevalence of HBV (23.4%) and HCV (19.6%) found in that study was nearly 10 times higher than those observed in this study.

The findings of this research may have important implications for the management of mentally ill patients. Clinicians should consider hepatic issues when treating patients with mental illness who are at higher risk for liver disease. In addition to addressing treatment issues such as psychotic symptoms, clinicians could better serve their patients by evaluating and monitoring risk factors and clinical indications of liver disease. Clinicians should be aware that hepatic disease may impair the liver’s synthetic function, resulting in alterations in the protein binding and the bioactivity of various treatments. Further, when severe, hepatic compromise may also affect drug metabolism. As a result, dose adjustment of most antipsychotics is often necessary in these patients. Liver diseases may reduce antipsychotic treatment options for these patients and clinical consideration of medications that place a lower metabolic burden on the liver may present a viable treatment option for some patients.

This study has some limitations. Claims database are not well suited to address epidemiology questions, and the true prevalence rate of liver diseases was not evaluated in the study. Medicaid data are confounded by people moving in and out of the system who may not be fully captured. In addition, some individuals at high risk for medical comorbidities, such as those who are homeless, may not have acquired Medicaid coverage. Further, the findings of this study were based on data from the South Carolina State Medicaid program and may not be generalizable. Similar studies in different populations or study settings would be useful to provide context for these findings. Because the data were collected for reimbursement rather than clinical purposes, it is possible that some diseases experienced by the members may be misclassified or omitted from the database. The authors’ strategy of using at least one hospital claim or two ambulatory claims for liver disease-related ICD-9-CM codes to identify study participants was aimed toward minimizing misclassification of liver conditions. Finally, claims databases generally lack clinical details, and the classification of various types of liver diseases may not be accurate.

 

Conclusion

In this study, Medicaid recipients with schizophrenia or bipolar disorder showed higher percentages of treated liver diseases than non-mentally ill Medicaid recipients, and the percentages observed were also higher than the prevalence rate reported for the general population. The differences in the percentages of patients with treated liver diseases between the disease group and the comparison group without mental illness were larger for patients with bipolar disorder than with schizophrenia. The true prevalence of liver diseases may be higher than that observed due to failure of asymptomatic cases to present for care. Clinicians should consider hepatic issues when treating patients with mental illness who are at higher risk for liver disease. PP

 

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28. ICD-9-CM: International Classification of Diseases. 9th Rev, Clinical Modification, 6th ed (CD-ROM). Baltimore, Maryland: Centers for Medicare and Medicaid Services; 2005.
29. Carney CP, Jones LE. Medical comorbidities in women and men with bipolar disorders: a population-based controlled study. Psychosom Med. 2006;68(5):684-691.
30. Kilbourne AM, Cornelius JR, Han X, et al. General-medical conditions in older patients with serious mental illness. Am J Geriatr Psychiatry. 2005;13(3):250-254.
31. Guo JJ, Keck PE Jr, Corey-Lisle PK, et al. Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, population-based, case-control study. J Clin Psychiatry. 2006;67(7):1055-1061.
32. Weiden PJ, Kozma C, Grogg A, Locklear J. Partial compliance and risk of rehospitalization among California Medicaid Patients with schizophrenia. Psychiatr Serv. 2004;55(8):886-891.
33. US Food and Drug Administration. The National Drug Code Directory. Available at: www.fda.gov/cder/ndc. Accessed September 12, 2007.
34. Chan KA, Truman A, Gurwitz JH, et al. A cohort study of the incidence of serious acute liver injury in diabetic patients treated with hypoglycemic agents. Arch Intern Med. 2003;163(6):782-734.
35. Centers for Disease Control and Prevention. National Center for Health Statistics. Summary Health Statistics for US Adults: National Health Interview Survey, 2004. Vital and Health Statistics. May 2006; series 10, number 228.
36. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatic Association; 1994.
37. Iino S. Natural history of hepatitis B and C virus infections. Oncology. 2002;62(suppl 1):18-23.
38. Ware JE, Bayliss MS, Mannocchia M, Davis GL. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. The Interventional Therapy Group. Hepatology. 1999;30(2):550-555.

 

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

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Medicinova, Ono Pharmaceuticals, Pfizer, and Somerset.

 


 

The introduction of several new atypical antipsychotics over the past decade poses uncertainties about what constitutes optimal drug therapy for an individual patient, both in choosing initial drug therapy and ongoing management. The advent of the second-generation antipsychotics (SGAs) bred a new category of drugs with some advantages over traditional agents, although the extent of superiority in efficacy and tolerability over first-generation antipsychotics (FGAs) remains unclear. SGAs are a pharmacologically heterogeneous group of drugs with differing liabilities, depending on the agent. Two recent monographs review the pharmacology and therapeutics of the antipsychotics and summarize available data to provide the most current information to guide clinical practice.1,2

Therapeutic indications for antipsychotics include short-term management of acute psychoses and agitated states as well as long-term treatment of chronic psychotic disorders such as schizophrenia and delusional disorders. SGAs have largely replaced FGAs in clinical practice, although the limited data from comparative trials do not show SGAs to be clearly superior. Purported therapeutic advantages of SGAs, which vary depending on the specific agent, appear relatively modest compared with traditional antipsychotics employed in moderate dosage and with adjunctive antiparkinson medication, if needed.1,3,4 As noted in a recent editorial,5 emerging data on SGAs make it apparent that the significant side-effect burden of antipsychotic drug therapy has shifted, not disappeared. 

 

Mechanism of Action of Antipsychotics

Although antipsychotics emerged in the 1950s with the introduction of chlorpromazine (the result of a serendipitous discovery), the principal mechanism of action of antipsychotics remained unclear for nearly a decade thereafter. In a milestone publication reviewing pharmacologic evidence elucidating the neuropathology of schizophrenia, Matthysse6 pointed out that dopamine agonists precipitate or worsen psychosis while dopamine antagonists (eg, antipsychotics) effectively treat chronic psychosis and mania. In ensuing years, the focus of drug discovery centered on dopamine-receptor antagonists, primarily dopamine (D)2-receptor blockers. Potent antidopaminergic drugs, while highly effective, also carried a significant risk of extrapyramidal symptoms (EPS) and tardive dyskinesia.

A major advance in understanding the pharmacology of antipsychotics derives from a clinical trial involving clozapine, the first of the SGAs.7 This trial compared clozapine and chlorpromazine in schizophrenic patients who failed a prior course of high-dose haloperidol and found clozapine superior to chlorpromazine, while devoid of the adverse neurologic effects of other antipsychotics.7 Clozapine was labeled “atypical” because it combined superior efficacy with low risk of EPS. This term subsequently was applied broadly (and uncritically) to all of the SGAs despite having significant pharmacologic heterogeneity—chemically, pharmacologically, and clinically.1

 

Neuropharmacology of Antipsychotics

The weight of the evidence indicates that dopamine-receptor blockade is essential to clinical antipsychotic activity, especially for controlling hallucinations and delusions, but emerging data suggest this may not be the only mechanism of action. Despite the advances in cloning neuroreceptor subtypes and defining specific receptor-binding characteristics of individual antipsychotics, a unifying theory of the mechanism of action of antipsychotics has not emerged. The ideal pharmacologic profile for an antipsychotic remains an unanswered question.1

Given its low propensity for EPS and unexcelled clinical efficacy, the pharmacologic profile of clozapine became the subject of intense scrutiny in designing new antipsychotics. The pharmacology of clozapine is especially complex; it binds loosely (and transiently) to D2 receptors as well as other dopamine receptor subtypes, and also binds with high affinity to histamine (H1), acetylcholine muscarinic (M1), α-adrenergic (α1), and multiple serotonin (5-HT2A, 5-HT2C, 5-HT7) receptors. This complexity leaves the minimal EPS risk and unexcelled antipsychotic effectiveness of clozapine unexplained.1 However, emerging data suggest that significant binding to 5-HT2A receptors in addition to D2 receptors confers lower risk of EPS.

The receptor-binding profiles of the atypical antipsychotics exhibit significant differences amongst the SGAs. Understanding and appreciating these distinctions can guide in selecting pharmacotherapy for the individual patient, a task that can be daunting. Clinicians are confronted with many options that span drug choice, dose optimization, adjunctive and augmentation therapy, and the decision to switch drugs. Given unclear evidence of therapeutic superiority of SGAs3-5 and their heterogeneous pharmacology, a panel of psychopharmacologists recently convened to address unresolved therapeutic issues and to offer guidance in clinical decision making.2 One factor deemed important by the panel was acquiring a thorough understanding of the differing pharmacologic profiles of the SGAs.

 

Receptor Affinities and Choice of Antipsychotic Drug

While comparative trials, if available, are useful in choosing pharmacotherapy, the panel stressed that knowledge of the pharmacodynamic profiles of the SGAs is helpful, given the modest differences in antipsychotic efficacy but clear-cut safety differences. The pharmacodynamic effects of an antipsychotic are dictated by its receptor-binding properties, both with respect to efficacy and adverse effects. While traditional antipsychotics bind principally and most avidly to D2 receptors, SGAs exhibit high affinities for other receptors equal to or exceeding that for the D2 receptor.

SGAs can be grouped according to patterns of receptor affinities and dissociation. For example, clozapine, olanzapine, and ziprasidone have higher affinity for 5-HT2A receptors relative to D2 receptors, a binding profile differing somewhat from other SGAs.1 Positron emission tomography (PET) studies show that the SGAs clozapine, olanzapine, quetiapine, and ziprasidone (but not aripiprazole and risperidone) have moderate affinity and low avidity (ie, rapid dissociation) for D2 receptors in the basal ganglia, a pattern consistent with low EPS liability. The anticholinergic effects of clozapine and olanzapine also may limit risk of EPS and avoid a need to add an antimuscarinic antiparkinson agent, as often required with conventional antipsychotics to rebalance critical dopamine-cholinergic functions in the basal ganglia.1 Clozapine and olanzapine (which resembles clozapine structurally and pharmacologically) have high affinities relative to the D2 receptor for M1, H1, 5-HT2C, and 5-HT2A receptors, in that order respectively. This profile of receptor interactions informs about both the therapeutic and side-effect profiles of these two SGAs, eg, well-established antipsychotic efficacy with minimal risk of EPS and significant liability for excessive weight gain and sedation (Table).2

 

 

Quetiapine exhibits high affinities relative to the D2 receptor for H1 and α1-adrenergic receptors, reflecting a propensity for causing sedation and postural symptoms. Risperidone binds significantly to 5-HT2A, α1, and D2 receptors, and may have a somewhat higher propensity for EPS than other SGAs. Ziprasidone, like risperidone, has high affinity for the 5-HT2A receptor relative to D2 receptors but differs from risperidone by binding to multiple dopamine-receptor subtypes as well as to 5-HT2C and 5-HT1A receptors.

 

Drugs Acting as Partial Agonists

Binding of a drug to a receptor can theoretically result in either an agonist or antagonist action, or in “partial agonism,” as discussed in a previous column.8 A drug acting as an antagonist blocks receptor activation and takes a receptor “out of play,” while an agonist functions like an endogenous neurotransmitter to fully activate a receptor.2 A partial agonist exhibits affinity for a receptor but lacks the full effect of the endogenous neurotransmitter. It competes with the natural transmitter and thereby produces an attenuated response. Aripiprazole has high-binding affinity for D2 receptors (as well as 5-HT1A and 5-HT2A receptors) and PET studies demonstrate high occupancy of D2 receptors (>90%) at therapeutic doses. However, its pharmacologic action as a partial agonist attenuates full response and diminishes receptor activation by the endogenous neurotransmitter dopamine.

Ziprasidone exhibits high affinity for 5-HT1A receptors where it functions as a partial agonist. In addition, it binds with moderate affinity to the serotonin transporter in brain tissues. It is postulated that these pharmacologic properties potentially convey efficacy of ziprasidone in anxiety and depressive states in addition to psychosis.1

 

Polypharmacy

On combining drugs or switching antipsychotic therapy, the additive receptor-binding properties of two concurrent SGAs should be considered. In general, D2-receptor blockade of ≥50% is needed for antipsychotic efficacy, while the threshold for risk of EPS is considered to be ≥80% occupancy (aripiprazole is an exception because it possesses high affinity for D2 receptors but acts as a partial dopamine agonist). Combined use of antipsychotics may have a greater propensity for side effects than either drug alone, depending on similar receptor-binding properties (Table).2

Another pharmacologic consideration is the fact that the brain adapts to psychotropic medications through a series of compensatory mechanisms, eg, upregulation of receptors in response to a drug acting as an antagonist, and downregulation of receptors in response to treatment with an agonist drug.2 The possibility of pharmacologic adaptation needs to be considered when switching drugs, since withdrawal effects may ensue from the withdrawn drug but be mistakenly attributed to the new medication. For example, abrupt discontinuation of a sedative SGA on switching to aripiprazole or ziprasidone, which do not block histamine receptors, may cause transient “activation” due to a pharmacologic withdrawal syndrome. As another example, on switching from an antipsychotic with potent muscarinic anticholinergic properties (M1 antagonist) to one with little anticholinergic activity, abrupt discontinuation may cause transient “cholinergic rebound.” This may be erroneously attributed to the new antipsychotic rather than to withdrawal of the prior drug, and lead to premature changes in therapy or drug dose.

 

Conclusion

SGAs do not differ substantially in efficacy from traditional antipsychotics but have differing side-effect burdens. Because of the pharmacologic heterogeneity of this group of drugs, an understanding of the specific receptor-binding properties of each antipsychotic can be helpful in selecting appropriate drug therapy for the individual patient. PP

 

References

1. Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical review. CMAJ. 2005;172(13):1703-1711.
2. Weiden PJ, Preskorn SH, Fahnestock PA, et al. Translating the psychopharmacology of antipsychotics to individualized treatment of severe mental illness: a roadmap. J Clin Psychiatry. 2007;68(suppl 7):6-46.
3. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness if antipsychotic drugs in patients with chronic schizophrenia. N Eng J Med. 2005;353(12):1209-1233.
4. Rosenheck RA, Leslie DL, Sindelar J, et al. Cost-effectiveness of second generation antipsychotics and perphenazine in a randomized trial of treatment of chronic schizophrenia. Am J Psychiatry. 2006;163(12):2080-2095.
5. Freedman R, Carpenter WT, Davis JM, Goldman HH, Tamminga CA, Thomas M. The cost of drugs for schizophrenia. Am J Psychiatry. 2006;163(12):2029-2031.
6. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc. 1973;32(2):200-205.
7. Kane J, Honigfeld G, Singer J, Meltzer HY. Clozapine for the treatment resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796.
8. Robinson DS. CNS receptor partial agonists: a new approach to drug discovery. Primary Psychiatry. 2007;14(8):22-24.

 

Dr. Smith is clinical assistant professor in the Department of Psychiatry at New York University School of Medicine in New York City.

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

Please direct all correspondence to: Matthew B. Smith, MD, Clinical Assistant Professor, Department of Psychiatry, New York University Medical Center, 333 E 34th St, Ste 1N, New York, NY 10016; Tel: 212-213-8104; Fax: 212-213-7805; E-mail: matthewbsmithmd@earthlink.net.

 


 

 

Abstract

Chronic pain involves a somatic basis that is distinct from that of acute pain. It differs in its subjective experience and involves behavioral, personality, and syndromal pathologies which serve to worsen function and quality of life. Prior psychopathology makes an important contribution. The final state is one of both somatic and psychic suffering such that the two are not phenomenologically or etiologically distinguishable. Assessment and treatment must deal with the psychopathology as well as the physical pathology.

 

Introduction

The lifetime prevalence of chronic pain is >20%. In addition to reduced quality of life, the morbidity of chronic pain includes further physical problems, vocational disability, and economic burden.1 Chronic pain syndromes are commonly seen as challenging and refractory. Patients and professionals view them either as physical phenomena, at times with consequent psychiatric comorbidity, or as primary psychiatric disorders of somatization, addiction, or malingering, with a minimal physical basis. Such views are commonly based on a simple extrapolation of models or experience of acute pain. However, this is a limited formulation of the syndrome, particularly with respect to the complexity of mind and body interaction, minimizing the extraordinary subjective experience and the intrinsic psychopathology of the patient in chronic physical pain. It is one reason for the modest treatment results commonly obtained in chronic pain syndromes. An examination of the nature of chronic pain; its subjective experience2; and its biologic, psychological, and psychiatric features may articulate the basis for the claim that chronic pain is a syndrome of both physical pathology and psychopathology, ultimately a unitary one requiring integrated treatment of both elements.

 

Psychiatry and Chronic Pain

Psychiatry sheds considerable light on chronic pain syndromes, offers critical help in directly or indirectly modulating pain, and gives useful input in patient management. It plays a necessary role in chronic pain management.3

By definition, psychiatry treats psychopathology. The term “pathology” applies when the associated psychological state itself becomes problematic, additionally contributing to reduced function, quality of life, or worsened pain, irrespective of whether that state is “understandable.” One might consider that chronic pain induces psychopathology, or that psychopathology induces or at least contributes to chronic pain. However, the connection is more intimate.

Consider that pain involves a physical process with an associated unpleasant subjective experience. Chronic pain, above and beyond this, rises to the level of an illness unto itself, encompassing more than the original underlying physical pathology. Indeed, chronic pain syndromes can be seen as a pathology of pain itself, necessarily implying a pathology in subjective experience. If this is so, it can be asserted that chronic pain is not merely associated with psychopathology but that it actually is psychopathology in addition to being physical pathology. This may become more evident after considering the differences of chronic pain compared to acute pain and, heuristically, its psychological consequences and antecedents.

 

Chronic Pain Syndromes

Chronic pain can involve virtually any system or anatomical site. However, common chronic pain syndromes which tend to exemplify the matters discussed in this article include chronic back pain; chronic headaches; chronic facial pain, including temporo-mandibular joint syndromes; chronic pelvic, urinary, and genital pain syndromes; chronic rheumatologic syndromes, including fibromyalgia; chronic gastrointestinal pain syndromes; neuropathic pain syndromes, including reflex sympathetic dystrophy; and chronic regional pain syndromes.

 

Acute Versus Chronic Pain

Besides the matter of time course, chronic pain is distinguished from acute pain by a relative refractoriness to treatment. However, additional, notable distinctions may be surprising to those not experienced with this syndrome.

 

Biological Aspects

The biology of chronic pain differs from that of acute pain. Acute pain involves classic peripheral nociceptors, well-defined afferent pathways, and discretely localizable central nervous system (CNS) representation. One conceptualizes a precise “pain generator.” Higher CNS levels are involved, including limbic and cortical structures, assigning emotional valence and intensity as well as personal and cultural meanings.

Nociception in chronic pain, however, is far less significant. Chronic pain is often referred to as central, neuropathic, deafferentation, or sympathetic pain, depending on its particular characteristics. Chronic sympathetic activation may induce relative muscle ischemia4 and may indirectly sensitize peripheral nociceptors, resulting in a vicious circle. Additional distinctions include involvement of wide dynamic receptors; long-term potentiation of nociceptive fiber synapses,5 with central sensitization; involvement of other ascending pathways, including the spino-thalamic, spino-hypothalamic, spino-reticular, and spino-amygdala tracts; and involvement of descending, serotonin-mediated tracts from the cortex, hypothalamus, periaqueductal grey, raphe nucleus, and locus ceruleus.6,7 Additional neurotransmitters involved include substance P and corticotropin-releasing factor. Cortico-limbic pathways and central representation are more prominent. Hypophyseal-pituitary axis (HPA) changes are present. There is no longer a discrete pain generator, but rather a complex process usually involving multiple systems, a “pain matrix,” such that chronic pain is considered an illness unto itself.

Valuable models have been developed to characterize the complex CNS changes in ascending, descending, and lateral influences. Mention might be made of Melzack’s spinal gate theory and his later neuromatrix model,8 cortical “reorganization theories,9,10 and recent findings of grey matter changes in chronic pain patients.11,12

 

Clinical Presentation

Symptoms in chronic pain differ from those in acute pain. The process of primary hyperalgesia reflects a change in the response characteristics of the nerve terminals in the periphery. The process of secondary hyperalgesia reflects the expression of a state of central sensitization. Strict anatomic localization of pain is lost, and typically the pain locus is much broader. Additional pain symptoms such as allodynia, hyperalgesia, and spontaneous autonomic phenomena are present. Pain suddenly worsens or lessens with only limited apparent connection to activity, sleep, time of day, barometric pressure, emotion, diet, or even exercise and medication. Chronic pain is relatively refractory to analgesics, including opiates, and at times it is absolutely refractory. Common patient experiences include overt agony, anger, hopelessness, neediness, stoicism, self-hate, denial, and addiction.

 

Psychological Aspects

The extreme presentation of such patients reflects the fundamental psychological impossibility of chronic pain. Usual definitions of pain involve reference to an uncomfortable or unpleasant sensation. However, they tend to overlook additional integral components of pain such as fear and a motivational pressure to eliminate or reduce pain. Thus, unlike some other uncomfortable sensations such as paresthesias or nausea, one cannot experience pain without simultaneously experiencing fear and an impulse to act to reduce pain. It is not just that one experiences hurt, but that the experience is frightening and intolerable. This is intrinsic to the experience of pain and is manifestly adaptive. However, the patient with chronic pain is faced with the need to find some means to accommodate to, tolerate, and accept that which is intrinsically pressuring him to not accept. The patient must oppose himself. He must determine that the next day will bring more pain, fear, and impulsion, when nothing can be done.

Although the signal denotes danger, it is a mistake. The alarm now sounds without associated danger and, for many patients, apparently at random. With respect to psychopathology, the difficulty of a patient to reassign a meaning to such pain must be considered.

Chronic pain becomes an experience for the patient that is more than strictly “somatic.” Body image is influenced such that the hurting part, as an object of constant focus and management, becomes more prominent but more negatively valenced. This includes the further involvement of CNS structures related to emotion and motivation; of related psychological constructs such as “self,” self-esteem, object relations, and interpersonal function; and of secondary reactions to broader system disruptions in conjugal and family relations, occupation, and avocation. In chronic pain, it becomes difficult to strictly distinguish between psyche and soma.

Successful management of chronic pain on the part of the patient, implying some measure of accommodation, is certainly achievable; however, it requires psychological resources beyond the usual demands of experience. Professional help is usually required. Personal resources such as resilience, “ego strength,” coping skills, and “emotional IQ,” are insufficient to meet the demands of the chronic pain dilemma, since it is fundamentally impossible. The result is reduced psychological adaptiveness.

A useful conceptualization of chronic pain for a psychiatrist is that it involves physical agony and functional disruption without function or meaning, with an indefinite future, and with limited controllability. A patient must seek to incorporate these factors into his or her “being.” Meaning is applied to this by the patient, reflective of the person and the state. Pre-existing psychological maladjustment, when present, is magnified.While psychopathology can certainly accompany acute pain, it is not as problematic since acute pain is limited in time and tends to be more responsive to control efforts, including analgesia.

Psychopathology in chronic pain can involve regression in usual personality features (“coping styles”); however, it can also involve associated, additional psychopathologic syndromes, which become incorporated into the global patient experience and presentation. Thus, chronic pain patients often present as overtly psychiatrically disturbed, leading to numerous differential diagnostic, management, and countertransferential problems.

Grasping the psychopathology of chronic pain calls for an effort on the part of the clinician since such suffering is beyond the experience of most of us. While psychiatrists are used to this phenomenon, in the case of chronic pain there is an additional, physical dimension. Psychopathology, in this instance, is importantly elucidated by the classic clinical models of psychiatry, especially the biological model but additionally by models which can more precisely articulate aspects of the inner life of the patient.

 

Psychiatric Comorbidity

 That chronic pain syndromes involve considerable psychiatric comorbidity is well established. Depression, especially, is prominent among chronic pain patients. However, additional frequently cited comorbidities include anxiety, somatoform, personality, and addictive disorders.

To use the term “pathology” is to suggest that psychologically based patterns are present and are maladaptive. In the case of chronic pain, this implies that such patterns contribute to the disruption in quality of life and function of the patient above and beyond the hypothetical simple experience of physical pain. Such patterns actually tend to contribute to a worsened overall subjective experience of pain.

Psychopathology in chronic pain can be conceptualized somewhat arbitrarily as secondary, primary, or incidentally comorbid. Secondary psychopathology is that which is induced by the experience of continued or frequently recurrent physical pain. Primary psychopathology is that which antedated the physical basis for the chronic pain and was potentially etiologically contributory to the syndrome. Incidentally, comorbid psychopathology is understood as that which is not causal either primarily or secondarily, but which has contributed to the overall disruption in function and quality of life.

This conceptualization of pain and psychopathology must be understood as heuristic, since pain is both physical and psychological, and chronic pain is both physically and psychologically pathologic.

 

Secondary Psychopathology

Psychopathology related to chronic pain manifests as “pain behaviors, personality change, and syndromal disorders.

 

“Pain Behaviors”

Common behaviors in chronic pain include numerous actions and activities that express suffering or strive to protect the patient. While they are “natural” concomitants of pain and adaptive in acute pain, they are problematic in chronic pain. They direct time, effort, and attention of the patient and others to pain, and overtly restrict other behaviors. They contribute to the preeminence of the pain experience in the patient’s life, amplifying its effects. They include guarding, wincing, various vocalizations such as moaning, rubbing, activity restriction, and lack of considered “pacing” in activities. In chronic pain, they contribute to the maintenance and progressive worsening of the dysfunctional state.

“Pain anxiety” is often mentioned in this context.13-19 Daily life of the patient consists of fearing the exacerbation of pain. The patient develops a vigilance for and hyperfocus on somatic sensation, “sensation, with an indiosyncratically rationalized warning system that indicates that pain worsening is imminent. The warnings may be associated with activities, times of day, diet, locations, and temperatures. There may be an accurate basis in the patient’s experience, and the intensity and frequency of exacerbations is certainly a factor in the severity of pain anxiety. However, the patient is unrealistically afraid. Typically, the warnings are overly restrictive, this resulting in activity limitation. Such anxiety can be considered phobic. The direct physiologic effects of the anxiety may worsen the pain.20 Inactivity results in psychological losses of usual involvements as well as in worsening of physical status.21-24 Deconditioning and even disuse atrophy can ensue, further solidifying the condition.25,26

 

Personality Change

Medical conditions can alter personality.27 Among the common personality changes in chronic pain are the emotional effects.28

Anxiety is hard-wired to pain, irrespective of content.23,29-31 The majority of the literature supports the “fear-pain” connection. Beyond “pain anxiety,” however, it is often generalized. The patient preoccupied with pain and its direct attendant fears is likely to be less capable of managing additional stresses in his life, provoking further anxiety. Various disruptions or losses in the patient’s life also contribute.

Pain makes one angry.32 (Recall the overt irritability of many in chronic pain and the transient rage when one stubs one’s toe.) Again, one wonders if this may be hard-wired.33-36 The anger may be displaced onto those who are blamed for the pain, or others, with interpersonal consequences. It may also simply require further inner psychological measures on the part of the patient to manage or defend against it.

As in any illness, passivity longings are present and related partly to the experience of helplessness, with the wish for a nurturing soothing maternal presence.

Depressive features, short of a full depressive syndrome, are common.37 When bodily experiences or secondary emotional reactions are intense, they may be experienced with shame, or even as a threat to psychic integrity. Helplessness may lead to various struggles involving control.38,39 The patient may “surrender” and become passive; seek to coerce his personal choices on his body, irrespective of physical pain matters; or even try to “defy” the apparently arbitrary demands of his spontaneous pain. The patient may seek ancillary arenas of control in his or her life, becoming an imposition on others, keeping deliberately odd hours, or even additionally inflicting or worsening pain by seeking to turn passive into active.

There are additional common psychologically regressive personality reactions, depending on the vulnerabilities of the individual patient.

Chronic pain is commonly viewed by patients as an indication of a personal shortcoming or failure, with reduced self-esteem.40-42 It may subjectively reflect a sense of bodily defect, lack of self-discipline, or a repugnance to others. Reactions on the part of others to the patient may actually be negative (eg, some may view the patient as lacking strength or discipline), and this may additionally fuel a patient’s sense of personal failure. It is certainly common for a patient to view himself as having lost, or perhaps never having had a global mastery of himself and his life.

To many, pain means punishment43,44 and it is common for a patient to react like a punished child. Among the various possibilities are self-recriminations, restitutional behaviors, excessive efforts to try to be “good,” or reactions to a perceived unfair punishment or abuse.

Regression to primitive object relations is common.45,46 Object constancy involves the capacity to reliably evoke the experience of the soothing maternal object in the presence of stress. In the case of chronic pain, however, the pain intensifications are only partly predictable and not easily soothed. The patient’s self-soothing capacity is exceeded. There is a greater tendency to interact with others in accord with primitive object patterns. Self and others are experienced according to primitive all-good or all-bad patterns, with a common intensification of emotions of rage and despair. Consciously or not, pain tends to be associated with a malevolent object.

It is striking how stressful interpersonal relations become for the patient with chronic pain, independent of prior maladaptive patterns.47 While much of this results from the patient’s psychological changes and consequent interactional biases, much is also due to others’ responses to the patient. Members of the patient’s inner circle often do not grasp the subjective difficulty of chronic pain, and are intolerant or overly solicitous.48,49 To be fair, chronic pain syndromes are subjectively threatening to empathize with since they are so severe, are puzzling and refractory to treatment, and are associated with overt psychopathology. However, pain patients are burdened by prominent allegations of malingering, addiction, madness, dramatics, selfishness, and laziness. Such allegations can be imparted by distant acquaintances as well as close family members, important vocational contacts, and physicians. Others respond to the patient’s emotional and behavioral changes, including demands implicitly or explicitly placed on them. There can be numerous pathologic synergistic interactions between patient and spouse including, in the circumstance of chronic pain, those based on stable and caring relationships.50,51 There may be excessive concern or misplaced devotion. The patient, in turn, often reacts maladaptively.52

 

Syndromal Disorders

In addition to maladaptive personality reactions, the development of Axis I psychiatric syndromal disorders is common.

Depressive Disorders
Perhaps the most common disorder is depression.53-57 It is well established that there is a strong association between chronic pain syndromes and depression.58-66 Depressive features in chronic pain need to be assessed in the same manner as depressive features otherwise. That is to say, if the patient has mood, motivation, neurovegetative, cognitive, psychomotor, and other symptoms of depression, one should diagnose depression. It is important to avoid thinking that pain “explains” the symptoms, even when patients insist otherwise. “I am depressed, but it is only because I am in pain,” is a common refrain among patients, which tends to result in inadequate treatment efforts and prolonged suffering. While precise epidemiologic details are lacking, a strong association is well established. The prevalence and impact of depression in chronic pain syndromes, requiring specific therapeutic attention, cannot be overstated.

Bipolar Disorders
There is a paucity of data regarding the prevalence of bipolar disorder among patients with chronic pain. Among those with established depressive disorders, at least some have unrecognized bipolar syndromes. This is consistent with current views regarding the underrecognized prevalence of bipolar spectrum disorders.

The diagnosis of bipolar disorder in chronic pain is sometimes controversial. In accord with recent thinking regarding bipolar spectrum disorders, it is likely that bipolar disorder, (in a cycling, mixed, or depressed state) is more common in the chronic pain population than has been previously recognized.67 The patient with a classic manic syndrome or clear history of bipolar disorder is certainly obvious. However, it is likely that there are less classical presentations of bipolar disorder that are more difficult to diagnose. One needs to consider lability of mood and affect, unusual sleep and eating patterns, minor thought disorders, and unusual responses to certain pharmacologic agents, among others signs.

Anxiety Disorders
Although anxiety as a concomitant of chronic pain is much reported, full anxiety syndromes are more commonly reported with acute pain. Some studies have suggested that they are also common in chronic pain,68,69 especially generalized anxiety disorder,70  panic disorder,71 and social anxiety disorder,72 as well as, noteably, posttraumatic stress disorder (PTSD), to be discussed below. Little is reported concering other phobias and obsessive-compulsive disorder.

If a patient meets criteria for an anxiety disorder, it is important to avoid determining that it is not worthy of psychiatric attention since it is related to pain. Further, as with all psychopathology in chronic pain, treatment must be considered whether or not criteria are fully met, since by definition the psychopathology is maladaptive.

Addictive Disorders
The topic of addictive disorders in chronic pain is burdened by controversies regarding opiate prescriptions. It is useful to distinguish among the following terms.

Drug Seeking
Drug seeking is a generic term.

Physical Dependence
Clinicians, associated health professionals, family members, and patients, need to be reminded that physical dependence is not addiction. Physical dependence includes a propensity toward a physiologic withdrawal syndrome, and may also involve tachyphylaxis. However, addiction typically entails much more, including an initial euphorogenesis, preoccupation with obtaining the substance, craving, and use despite harmful consequence, with a complex neurobiologic underpinning involving the dopamine mediated reward system. Of note, the vast majority of chronic pain patients do not pose problems with respect to drug addiction, though some degree of physical dependence is frequent.

Pseudo-Addiction With a Chronic Pain Syndrome
Pseudo-addiction with a chronic pain syndrome is one basis for drug-seeking behavior.73,74 This refers to the patient in pain pressuring or manipulating for drugs, including addictive drugs, for the purpose of pain relief rather than for the purpose of gratifying an addictive need or craving. Commonly, such patients do not obtain adequate pain relief when they are prescribed the drugs they wish, since they lack the judgment to determine the proper treatment. Some misuse such drugs when prescribed. Although pseudo-addiction carries a risk of developing into a true addiction, an effort should be made to distinguish it from addiction, even if this is at times clinically difficult.75-78 Physicians must manage addictive drugs responsibly to insure that patients do not actually become addicted.79

Addiction With Associated Malingering for Narcotics
While malingering for narcotics can be a significant matter requiring vigilance, with responsible prescribing practices, a physician need not unduly limit this treatment option. A more prevalent concern is that of the patient requiring opiates who does not obtain them because of the physician’s unrealistic fear of enabling or inducing addiction. Malingering is not a frequent finding among chronic pain patients, but is certainly an important differential diagnostic concern.

Active Addiction, Past Addiction, or Addiction Potential With an Associated Chronic Pain Syndrome
Drug addiction is a common problem in our population, and offers no immunity to chronic pain.80,81 Consequently, patients with addictions or addiction tendencies are seen in this population. As with other syndromal disorders, chronic pain can trigger a relapse or a new disorder. While it is untenable to determine that potentially addictive medications are absolutely contraindicated among such patients, management can pose a significant challenge, requiring extra steps on the part of the treatment team and the patient.82-87

Psychotic Disorders
Psychotic disorders are uncommon in the established chronic pain population. It is unclear why this is the case. It has long been a matter of psychiatric lore that many psychotic patients are insensitive to pain.88-90 However, this awaits a better evidence basis. Some psychotic patients may simply be poor reporters of pain. Additionally, one might speculate that chronic pain functions as something of an antipsychotic (eg, that the physical experience of pain augments body boundaries or pressures the patient to look to concrete physical reality). When psychotic patients do present, there are associated delusions regarding the pain, delusions of influence, passivity, toxicity, or bizarre delusions. These should be distinguished from erroneous health or illness beliefs with a possible germ of truth, such as environmental or chemical toxicity or allergy, even when elaborated by psychopathology classified otherwise.

Diathesis Stress Model
The frequent secondary occurrence of psychiatric syndromal disorders in chronic pain syndromes is consistent with classic models regarding the pathogenesis of such disorders.91,92 In a diathesis stress model the stress in chronic pain is pain itself.

The tendency of chronic pain to function as a precipitant for a psychiatric syndromal disorder is proportional to a number of factors. These include the severity of the pain, the duration of the pain syndrome and of the daily exacerbations, the unpredictability of the exacerbations, and the degree of control that can be exercised over the pain. An additional consideration is the degree of stress given by the idiosyncratic meaning of the pain. Finally, there is the stress of the consequences of the pain, with reference to interpersonal and vocational losses and changes.

The “stimulus barrier” or screen93,94 denotes the psychological capacity to effectively organize and integrate stimuli according to importance and associated meaning. It includes not only the perceptual threshold of sensitivity but also the capacity to distinguish and disregard, or at least cope with, stimuli which have no immediate value, permitting relative psychological autonomy from stimuli that serve little significant purpose. The stress of such stimuli is, therefore, reduced. Pain, for example, if not serving a useful function, can be placed in its “box,” and managed, while the remainder of important life matters are attended to. However, this is precisely what tends not to happen in the case of chronic pain, which continues to sound its alarm often unpredictably and intensely. Chronic pain tends to breach the stimulus barrier.

“Trauma” as originally formulated, related to a breach of the stimulus barrier, refers to an inescapable stimulus that exceeds that psychological capacity of the person to manage it. It is an event that is overwhelming and that induces psychological maladaptation and regression. It requires psychological reorganization beyond existing coping skills, with new structures of self and other, as well as processing of losses.95 In the older sense, the term is not restricted to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)27 criterion of an event that involves actual or threatened death or serious injury, or a threat to the physical integrity of self or others. However, that criterion might apply in some chronic pain patients. The notion of trauma has been usefully extended to “cumulative” or “strain” trauma rather than one discrete event. This is not to suggest that chronic pain patients have  PTSD, though in numerous cases pain derives from an event-related injury that was also psychologically traumatic. However, it can be argued that the heuristically separated physical component of chronic pain itself tends to become traumatic in a broader sense.

From a biologic point of view, disruptions in the HPA, with cortisol hypersecretion, are a component of chronic pain. Chronic cortisol hypersecretion additionally psychologically destabilizes the person, resulting in maladaptive behavior and regression.96

 

Primary Psychopathology

Chronic pain is best understood as multifactorial in etiology. It is clear that psychiatric or psychological factors play at least some role, one possibly being a vulnerability to develop the full psychophysical syndrome if a physical pain condition develops.

 

Predispositions

Predisposing psychopathology entails a relative inability to adaptively cope with a pain condition, usually malignantly worsening it. It may be neurologically, neurochemically, psychologically, developmentally, interpersonally, or environmentally based, these matters not being mutually exclusive.

It is difficult to clearly and firmly establish a neurologic or neurochemical vulnerability; yet, it is difficult to avoid hypothesizing one. It is suggested by prior psychiatric states with associated biologic dysfunction, such as depression, bipolar disorder, and anxiety states. For example, since serotonergic pathways are involved in chronic pain, preexisting mood disorders may be a diathesis toward chronic pain. How this might actually develop, neurochemically, is unclear. Could such a pre-existing neurochemical dysfunction entail kindling, recruitment, or sensitization such that the central sensitization of pain is more easily set in motion? Neurologic bases should be considered with respect to temperament, and specifically with respect to autonomic overreactivity and underreactivity. Additionally, cognitive disorders, with their associated neurologic bases, should be considered since they pose a risk for chronic pain conditions.

What psychological configurations might establish a basis for a chronic pain syndrome? A patient with a relatively deficient stimulus barrier would tend to be impulsive, easily overwhelmed, and perhaps traumatized. From the deficit point of view, such an individual would be relatively deficient in object constancy; would be prone to experience difficult stimuli as extremely threatening, perhaps annihilating, experiencing his or her body as “fragile”; would experience profound unmet passivity needs with associated abandonment fears; and would have difficulty in managing anger and aggression.

An early history of trauma, in the broad sense, may be involved. This includes early loss, violence, sexual abuse, and emotional abuse—associations often cited in chronic pain literature.97-110 In such instances, the chronic pain itself assumes meanings connected to earlier trauma. In the case of past trauma of physical violence, a special vulnerability is present, since such episodes involve direct bodily pain. This is also true with respect to sexual trauma. Some such cases result in a latent component in body image which reflects the hurt or injured physical part, now laden with emotional significance and reactivity and incompletely integrated with the rest of the body image and the self. An adult pain syndrome includes a reactivation of the unmastered features of the earlier trauma. Pain takes on a role with respect to bodily boundaries, both reinforcing the physical experience of body and simultaneously indicating a breach in body integrity. Finally, as hateful as such abuses may be, there are the contradictory, unintegrated, emotional dimensions of both love and hate in the experience of developmental trauma, now woven into pain. Thus, pain can be associated with parental approval or nurturance and sexual matters.

Some patients, variously called “presymbolic,” “concrete,” or “alexithymic,” are deemed to have a relative inability with respect to fantasy and symbolization, with difficulty in maintaining views of themselves and others apart from concrete experience. Their emotional lives tend to be reflective of their immediate sensory experiences. There may be overreactivity or underreactivity of the autonomic nervous system, with a relative developmental inability to channel pre-emotional autonomic activity into symbolic emotional patterns. Thus, there is a reduced mentalization of experience, such that patients remain “stimulus bound,” regressively holding onto physical experience.111,112 There is often an associated subjective experience of fragility of body and self. Such patients can have problems in managing pain since they are unable to manage the emotional dimension, and find the sensory experience overwhelming.113-116

An additional developmental background would include the patient who identifies with an adult figure from childhood such as a parent who had chronic illness, perhaps with overt pain. The continued identification, and with it the pain, serves a psychological need, though it is rarely present without conflict.117-119 Likewise, long-standing chronic pain or illness, especially when present from childhood, serves multiple psychological functions and is typically incorporated into object relations and well-defended narcissistic structures, including self-image and world view.120 Additional psychological patterns that may function as a risk for a chronic pain syndrome include body image problems, guilt or a need for punishment, and passivity needs.

Some research demonstrates traits involving “anxiety sensitivity”121-126 as well as other traits which predispose toward “pain anxiety” (eg, neuroticism, hypochondriasis, harm avoidance, anger-management styles, negative interpretational bias, and tendency to catastrophize). One might also speculate here regarding trait reactivity of the autonomic nervous system.
As a generalization, a chronic pain syndrome can be a risk if it might function to fill prior conflicted or unfulfilled developmental or personality needs.127 This applies to almost any psychopathology since pain and its demands can place a burden on the patient that is greater than his adaptive capacity can manage. Thus, such patients are seen to have poor coping skills. In such instances, while the patient is “invested in” the pain and typically threatened by or resistant to treatment, it should be recalled that the patient is suffering no less and that treatment options are not closed. Recall that maladaptive investment in psychological patterns is at the heart of all psychopathology, and that psychiatrists routinely deal with such situations.128

The patient’s efforts to deal with his pain are likely to result in more maladaptive interpersonal behavior, further stressing the various systems and himself.

There are broader system issues that place patients at risk for chronic pain syndromes. These include matters related to access to medical care as well as financial and legal matters. Delays or complications in access often result in prolongation of immediate pain and in otherwise unnecessary stress that can promote maladaptive responses.129 For example, in some state systems, work-related disability is a quasi-judicial matter obtained in an adversarial process, which promotes both skepticism of chronic pain on one side but overstatement and overinvestment in chronic pain on the other. Our medical and legal systems have not found a means to provide adequate care, support, and compensation without inducement of “secondary gain.” Financial and legal issues, rather than medical and psychiatric concerns, are the bottom line and patients respond accordingly.

 

Predisposing Syndromes

It remains unclear to what extent psychopathologic predispositions to a chronic pain syndrome correlate with defined psychiatric syndromes. However, some associations are established.

Personality Disorders
Much research has sought personality patterns which might predispose to chronic pain syndromes. However, the findings have not tended overall to correlate with DSM-IV-TR categories.130 They have included neuroticism, introversion, harm avoidance, trait anxiety, anger-regulation difficulties, prevalent negative emotions, alexithymia, counterdependency, insecure attachment, hypochondria, hysteria, inhibition, sensitivity, reduced awareness of inner states, negative coping resources, passivity, demandingness, and other traits.120,131-136 Such “trait” findings do not clearly establish pre-existing personality pathology, but are certainly suggestive. They additionally reinforce the notion that there are diverse vulnerabilities. A single personality variable is unlikely to determine a high risk of a chronic pain syndrome.

Features of borderline personality disorder are commonly seen among chronic pain patients.137 Among borderline patients, the frequency of self-inflicted injury suggests that pain has emotional  value.138

Depressive Disorders
A particularly strong association is seen with depression, though most studies have not clarified that a depression history antedated the pain syndrome. However, that prior depression constitutes a risk is likely.

It is unclear what the connection might be. One might speculate that residual subsyndromal depressive features render the patient less capable of coping with pain. As examples, one might consider relative passivity, tendencies to amplify pain in accord with depressive ideation, and the role of muscle tension with relative ischemia. Depressed patients often complain of various aches and pains. This may reflect a trait of autonomic vulnerability; a disturbance in proinflammatory cytokine activation (recall the immunologic theory of depression)139-141; an HPA disturbance; or a neurochemical disturbance with respect to serotonin, norepinephrine, or endogenous opiates.142,143 The fact that neurochemical treatments of both conditions tend to involve some similar agents suggests this.

Bipolar Disorders
Anecdotal experience points to the frequent occurrence of chronic pain syndromes that develop among bipolar patients, but there are no studies to support this.

Patients with bipolar spectrum disorders, due to impairments in judgment, probably have a higher frequency of injuries and medical conditions, some of which result in chronic pain. Cognitive and affective problems among such patients tend to lead to poor management of pain and such conditions, thereby resulting in a typical chronic pain syndrome.

Little is understood about bipolar disorder and chronic pain with respect to a common underlying endocrine or neurochemical basis, or to what extent vulnerabilities of depression may apply.

It is unlikely that the acutely manic patient will present with a chronic pain syndrome since the subjective state is one of euphoria or irritability, with denial and considerable inattention to self-care and safety. However, the chronically manic patient may be very different, especially since such patients commonly make partial adaptations with respect to safety and self-control, this being consistent with their denial of their own psychopathology. A chronic pain complaint, coupled with use of sedating medications, might function to assist such a partial adaptation.

Furthermore, a bipolar spectrum presentation is not unlikely, whether mixed or atypically cycling. Among chronic pain patients, one is struck by the frequency of mood swings, usually reflective according to the patients of changes in pain severity. However, mood swings may also be due to bipolar disorder secondarily affecting pain, or swings of pain and mood may have entrained each other or become equally reactive to outside pressures.

While a significant number of chronic pain patients respond well to standard antidepressants, there are some who do not, and some who offer paradoxical, agitated, or otherwise unexpected responses. A common presentation of a patient with chronic pain is overt affective and behavioral psychopathology, and sensitivity to all medications except sedatives and opiates. The patient recounts a history of other physicians having tried antidepressants, with unusual responses. Such a patient requires consideration of a bipolar spectrum disorder.

In general psychiatry, recognition of milder forms of bipolar spectrum disorders is a significant challenge. In the absence of better research, the clinician is advised to maintain a high index of suspicion in accord with his or her own experience and acumen.

Anxiety Disorders
Studies demonstrate that anxiety is a common feature of chronic pain, and often a predisposition. Therefore, it is likely that anxiety disorders are a risk, though studies assessing this are lacking. Pain and anxiety mutually reinforce each other. In the case of unremitting pain, the maladaptive cascade contributes to the final syndrome. Patients with GAD and some other anxiety disorders are likely to be prone to develop this process.

Panic Disorder
Chronic pain and panic disorder are associated. Common features of both syndromes include the frequent somatic focus, fears of loss of control, phobic avoidances, and autonomic overreactivity of such patients.59,144

Posttraumatic Stress Disorder
In the case of PTSD, the commonly observed comorbidity is partly explained by the notion that the psychological trauma also involved an accident, the result of which is a chronic pain condition. However, there may be the additional contribution of the somatosensory flashback experience of pain.145 Furthermore, HPA alterations are present in PTSD, which may predispose to alterations in inflammatory mediators. The psychological mechanisms of denial, avoidance, emotional constriction, and dissociation as well as heightened arousal, intrusive experiences, and affective overload suggest a predisposition to chronic pain or early patient pain mismanagement.146

Chronic pain can be seen as trauma itself, different from continuing effects of a past trauma. Those who have not sufficiently mastered a past trauma are less likely to have the ability to handle a further trauma, and with both a psychological and a biological vulnerability and a cumulative result.

Addictive Disorders
An addiction history could involve an associated vulnerability to a chronic pain condition.147,148 Such conditions are certainly associated with injuries and conditions. Addiction disorders commonly involve psychological problems such as impulse dyscontrol, externalization tendencies, affect management, and conflicts regarding dependence and shame, which overlap with psychological problems commonly seen in chronic pain patients.

One can additionally speculate regarding a common neurochemistry in addictive disorders and chronic pain. As currently formulated, addictive disorders involve dysregulation in the dopaminergic reinforcement pathway, with major influence by endogenous opioids and by exogenous opiates. Clearly, a dysregulation in the opiate system may predispose an individual to a chronic pain disorder.128,149-152

Somatoform Disorders
Somatoform disorders are obvious possibilities among disorders that predispose to the development of chronic pain.

Somatoform Pain Disorder
Somatoform pain disorder, the subjective experience of pain unrelated to known physical pain generators is itself a syndrome of chronic pain rather than a predisposition. It is deemed to involve an influence from higher central structures on relatively lower central structures, generating the subjective experience of pain, perhaps with a classic conversion basis. It is strictly psychogenic, determined by current stressors, coping ability, conflicted passivity needs, identifications, and repressed wishes. A classic differential diagnostic method to distinguish conversion phenomena from “organic” phenomena involves assessing whether the sensory pattern corresponds to known neurologic sensory distribution patterns or known organic structures. Unfortunately, this method rarely has utility in chronic pain due to the phenomenon of centralization.

There is a an additional confounding factor, with respect to the diagnosis of somatoform pain disorders. Patients with primary psychiatric disorders may present with unusual pain features related to the primary disorder but which are not, in fact, conversion phenomena. For example, the patient with an anxiety disorder and muscle tension may present with pains related to the relative ischemia or inefficient muscular work. Such pains, while they are derivative of primary psychopathology, are not correctly understood as conversion phenomena since they are truly musculoskeletal in origin. Likewise, autonomic or endocrine disturbances related to primary psychiatric disorders may result in changes in bodily digestive, secretory, excretory, or even vascular functions, with consequent painful physical consequences. Such pains are not conversion phenomena, although they may be secondarily elaborated by the patient especially if unmet psychological needs are present. This may involve repressed wishes, identifications, passivity needs, poor coping abilities, and maladaptive responses to current stressors, with a worsening of subjective pain, all in effect conversion-like features.

Somatoform pain disorder may be best understood as a spectrum chronic pain syndrome, with an undetermined or minimal physical basis and a prominent psychological basis, often with classic conversion features.

It is worth mentioning that syndromes initially seen as psychogenic are frequently later understood to have a physical basis, and one is often justified in hedging with respect to a strict psychogenic etiology.

Somatization disorder requires the presence of recurrent pain symptoms, among others. It includes conversion-like, alexithymic, and hypochondriacal features. It also most likely reflects autonomic nervous system disturbances in at least some cases. The broader psychopathology suggests a pseudoadaptation involving reactivity to bodily sensation and conflicts regarding illness and nurturance figures.

Vaginismus and psychogenic male and female dyspareunia may be considered chronic pain disorders with a psychogenic basis.

Body Dysmorphic Disorder
There is little evidence that body dysmorphic disorder predisposes to chronic pain. While there is a preoccupation with a bodily feature, its basis is one of appearance to others rather than pain or medical disturbance. One might speculate that since the imagined dysmorphic feature is chronically emotionally painful to the patient, a further elaboration of an uncomfortable physical sensation or a further conversion-like reaction could develop into a chronic pain syndrome. However, the frequency of this is not established.

Hypochondriasis
Hypochondriasis, defined as the excessive tendency to fear that minor physical symptoms point to a serious physical illness, needs to be considered. Chronic pain patients often show hypochondriacal features with respect to their pain, and it can be difficult for them to accept that their pain does not portend additional illness. However, this does not constitute a full syndrome of hypochondriasis. One must also recall the adaptive monitoring of current pain to insure that no additional physical complications are developing. Preexisting hypochondriacal features are likely to contribute to the establishment of a full chronic pain syndrome, perhaps mediated by somatically focused anxiety.

Dementias
Patients with dementia can develop chronic pain. Among the common dementias with pain syndromes are the degenerative dementias among the elderly who have comorbid medical conditions with pain, and victims of head trauma with associated injuries or PTSD.

Dementia constitutes a risk factor for a chronic pain syndrome because of the loss of cognitive and executive function. This can result in impaired management of impulse and affect, limited patient understanding with a consequent reduction in pain control, reduced communication, and strains on the social system.

Chronic pain syndromes among patients with dementia, especially more severe dementia, are underrecognized and undertreated.153 However, the prevalence of chronic pain is likely to be greater among patients with dementia than in the general population due to medical comorbidities.154,155 This discrepancy is partly due to stereotypes regarding dementia and aging, communication difficulties, and limited care resources. In addition to humanistic considerations, consequences of such underrecognition and undertreatment can include behavioral disturbances, underrecognition of comorbid medical problems, and other inappropriate or excessive pharmacologic interventions.

Other Syndromes
Numerous other syndromes predispose to chronic pain disorders and complicate the management and prognosis. One might consider eating disorders, impulse-control disorders, sexual masochism, and continued or residual disorders from childhood, including pervasive developmental disorders and mental retardation. Factitious disorder can certainly involve fabricated subjective complaints of pain or self-inflicted physical injury involving pain for the purpose of assuming the sick role.

 

The Clinical Encounter

Chronic pain patients often present with a complex picture: a physical basis for pain, pain that does not fully conform to anatomic structures or neurological pathways, and a subjective experience of pain that is difficult to understand with respect to intensity or time pattern. Often there are severe effects on the vocational, emotional, and interpersonal aspects of the patients life. Patients can be intensely emotional, the particulars running the gamut from depressed resignation to noisy hostility. They have seen many doctors, may be currently doctor shopping, and may be overtly disturbed in their manner of relating to the treating physician. They have tried many different treatments, and may be taking unusual doses of analgesics. They may have unusual or irrational beliefs concerning the origins or patterns of their pain, or strong opinions regarding what treatment they need. They may be inclined to be uncooperative or overly supplicant regarding treatment. Many have histories of psychiatric or psychological difficulties that antedated or accompanied their pain. The presence of overt psychopathology is frequent and often dramatic.

 

Chronic Pain: Physical and Psychological

It is useful for the clinician to attempt to conceptually separate the physical and psychological bases as well as the primary and secondary features. However, this is often impossible. Primary psychopathology of many forms predisposes to chronic pain and reinforces its development and maintenance. Pain induces secondary psychopathology which worsens the physical component of pain and exacerbates the primary psychopathology. The physical pathology and psychopathology amplify each other in a mutually cascading spiral of suffering and functional disability. It is often impossible to determine which component is truly antecedent; in addition, given that the end result is a psychophysical and interpersonal collapse, it is theoretically erroneous to do so. Pain is not exclusively physical or psychological, but rather both. If the body’s function is to support the autonomy and function of mind, it is unable to do so; if the mind’s function is to direct and maintain the body, it is unable to do so. The mind is unable to separate from the suffering of body, and the body is unable to free itself from the terrors and desperation of the mind. Even the notion of “psychogenic overlay,” useful to the clinician in reminding himself to consider both psychogenic and somatogenic components, fails to convey the ultimate unitary collapse of the barrier between mind and body.

Such a state generates difficulties in diagnosis, management, and doctor-patient relationship, including countertransference. The severity of disability and suffering do not imply the necessity of nihilism or hopelessness in prognosis or treatment. In fact, the rule of thumb is that such chronic pain syndromes tend to be highly treatable conditions.

 

Management

Because chronic pain conditions themselves are multidimensional and complex, management must be multimodal and can also become complex. Management of the physical dimension of pain is often itself complex, requiring attention to the underlying physical pathology, secondary inflammatory mediators, neurologic irritability and transmission, and effects of pain on other systems. In addition, there is the need to address the psychopathology, associated conditions, and social system. This is often more than one clinician can manage. Consequently, a team approach is common, involving a pain management physician, a primary care physician, other specialists, and a psychologist or psychiatrist experienced in pain management. This then introduces the importance of team communication and dynamics.

The psychiatrist requires multiple perspectives. The biologic dimension is a necessary orientation, since chronic pain syndromes often require biologic treatment of the associated psychopathology with attention to effects on other conditions and treatments. Because of the behavioral and cognitive disturbances in chronic pain, approaches directly addressing these dimensions are often required. Supportive or eclectic psychotherapy is often valuable.

While a psychoanalytic perspective is unique in offering a window into the subjectivity of the patient and can therefore inform all treatment approaches, a classic insight-oriented psychoanalytic treatment is rarely useful. This is to be expected in the presence of an active trauma, expecially among patients with marked somatic concerns. However, such a treatment may become useful for some patients when they are relatively stabilized.

Some additional psychiatric treatments call for consideration, including specialized addiction approaches and personnel, involvement with couples and families, and group psychotherapies— all of which may be significantly underutilized.

 

Countertransference

Patients with chronic pain syndromes bear a resemblance to certain other patients, such as those with borderline personality disorder, antisocial personality disorder, and addictive disorders, in that strong reactions tend to be elicited from others, including clinicians. Common reactions from nonprofessionals are often a tip; the patient is lazy, addicted, manipulative, dramatic, or too reliant on doctors. On the other hand, the patient is misunderstood, neglected, victimized, or abused.

Common countertransferential thoughts among professionals include, in addition to the above, hopelessness (eg, “Palliation only”; “Nothing can be done because it is all physical pain”); denial, minimization, or suspicion (eg, “It cannot be that bad”; “It is dramatization, manipulation, attention seeking, lying, psychosis, or addiction”; “It is all psychological”; anger or hatred directed toward the personnel or system that “failed” the patient or toward the patient; and guilt (eg, “I am failing” the patient for accomplishing so little for the suffering). Professionals may also respond with an overidentification with the suffering of the patient, or may tend to blame other professionals.

As usual, one needs to remember that countertransference is not “wrong,” or “bad”; rather, it is useful and informative regarding the patient, provided one recognizes it as countertransference. Recalling that chronic pain patients have often regressed to primitive object relations, one can expect frequent experiences of projective identification, projection, splitting, schizoid withdrawal, somatization, and narcissistic entitlement, with attendant countertransference responses.

The role of the psychiatrist or psychologist in chronic pain management is central. He is uniquely able to make use of such reactions and to guide other team members regarding the psychological status and interpersonal manner of the patient.

 

Conclusion

Chronic pain can be considered a physical disorder with frequent antecedent or consequent psychiatric comorbidity. Such a formulation is often useful but ultimately short sighted. Considered as a condition reflecting the stress-diathesis model, it is similarly helpful but limited.

Pain, usually understood as a physical process, in the case of chronic pain becomes integrated into the totality of the person. Pain reciprocally interacts with and modifies baseline maladaptive vulnerabilities in personality and syndromal diatheses, doing so psychologically, neurochemically, and neurologically. The consequence is a syndrome that is truly both “psychic,” and somatic, or psychosomatic, with intrinsic physical and psychopathology. Chronic pain is best understood as a psychophysical or biopsychosocial disorder. A treatment approach which simultaneously incorporates these differing perspectives is required. It is pleasing to note that with such consideration and management, patient improvement in function and quality of life is the rule rather than the exception. PP

 

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74. Kirsh KL, Whitcomb LA, Donaghy K, Passik SD. Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain. 2002;18(4 suppl):S52-S60.
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79. Weaver M, Schnoll S. Abuse liability in opioid therapy for pain treatment in patients with an addiction history. Clin J Pain. 2002;18(4 suppl):S61-S69.
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105. Goldberg RT, Goldstein R. A comparison of chronic pain patients and controls on traumatic events in childhood. Disabil Rehabil. 2000;22(17):756-763.
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115. Lumley MA, Asselin LA, Norman S. Alexithymia in chronic pain patients. Compr Psychiatry. 1997;38(3):160-165.
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122. Stewart SH, Asmundson GJ. Anxiety sensitivity and its impact on pain experiences and conditions: a state of the art. Cogn Behav Ther. 2006;35(4):185-188.
123. Greenberg J, Burns JW. Pain anxiety among chronic pain patients: specific phobia or manifestation of anxiety sensitivity? Behav Res Ther. 2003;41(2):223-240.
124. Zvolensky MJ, Goodie JL, McNeil DW, et al. Anxiety sensitivity in the prediction of pain-related fear and anxiety in a heterogeneous chronic pain population. Behav Res Ther. 2001;39(6):683-696.
125. Asmundson GJ, Bonin MF, Frombach IK, Norton GR. Evidence of a disposition toward fearfulness and vulnerability to posttraumatic stress in dysfunctional pain patients. Behav Res Ther. 2000;38(8):801-812.
126. Asmundson GJ, Norton PJ, Veloso F. Anxiety sensitivity and fear of pain in patients with recurring headaches. Behav Res Ther. 1999;37(8):703-713.
127. Novick KK, Novick J. The essence of masochism. Psychoanal Study Child. 1987;42:353-384.
128. Perlman SD. Psychoanalytic treatment of chronic pain: the body speaks on multiple levels. J Am Acad Psychoanal. 1996;24(2):257-271.
129. Aronoff GM, Livengood JM. Pain: psychiatric aspects of impairment and disability. Curr Pain Headache Rep. 2003;7(2):105-115.
130. Ham LP, Andrasik F, Packard RC, Bundrick CM. Psychopathology in individuals with post-traumatic headaches and other pain types. Cephalalgia. 1994;14(2):118-126.
131. Krueger RF, Tackett JL, Markon KE. Structural models of comorbidity among common mental disorders: connections to chronic pain. Adv Psychosom Med. 2004;25:63-77.
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133. Calabrese SK, Lyness JM, Sorensen S, Duberstein PR. Personality and the association of pain and depression. Am J Geriatr Psychiatry. 2006;14(6):546-549.
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143. Delgado PL. Common pathways of depression and pain. J Clin Psychiatry. 2004;65(suppl 12):16-19.
144. Schmidt NB, Cook JH. Effects of anxiety sensitivity on anxiety and pain during a cold pressor challenge in patients with panic disorder. Behav Res Ther. 1999;37(4):313-323.
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Dr. Dubois is professor of anesthesiology at the New York University (NYU) Medical School and director of the NYU Pain Program in New York City.

Disclosure: Dr. Dubois receives grant support from Archimedes, Pfizer, Purdue, and Wyeth.

Please direct all correspondence to: Michel Y. Dubois, MD, Director, NYU Pain Program, 317 E 34th St, Room 902, New York, NY 10016; Tel: 212-263-7316; Fax: 212-685-5365; E-mail: Michel.Dubois@nyumc.org.

 


 

 

Immense progress in pain research in the last 40 years has led to improved diagnosis and treatment of pain patients. Since Melzak and Wall’s1 landmark gate theory published in 1965, overwhelming evidence, from both basic science research and clinical investigation, has replaced the simplistic “wire concept” of pain transmission with new and more subtle pathophysiologic mechanisms. One of the main findings has been that, whereas acute pain can be related to tissue injury, and pain is usually a symptom of this injury, lasting chronic pain has been shown to represent a different condition which is not related to peripheral nociceptive input but represents a disease state of its own. This disease state is created by neural plastic changes of the nervous system usually referred to as “sensitization.” Because it is a disease involving the nervous system, it is not surprising that chronic pain may be associated with significant psychological effects leading to psychopathology.

Conditions such as major depressive disorder (MDD), anxiety, posttraumatic stress disorder, substance abuse, somatoform disorder, and personality disorders have all been shown to be present at a significantly greater rate in chronic pain patients than in the general population. For example, MDD has been found to be present in 45% (current rate) and 65% (lifetime rate) of patients with chronic low back pain, while MDD rates are 5% (current rate) and 17% (lifetime rate) for the entire United States population.2

Although it has been suggested that patient characteristics, predating the onset of chronic pain, may influence the onset of psychopathology, no single model explains the relationship between chronic pain and psychopathology in all patients. For example, MDD, when shown to precede a chronic pain condition, is usually exacerbated by chronic pain. Some patients have developed MDD as a direct consequence of chronic pain, while others develop the two conditions concomitantly. Even if the “chicken and egg” dilemma cannot always be solved, it has been found that treatment of a psychiatric disease in chronic pain patients leads to more rapid improvement in pain complaints, and, vice versa, treatment of pain improves psychopathology. Therefore, it is no surprise that therapeutic modalities, used separately in pain medicine and psychiatry, are in fact overlapping. It is also logical that support and interaction are often needed between the two specialties when taking care of chronic pain patients.

This issue of Primary Psychiatry presents papers from mental health professionals, all with extensive experience diagnosing and treating patients with chronic pain.

First, cognitive-behavioral treatments and psychotherapy are now routine modalities for the treatment of chronic pain. Allen Lebovits, PhD, describes the wide variety of techniques used as well as their indications, outcomes, and limitations. He stresses the importance of public and professional education on psychological evaluation and treatment in chronic pain in order to alleviate existing barriers that prevent patient access to those treatments, shown to be highly effective in many cases.

Next, Matthew B. Smith, MD, examines the interplay between psychopathology and chronic pain, describing the psychiatric conditions believed to be caused by chronic pain, including pain behaviors, personality changes, and syndromal disorders. In cases where pre-existing psychopathology appears to be greatly aggravated by chronic pain, predisposing factors and the relative contribution of each condition need to be carefully assessed. Clinical encounter with the patient, often difficult but always essential to achieving a precise diagnosis and allowing a more efficient treatment, is particularly emphasized.

Michael R. Clark, MD, MPH, describes the psychopharmacology of pain in detail. Many medications used to treat pain, especially neuropathic pain, are, in fact, commonly used in psychiatry. Since the neurochemistry of pain has been found to be very similar to the neurochemistry of, for example, MDD (ie, common receptors and mediators involved), it is not surprising that the same medications have a beneficial effect on both pain and specific psychiatric diseases. This serves to underline the importance of the psychiatrist contributing to the treatment plan of chronic pain patients through interdisciplinary modalities.

Finally, William Breitbart, MD, FAPM, FAPA, and Christopher A. Gibson, PhD, applying wide-ranging experience in the psychiatric aspects of the terrible ordeal of cancer pain on patients, lay out the problems and solutions encountered in caring for these patients. Although cancer pain has many of the same characteristics as chronic non-cancer pain, it is usually the direct result of aggressive tumor-induced tissue damage, creating a different clinical context. Management of cancer pain, therefore, requires unique skills and competence. Breitbart and Gibson’s approach to pain management in cancer patients gives a good description of a multi-modality treatment, which is the only proven solution to providing optimum care for these patients.

The role of psychiatry in the diagnosis and treatment of the chronic pain patient is established.3 Psychological and psychiatric expertise is often required in order to optimize the treatment of such patients. This ideally occurs within an interdisciplinary evaluation and treatment arrangement where both psychological and psychopharmacologic modalities are routinely available and used.

Since psychiatry plays a growing role in the management of chronic pain patients, training requirements in psychiatry have been established by the Accreditation Council for Graduate Medical Education as part of the pain medicine fellowship curriculum.4 The American Board of Psychiatry and Neurology now offers a sub-specialty certification in pain medicine. Because of the recognition during the last few years that pain is a sensation influenced by cognitive, emotional, and psychological factors, an “irreversible symbiosis” has been established between pain medicine and psychiatry. This alliance is here to stay and to develop. PP

References

1. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150(699):971-979.
2. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: research findings and theoretical considerations. Psychosom Med. 2002;64(5):773-786.
3. Sharp J, Keefe B. Psychiatry in chronic pain: a review and update. Curr Psychiatry Rep. 2005;7(3):213-219.
4. Leo RJ, Pristach CA, Streltzer J. Incorporating pain management training into the psychiatry residency curriculum. Acad Psychiatry. 2003;27(1):1-11.

 

Dr. Ginsberg is vice-chair of clinical affairs in the Department of Psychiatry at New York University Medical Center in New York City.

Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

 


 

Rabeprazole-Induced Panic Attacks

Rabeprazole is an anti-ulcer drug in the class of proton pump inhibitors (PPIs). Psychiatric adverse effects reported for rabeprazole during controlled trials and postmarketing experience are rare and include insomnia, anxiety, depression, somnolence, abnormal dreams, decreased libido, agitation, amnesia, and confusion.1 The following is a published report in which a patient developed marked anxiety and panic attacks in association with use of rabeprazole.2

 A 55-year-old white woman was prescribed rabeprazole 20 mg/day administered in the morning for persistent symptoms of dyspepsia. Her history was notable for a depressive episode 8 years earlier, which resolved and did not recur after 4 months of treatment with an (unspecified) antidepressant. She was not taking any other medications, including over-the-counter drugs or herbal remedies. She had no known allergies or history of alcohol abuse or illicit drug use. She smoked 15 cigarettes a day. She denied any stressful or traumatic change in her lifestyle during the prior 6 months.

Ten days after initiation of rabeprazole, she presented with a 7-day history of marked anxiety associated with panic attacks, night terror (pavor nocturnus), episodic mental confusion, and attention deficit. The panic attacks lasted from a few minutes to approximately 1 hour and consisted of intense apprehension, dyspnea, palpitations, fear, and a feeling of impending disaster. Within 2 days of discontinuing rabeprazole, all of her symptoms completely resolved. Later work-up revealed the presence of gastroesophageal reflux disease with erosive gastro-duodenitis positive for Heliobacter pylori. Subsequent treatment with esomeprazole for a period of 4 weeks did not result in any psychiatric adverse effects.

It appears that rabeprazole induced this patient’s anxiety and panic symptoms. Among PPI, rabeprazole has the highest capacity to induce increased secretion of gastrin.3,4 PPI-induced secretion of gastrin is mediated by the release of gastrin-releasing peptide (GRP).5 GRP and its receptor are found in the dorsal hippocampus and amygdala, where they are involved in regulating synaptic plasticity and aspects of behavior that might be altered in disorders such as anxiety, depression, and dementia.6 It is known that pentagastrin, a synthetic pentapeptide derived from gastrin, when administered to healthy volunteers, leads to increases in anxiety, heart rate, and physical symptoms of panic in a dose-related manner.7,8 Furthermore, the highly selective gastrin receptor antagonist PD-136,450 has anxiolytic activity in rats and rabbits.9

Regardless of mechanism of action, rabeprazole may be anxiogenic in certain vulnerable patient populations. Further studies are needed to confirm these preliminary observations. PP

 

References

1. Aciphex [package insert]. Tokyo: Eisai Co., Ltd; 2003.
2. Polimeni G, Cutroneo P, Gallo A, Gallo S, Spina E, Caputi AP. Rabeprazole and psychiatric symptoms. Ann Pharmacother. 2007;41(7):1315-1317.
3. Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and serum gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther. 1998;12(11):1079-1089.
4. Warrington S, Baisley K, Boyce M, Tejura B, Morocutti A, Miller N. Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, on 24-h intragastric pH and serum gastrin in healthy subjects. Aliment Pharmacol Ther. 2002;16(7):1301-1307.
5. Takehara Y, Sumii K, Tari A, et al. Evidence that endogenous GRP in rat stomach mediates omeprazole-induced hypergastrinemia. Am J Physiol. 1996;271(5 Pt 1):G799-804.
6. Roesler R, Henriques JA, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurologic disorders. CNS Neurol Disord Drug Targets. 2006;5(2):197-204.
7. McCann UD, Slate SO, Geraci M, Uhde TW. Peptides and anxiety: a dose-response evaluation of pentagastrin in healthy volunteers. Anxiety. 1994-1995;1(6):258-267.
8. Geraci M, Anderson TS, Slate-Cothren S, Post RM, McCann UD. Pentagastrin-induced sleep panic attacks: panic in the absence of elevated baseline arousal. Biol Psychiatry. 2002;52(12):1183-1189.
9. Bastaki SM, Hasan MY, Chandranath SI, Schmassmann A, Garner A. PD-136,450: a CCK2 (gastrin) receptor antagonist with antisecretory, anxiolytic and antiulcer activity. Mol Cell Biochem. 2003;252(1-2):83-90.

 

Olanzapine-Induced Pancreatitis Due to Chylomicronemia

Currently Food and Drug Administration approved for the treatment of schizophrenia and bipolar mania, olanzapine is an atypical antipsychotic that binds to multiple sites including serotonin (5-HT)2A and 5-HT2C, dopamine (D)2, D4, D1, μ1, histamine-1, and a1-adrenergic receptors.1 A side effect reported in association with olanzapine is metabolic dysregulation, which includes weight gain, hyperinsulinemia, and lipid abnormalities. The following a report of olanzapine-induced chylomicronemia resulting in acute pancreatitis.2

A 36-year-old Libyan man presented with a 3-day history of epigastric pain. For the prior 6 months, he had been taking venlafaxine 300 mg/day and diazepam 2 mg/day. Six weeks prior to the current presentation, he was diagnosed with schizoaffective disorder; at the time, olanzapine 10 mg HS was initiated. Over this period, his weight increased from 85 kg (187 lbs) to 92 kg (202.4 lbs). Initial laboratory testing revealed hyperglycemia (13.1 mM), trace ketonuria, and hypertriglyceridemia (105.5 mM) due to accumulation of chylomicrons. The latter are large lipoprotein particles that transport exogenous lipids to liver, adipose, cardiac, and skeletal tissue where they are broken down by lipoprotein lipase into very low-density lipoproteins. Serum amylase was 554 U/L (normal, <135 U/L). The patient consumed no alcohol and had a normal gallbladder on ultrasound. A diagnosis of hypertriglyceridemia-induced acute pancreatitis was made.

The pancreatitis was managed conservatively with fluids, antibiotics, and intravenous insulin. Olanzapine was held for 5 days, then tapered down over 19 days and replaced with quetiapine. After 5 days, insulin was discontinued. The patient remained normoglycemic. Subsequently, serum triglycerides fell rapidly. Three months after discontinuation of olanzapine, the blood glucose remained normal while triglycerides remained <10 mM. No other medications were discontinued. Moreover, no lipid-lowering therapy had ever been prescribed. The patient’s recovery was complicated by development of a pancreatic pseudocyst.

While there have been several prior reports describing the association of olanzapine with acute pancreatitis,3,4 the exact mechanism remains unclear. Based on the case described here, it appears that chylomicronemia may underlie the association between olanzapine and acute pancreatitis. Regular monitoring of serum lipids is essential not only for general cardiovascular health, but to prevent this potential life-threateing condition. PP

 

References

1. Moore NA, Tye NC, Axton MS, Risius FC. The behavioral pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther. 1992;262(2):545-551.
2. Rossor AM, Leech N, Neely RD. Olanzapine-induced chylomicronemia presenting as acute pancreatitis [letter]. J Clin Psychopharmacol. 2007;27(4):395-396.
3. Doucette DE, Grenier JP, Robertson PS. Olanzapine-induced acute pancreatitis. Ann Pharmacother. 2000;34(10):1128-1131.
4. Hagger R, Brown C, Hurley P. Olanzapine and pancreatitis. Br J Psychiatry. 2000;177:567.

 

Cervical Dystonia Due to Quetiapine-Valproic Acid Interaction

Quetiapine is a second-generation antipsychotic indicated for the treatment of schizophrenia; as monotherapy for the acute treatment of manic episodes, as well as an adjunct to treatment with lithium or divalproex for bipolar type I disorder; and for bipolar depression. Pharmacologically, it is an antagonist at serotonin (5-HT)1A and 5-HT2, dopamine (D)1 and D2, histamine-1, and adrenergic α1 and α2 receptors.1 Its affinity for the D2 receptor is low. Sodium valproate is a commonly used medication for the treatment of mania associated with bipolar disorder, complex partial and absence seizures in epilepsy, and prevention of migraine headaches. The following is a report of a patient with an acute schizoaffective episode who developed severe cervical dystonia while being treated with a combination of quetiapine and valproic acid.2

A 60-year-old woman with schizoaffective disorder was admitted to the inpatient psychiatry unit at the University Hospital in Basel, Switzerland due to symptoms of mania and psychosis. She had recently been discharged from the hospital on quetiapine monotherapy 500 mg/day, which led her to remission and had been well tolerated. During that last hospitalization, she suffered two generalized seizures; an electroencephalograph and brain magnetic resonance imaging scan were normal. Nonetheless, valproic acid had been added to her medication regimen to serve as both an anticonvulsant as well as an additional mood stabilizer.

Subsequently, however, she discontinued the quetiapine on her own, resulting in a rapid return of psychotic symptoms. She developed paranoia about being poisoned, as manifested by her persistent refusal of food and fluid intake.

Upon readmission to the hospital, quetiapine was rapidly increased to 800 mg/day. After the increase, the plasma concentration of quetiapine was 0.15 mg/L (therapeutic range, 0.05–0.170 mg/L). Her psychopathology improved daily. Quetiapine was lowered to 600 mg/day. Four days after initiation of valproic acid at a dosage of 900 mg/day, the patient developed a severe anterocollis. The quetiapine plasma concentration was .24 mg/L (therapeutic range, 0.05-0.170 mg/L), whereas the valproic acid concentration was 75.5 mg/L (therapeutic range, 50–100 mg/L). The cervical dystonia improved with biperiden and resolved totally after reduction of both quetiapine and valproic acid. The patient was discharged on a combination of olanzapine and valproic acid.

The temporal sequence of events suggests that the patient’s extrapyramidal symptoms—in this case anterocollis—was triggered by a drug-drug interaction in which valproic acid inhibited the metabolism and thereby increased the plasma concentration of quetiapine. The latter is metabolized principally in the liver via the cytochrome P450 (CYP) isoenzyme CYP 3A4 and to a lesser extent via CYP 2D6. Inhibitors of CYP 3A4 increase plasma levels of quetiapine.3 In vitro studies demonstrate that valproic acid inhibits CYP 2C and to a lesser degree, CYP 3A4.4 A recent study has shown that administration of valproic acid increases plasma concentration of quetiapine by approximately 77%.5 This may explain why in the case described here, the plasma quetiapine concentration increased from 0.15 mg/L to 0.24 mg/L even though there was a 25% reduction in quetiapine dosage (ie, from 800 mg/day to 600 mg/day). What also changed was the addition of valproic acid, which served to inhibit metabolism of quetiapine. When adding valproic acid to quetiapine, consideration should be given to reducing the dose of quetiapine, perhaps by as great as 50%. PP

 

References

1. Seroquel [package insert]. Wilmington, DE: AstraZeneca; 2006.
2. Habermeyer B, Rabovsky K, Jentzsch C, Pinard K, Müller-Spahn F. Cervical dystonia due to interaction of valproic acid and quetiapine [letter]. J Clin Psychopharmacol. 2007;27(4):396-397.
3. Kohnlein O, Lutz R, Schmauss M, Messer T. Determining serum concentrations of the modern antipsychotic quetiapine: clinical relevance in therapeutic drug monitoring [German]. Psychiatr Prax. 2004;31(suppl 1):S175-S177.
4. Wen X, Wang JS, Kivisto KT, Neuvonen PJ, Backman JT. In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol. 2001;52(5):547-553.
5. Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemmler G. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol. 2006;21(2):81-85.

 

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, is a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and is the president of Pacific Sleep Medicine Services.

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.


 

“It appears that every man’s insomnia is as different from his neighbour’s as are their daytime hopes and aspirations.”
— F. Scott Fitzgerald
1

 

Medications are never entirely “risk free,” but the various agents used to treat insomnia have always been a source of concern for practicing physicians and regulatory bodies. Various classes of agents have been shown to be associated with risks of abuse, dependency, and toxicity with overdosage, but among classes of agents perceived to be more safe have been the antidepressants, various herbal reparations thought to be effective in promoting and sustaining sleep, and the naturally occurring hormone melatonin. This column reviews the safety and efficacy of these agents, including suggestions and concerns about their use from the 2005 State of the Science Conference on Insomnia sponsored by the National Institutes of Health (NIH).2

 

Melatonin

Studies in Melatonin Use

Melatonin is a naturally occurring “lights off” hormone produced by the pineal gland. Although it is widely perceived to be a sleep promoting substance or hypnotic agent, its specific actions in human physiology are not well-understood. Melatonin clearly plays a role in helping to regulate human circadian rhythms, likely through its effects on melatonin receptors in the suprachiasmatic nucleus of the hypothalamus. However, data supporting the hypothesis that melatonin is effective in the treatment of human sleep disorders is scanty at best. For example, Buscemi and colleagues3,4 performed two meta-analyses of the available literature on the use of melatonin in the treatment of primary and secondary sleep disorders.

In the evaluation of primary sleep disorders,3 14 trials were included for efficacy and 10 for safety. No difference was seen between melatonin and placebo for any efficacy outcome except for sleep-onset latency, which was reduced with melatonin by 11.7 minutes. However, the greatest effect of melatonin with regard to sleep latency was seen for delayed sleep phase syndrome, with a reduction of sleep latency of 38.8 minutes, contrasted with reduction of sleep latency of 7.2 minutes for subjects with insomnia. The conclusions of this study were that evidence suggests that melatonin is not effective in treating most primary sleep disorders with short-term use (≤4 weeks). Some evidence suggests that melatonin effectively treats delayed sleep phase syndrome with short-term use. Evidence also suggests that melatonin is safe with short-term use (<3 months).

In another study,4 a meta-analysis was performed of studies examining sleep disorder secondary to other medical conditions or due to sleep restriction. A total of 32 trials were analyzed for efficacy and/or safety. Conditions in which melatonin was utilized included sleep disorders associated with sleep restriction such as jet lag and shift work sleep disorder (primary conditions in which sleep-promoting effects of melatonin might expect to be seen). The study concluded that there was no evidence that melatonin effectively treats secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shift work disorder. However, evidence suggests that short-term use of melatonin is safe.

 

Melatonin Receptor Agonist

Ramelteon (8 mg/day) is a melatonin receptor agonist, currently the only agent of its type approved for the treatment of insomnia. Its therapeutic effects are believed to be generated by melatonin agonist activity at melatonin (MT)1 and MT2 receptor sites in the suprachiasmatic nucleus. It appears to have no activity at the γ-aminobutyric acid type-A receptor complex, the site-of-action of benzodiazepine and benzodiazepine receptor agonist hypnotic agents.5 Ramelteon has been studied in outpatient and inpatient environments and has been approved at an 8 mg dose for sleep maintenance only. In a crossover study involving 107 adults with chronic primary insomnia, doses of 4, 8, 16, and 32 mg all yielded reductions in sleep latency and increases in total sleep time without evidence of next-day residual effects.6 A 5-week outpatient study was performed involving 829 adults >65 years of age with chronic insomnia. Using the patient-reported sleep data, sleep latency was significantly reduced compared to placebo at weeks 1, 3, and 5, without evidence of rebound insomnia or withdrawal effects following treatment discontinuation.7 Ramelteon has a half-life of 1–2.6 hours and is only indicated for sleep initiation. It appears to have minimal abuse potential or evidence of psychomotor or cognitive toxicity, even at doses of up to 160 mg, 20 times the therapeutic dose.8 Ramelteon is not restricted to short-term use.

 

Antidepressants

Off-label use of antidepressants for the treatment of insomnia is extremely common in the United States. Prominent among these agents is trazodone, a heterocyclic antidepressant, although studies examining its use in the treatment of insomnia are quite limited. One such study,9 a large parallel-group study of well-defined primary insomniac patients, compared trazodone 50 mg, zolpidem 10 mg, and placebo during 2 weeks of administration. Compared with placebo, trazodone and zolpidem shortened subjective sleep latency and increased total sleep duration, with greater reduction in sleep latency seen with zolpidem than with trazodone. The sleep-promoting effects of trazodone compared to placebo were seen only during week 1. In week 2, zolpidem was superior to placebo on sleep latency but not on total sleep time. The findings of this study suggest that trazodone 50 mg may have some short-term hypnotic benefits in primary insomnia, but appeared to be less potent than zolpidem.

Trazodone use has increased dramatically in recent years, with approximately 150% increased usage for the treatment of insomnia between 1987 and 1996.10 The use of trazodone and other sedating antidepressants (including tricyclic antidepressants such as amitriptyline and doxepin) to promote sleep is based on the sedative effects of these agents rather than on demonstrated sleep-promoting properties. Trazodone use is associated with the risk of adverse effects such as orthostatic hypotension, arrhythmias, and priapism, necessitating close supervision of patients who are prescribed this medication for any reason.11 Side effects associated with TCAs include hypotension with syncope, ventricular arrhythmias, and cardiac conduction disturbances.12

Table 1 lists the sedating and activating antidepressants as they relate to insomnia.13

 

 

The NIH State of the Science Conference2 on insomnia found data supporting the use of antidepressants to be lacking. The conference report made the following statement about use of antidepressants for the treatment of insomnia:

 

All antidepressants have potentially significant adverse effects, raising concerns about the risk–benefit ratio. There is a need to establish dose-response relationships for all of these agents and communicate them to prescribers.2

 

Antipsychotics

Antipsychotics have long been used to promote sleep. In the 1960s, patients with histories of substance abuse were likely to be prescribed agents such as thioridazine or chlorpromazine. The risk profile of these agents were acceptable, and they were perceived to be superior to other available agents (chloral hydrate, flurazepam) with regard to safety and abuse potential. Unfortunately, some patients treated with these agents developed tardive dyskinesia.

Currently, atypical antipsychotics (eg, quetiapine and olanzapine) are used off label to promote sleep for patients with and without major psychiatric disorders. For some patients, it may be argued that the sedative and anxiolytic effects of these medications are helpful in reducing daytime anxiety and agitation, or that the antipsychotic effect of the medications help to stabilize mood or reduce “acting out” or other unwanted behaviors. However, the common motivations for choosing these agents appeared to be access and perceived safety. There are a few issues associated with antipsychotics. First, the doses for the treatment of insomnia are uncertain since there are no published studies demonstrating the effectiveness of these agents in patients with insomnia. Second, the risk of certain side effects (neuroleptic malignant syndrome, tardive dyskinesia, and metabolic syndrome) is high. Last, the capacity of these agents to lead to hyperglycemia is well recognized, and the capacity of both newer and older antipsychotics to increase the risk of developing diabetes has recently been demonstrated.14

The NIH Conference also reviewed the safety and efficacy of antipsychotics and made the following observation with regard to their use:

 

Studies demonstrating the usefulness of these medications for either short- or long-term management of insomnia are lacking. Furthermore, all of these agents have significant risks. Thus, their use in the treatment of chronic insomnia cannot be recommended.2

 

Alcohol

Insomniacs often use alcohol to try to promote sleep initiation. The effects of alcohol on sleep are well known, including rapid development of tolerance and sleep fragmentation through the night after initial sedative effects diminish. The State of the Science Conference report stated:

 

While alcohol does reduce sleep latency, drinking large amounts has been shown to result in poorer quality of sleep and awakening during the night… The risk of excess alcohol consumption in persons with alcohol problems makes this an inappropriate treatment for them.2

 

Older Hypnotics

Older hypnotics have demonstrated efficacy in the treatment of insomnia. However, their risk, tolerance, and abuse profiles make them poor choices in comparison with other available compounds. For example, chloral hydrate was synthesized in 1832 and is still available as a hypnotic. Barbiturates were synthesized and first used to promote sleep in the early 20th century. “Barbiturate-like” agents, such as methaqualone, ethchlorvynol, and glutethimide, initially thought to be as effective as the barbiturates but with less potential for tolerance and abuse, were introduced in the mid-20th century. Although these medications were effective in sleep promotion, tolerance to them developed rapidly, dependence was frequent, and overdoses were often lethal due to their potent respiratory suppressant effects. Ironically, barbiturate-like agents were initially believed to be a superior alternative to the barbiturates on the basis of greater safety and less risk of abuse. However, in the 1970s, it became apparent that these agents were unsafe, with a high risk of abuse and a low safety margin or “therapeutic index.” Methaqualone, marketed as Quaalude, became a widely abused recreational drug in the US during the 1960s and 1970s. As the limited therapeutic effects of methaqualone and its addictive nature became more apparent, it was withdrawn from national formularies in many developed countries in the 1980s. In the US in 1984, it was reclassified as a Schedule I drug, an agent with high potential for abuse and no accepted medical use.

 

Herbal and Over-the-Counter Medications

Antihistamines

Sedating antihistamines (ie, hydroxyzine and diphenhydramine) and muscle relaxants (cyclobenzaprine) have long been used for treatment of insomnia. Similar to antidepressants and antipsychotics, the percentage of their total prescription use that is directed toward treatment of insomnia is unknown. Antihistamines such as diphenhydramine are the most commonly used over-the-counter medications for chronic insomnia, but there is no systematic evidence for efficacy and there are significant concerns about risks of these medications. Adverse effects include residual daytime sedation, diminished cognitive function, and delirium, the latter being of particular concern in the elderly. Other adverse effects include dry mouth, blurred vision, urinary retention, constipation, and risk of increased intraocular pressure in individuals with narrow angle glaucoma (Table 2).

 

 

 

Valerian

Many types of agents purported to be of benefit for insomnia are available without prescription. These include herbal agents such as valerian. Regarding valerian, the State of the Science conference report stated:

 

Valerian…is thought to promote sleep. Limited evidence shows no benefit compared with placebo…. Safety data are minimal, but there have been case reports of hepatotoxicity in persons taking herbal products containing valerian. Other herbal remedies have also been promoted, but efficacy evidence is also lacking.2 PP

 

References

1. Fitzgerald FS. Sleeping and waking. Esquire. 1934;2(34):159-160.
2. National Institutes of Health. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
3. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2005;20(12):1151-1158.
4. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006;332(7538):385-393.
5. Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48(2):301-310.
6. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7(1):17-24.
7. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7(4):312-318.
8. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry. 2005;66(suppl 9):31-41.
9. Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic effect of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol. 1998;13(3):191-198.
10. Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep. 2004;27(8):1441-1442.
11. Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging. 1994;4(4):331-355.
12. Witchel HJ, Hancox JC, Nutt DJ. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol. 2003;23(1):58-77.
13. Ancoli-Israel S. Insomnia in the elderly: a review for the primary care practitioner. Sleep. 2000;23(suppl 1):S23-S30.
14. Guo JJ, Keck PE, Corey-Lisle PK, et al. Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, population-based, case-control study. J Clin Psychiatry. 2006;67(7):1055-1061.

 

Suicide Attempts: Time Patterns Before and During Treatment

The debate over the 2004 Food and Drug Administration black box warning on antidepressants is barely waning. Are suicide rates higher or lower for patients on antidepressants, regardless of age? Has the FDA warning prevented deaths by suicide or unintentionally caused more? The FDA warning specifically referred to the use of antidepressants for treatment of pediatric and adolescent depression. Currently, there are clinical trials and observational studies that present conflicting evidence for the safe use of antidepressants, and clinicians have had to evaluate the evidence on their own. A new study by Gregory E. Simon, MD, MPH, and James Savarino, PhD, at the Center for Health Studies in Seattle, Washington, has received national attention from both the mainstream and medical press for its findings, which seem to vindicate antidepressants. The authors state that this study does not counter the FDA warning, however, and that parents and clinicians should continue to exercise caution when prescribing these drugs to young patients.

Simon and Savarino studied the time frames in which suicide attempts occurred for patients beginning new episodes of antidepressant treatment. Outpatient and pharmacy claims data were gathered from the database of a prepaid health plan serving 500,000 members in Idaho and Washington. The study’s criteria for new episodes of antidepressant treatment included no filled antidepressant prescription within the past 180 days, at least one outpatient visit with diagnosis of depressive disorder within 30 days of the initial prescription, and that the patient be ≥7 years of age. Suicide attempts were identified with hospital and emergency room claims attributed to attempted or completed suicides during the 90 days before and 180 days after new treatment episodes.

After filtering claims through these and other criteria, the authors identified 131,788 unique treatment episodes among 109,256 patients. Most treatment episodes,  approximately 55%, began with an antidepressant prescription from a primary practitioner; approximately 40% began in psychotherapy, and approximately 5% began with an antidepressant prescription from a psychiatrist.

The time pattern for attempted suicides was nearly identical for all three treatment groups, although the number of attempts was nearly doubled among patients ≤25 years of age. Among all patients from all treatment groups, however, the incidence of suicide attempt was highest in the month before beginning treatment, next highest in the month after beginning treatment, with a subsequent, steady decline occurring over the following 6 months. This data, according to the authors, “reflects the expected improvement in depression and suicidal ideation when starting treatment rather than any specific effect of either medication or psychotherapy.”

Incidence of suicide attempts was highest among patients prescribed antidepressants by psychiatrists (1,124 per 100,000), lower for those receiving psychotherapy (788 per 100,000), and lowest for those receiving antidepressants from a primary practitioner. However, Simon and Savarino believe that the data do not suggest that psychiatric care increases risk of suicide; rather, patients referred to psychiatrists had undergone an accurate assessment of risk by the referring clinician. That is, higher risk patients were referred to psychiatrists for specialty care rather than to other physicians. All three treatment groups, after all, showed a decline in suicide attempts following initial treatment episode.

Funding for this research was provided by the National Institute of Mental Health. (Am J Psychiatry. 2007;164(7):1029-1034) —LS

 

Phone Counseling Can Coax Males With Alcohol-Use Disorders Into Treatment

While alcohol screening, brief intervention, and referral to a specialist can reduce drinking, many people with alcohol-use disorders either do not respond well to short-lived interventions or do not receive treatment at all. Phone counseling may be of particular help to such individuals who have yet to be helped with their disorder.

Richard L. Brown, MD, MPH, and colleagues, at the University of Wisconsin School of Medicine and Public Health in Madison conducted a 12-month randomized controlled trial of a mail and telephone intervention for primary care patients with alcohol-use disorders who were not undergoing treatment. Systematic screening in 18 primary care waiting rooms around the Madison and Milwaukee, Wisconsin areas, as well as follow-up diagnostic interviews via telephone, resulted in 897 voluntary patients enrolled in the trial. Patients also earned a small fee at each step of the study, amounting to <$125. Up to six sessions of protocol-driven telephone counseling were provided to the patients and were based on motivational interviewing principles and stages of readiness to change. Counselors were assigned to the experimental group to help patients identify their goals and examine how their alcohol-use disorders affected their achievement of such goals. Pamphlets on healthy lifestyles were given to the control group.
In both male and female groups, more telephone counseling sessions were associated with greater decline in drinking. Male patients (N=199) showed a decline of 30.6% in risky drinking days compared to an 8.3% decline in the control group (N=201, P<.001), and total consumption declined by 17.3% compared to 12.9% in the control group (P=.001). Declines in the female groups were not as significant, with a 17.2% decline in risky drinking days in the experimental group (N=246) compared to an 11.5% decline in the control group (N=251; P=not significant [NS]). In addition, total consumption in the female experimental group declined by 13.9% compared to 11.0% in the control group (P=NS). Of note, males with alcohol dependence, as opposed to alcohol abuse, showed a 31.8% decline in risky drinking days over the course of 3 months compared with a 9.7% decline in the control group.

Limitations to the study include inadequate enrollment procedures, such as that the enrollment interview itself affected drinking behaviors independent of the phone counseling intervention sessions. Brown and colleagues are currently studying the benefits of phone counseling over a 12-month period.

Funding for this research was provided by the American Academy of Family Physicians Foundation, the Department of Family Medicine of the University of Wisconsin School of Medicine and Public Health, and the National Institute of Alcohol Abuse and Alcoholism. (Alcoholism: Clinical and Experimental Research. 2007;31(8):1372-1379). —DC

 

Evidence Is Limited on Efficacy of Talk Therapy and Behavioral Interventions for the Treatment of Psychosocial Disorders

When patients experience symptoms stemming from a psychosocial condition, such as major depressive disorder (MDD) or generalized anxiety disorder (GAD), a primary care physician (PCP) is often the first clinician to which the patient will present. In addition, patients may suffer from disorders that present with unexplained physical symptoms but are psychosocial in nature, such as somatization disorder, which can cause chronic physical symptoms.

However, research has shown that there are few evidence-based, nonpharmacologic treatment options for PCPs to provide patients who have mental health disorders. For clinicians, accurate diagnosis and treatment of such patients can be time consuming and patients may not have access to recommended pharmacologic treatment because of medication cost or other factors.

Researchers recently studied whether clinicians employing various therapy-based psychosocial treatment tools or behavioral interventions would be beneficial for patients who first present with psychosocial conditions. Led by Marcus Huibers, PhD, of Maastricht University in The Netherlands, researchers evaluated several randomized controlled trials, clinical trials, and controlled patient preference trials that studied the effectiveness of psychosocial interventions performed by PCPs for any disorder. Prior studies have shown that intervention has been effective treatment for psychosocial disorders, although studies have not examined the efficacy of these methods when performed by PCPs.

Huibers and colleagues included results from 10 studies, which addressed MDD, smoking cessation, alcohol abuse, unexplained fatigue, and somatization disorder, in their evaluation. All studies were gathered from The Cochrane Library, the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, reference lists of relevant studies, and personal communication with clinicians.

The authors found that none of the studies showed conclusive evidence of the effectiveness or ineffectiveness of PCPs performing psychosocial interventions to treat patients with mental health disorders, except for problem-solving treatment for those with MDD. Problem-solving treatment focuses on helping patients recognize that symptoms may be caused by external problems and create solutions to those problems. Regarding the remaining interventions by PCPs—cognitive-behavioral therapy (CBT) for somatization disorder, CBT for unexplained fatigue, therapy for smoking cessation, and behavioral intervention for alcohol abuse—the authors found efficacy evidence to be either limited or conflicting.

Huibers and colleagues concluded that although results showed that therapy and behavioral interventions when performed by PCPs were not effective for patients with mental health disorders, PCPs should continue to use these or similar methods in the treatment of patients with psychosocial disorders. The authors said treatment methods used in evaluated studies did not cause any negative outcomes for patients as well.

The authors added that problem-solving treatment does show efficacy when PCPs utilize this intervention with MDD patients. However, the authors said as there is little evidence on the use of psychosocial interventions by PCPs overall, more research and use in clinical practice is necessary to determine the overall benefit of problem-solving treatment for MDD patients. (Cochrane Database Syst Rev. 2007;3:CD003494). —CP

Psychiatric Dispatches is written by Dena Croog, Carlos Perkins, Jr., and Lonnie Stoltzfoos.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Psychiatrists and other clinicians working in general medical or specialized neurologic settings frequently encounter important psychiatric issues affecting diagnosis and management of patients with neurologic illnesses. These include cognitive impairment either as a primary presentation or as a secondary complication of a known neurologic condition such as multiple sclerosis; other psychiatric symptoms as a manifestation or complication of neurologic disease; and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease, ie, conversion disorder or somatization disorder. In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. A more detailed coverage of these topics can be found elsewhere.1,2 This column illustrates the principles of evaluating and treating psychopathology in neurologic illness in the most common disorder affecting the central nervous system, stroke.

A cerebrovascular accident, or stroke, is defined as a focal disturbance of cerebral function of presumed vascular origin with rapid onset and lasting >24 hours, caused by cerebral infarction or hemorrhage. Infarction results from thrombosis of vessels or emboli. Infarctions are much more common than hemorrhages and, as a result of a lower immediate fatality rate, are a much greater source of enduring disability. Strokes are the third most common cause of death in the Western world.

Psychosocial factors influence the risk for stroke. Stroke is more common in widowers, divorcees, those with less education, those engaged in hard manual labor, and those with low social support. There is also evidence that depression and other psychological factors constitute risks for stroke, consistent with widespread lay and folk beliefs regarding stress and stroke. There is some evidence that anger/hostility may pose a risk for carotid atherosclerosis just as it may for coronary disease. In some longitudinal prospective epidemiologic studies, depression appears to significantly predict greater stroke frequency, but the finding sometimes disappears when other significant predictors are taken into consideration (eg, age, sex, smoking, hypertension, diabetes) As with many other major medical illnesses, stroke patients who have extensive social support have better functional outcomes than those who do not.

 

Cognitive Disorders After Stroke

Delirium occurs in 30% to 40% of patients during the first week after a stroke, especially after a hemorrhagic stroke. Delirium after a stroke is associated with poorer prognosis, longer hospital stays, and increased risk of dementia.1

Dementia is common following stroke, occurring in approximately 25% of patients at 3 months after stroke. Vascular dementia is an overarching term encompassing subcortical ischemic dementia, multi-infarct dementia, and dementia due to focal strategic infarction, ie, unexpectedly severe cognitive impairment following limited infarction in critical brain areas such as the thalamus, internal capsule, and basal ganglia.1

 

Psychiatric Issues that May Present After Stroke

A wide variety of focal cognitive deficits as well as emotional and behavioral changes may occur after stroke, depending on the location of the vascular occlusion or bleed. Such changes reflect the specific affected cerebral area and are not unique to stroke. These include aphasia, anosognosia, dysprosody, apathy, depression, anxiety, emotional incontinence, catastrophic reactions, psychosis, obsessive-compulsive symptoms, and hyposexuality.

 

Aphasia

Global aphasia occurs when all linguistic abilities have been lost, making communication extremely limited, and the physician must infer mental state from behavior and nonverbal communication. In expressive (Broca’s) aphasia, intense emotional frustration is common due to the difficulties in patients’ making themselves understood and the resulting problems in social interaction.3 In receptive (Wernicke’s) aphasia, patients manifest irritability and rage because they do not understand what others are saying, and therefore lack insight. Some recovered patients have reported that they thought their physicians were being deliberately incomprehensible.4

 

Anosognosia

Anosognosia refers to partial or complete unawareness of a deficit. In extreme cases, patients may deny that a limb or an entire side of their body belongs to them, attributing it to someone else. Anosognosia occurs more frequently with nondominant parietal lobe strokes.

 

Dysprosody

Dysprosodia is impairment of the production of those aspects of speech that communicate emotions,. It is characterized by alterations in intensity, timing, rhythm, cadence, melody, and intonation of words. Dysprosody is a deficit in the ability to communicate emotions, but is not associated with an actual deficit in the ability to experience emotions. Dysprosodic speech sounds flat and robotic. Others must infer the patient’s emotional state from the content of the patient’s speech and facial expressions.

 

Apathy

Patients with apathy show absence of passion, emotion, or excitement. They lack interest in or concern for things that others find moving or exciting. Apathetic patients produce little spontaneous action or speech. Apathy is associated primarily with frontal lobe strokes.

 

Depression

Depression is very common following stroke but its diagnosis is problematic because it can be unclear which symptoms are attributable to the stroke and which are attributable to depression. In patients with strokes that result in significant deficits, one must also distinguish between normal or adjustment reactions and major depressive disorder (MDD). Persistent dysphoric mood, anhedonia, vegetative symptoms (eg, insomnia, anorexia), and poor participation in rehabilitation point to a diagnosis of MDD. The 9-item Patient Health Questionnaire performs well as a screening instrument for poststroke depression.5 Depression after stroke has been associated with increased disability6 and mortality.7

Many studies have examined whether depression is associated with the location of the stroke lesion (particularly the left frontal lobe), but a consensus has not been reached in the literature. Meta-analyses have both supported8 and not supported a relationship between stroke location and incidence of subsequent depression.9,10

Treatment for depression should be started early after stroke in order to improve participation in rehabilitation and maximize functional outcome. There is some evidence that effective treatment of depression leads to a reduction in overall disability1 and even reduction in mortality.11 However, in many patients, poststroke depression tends to improve over time irrespective of treatment. While there have been several randomized placebo-controlled trials demonstrating the effectiveness of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in poststroke depression,12,13 antidepressants have not been more effective than placebo for treatment of poststroke depression in numerous recent controlled trials.14-16

Antidepressants have been demonstrated to improve some of the related symptoms that may accompany poststroke depressive states, including emotional incontinence,15 anger proneness,15 and executive dysfunction,17 but not fatigue.18 There have also been mixed results in controlled trials to determine if early antidepressant therapy after stroke can prevent the development of depression16,19; however, a recent meta-analysis concluded that antidepressant prophylaxis is associated with a significant reduction in the occurrence rate of newly developed poststroke depression.20

Randomized controlled trials have also supported the efficacy of exercise,21 case management,22 and acupuncture23 in the treatment of poststroke depression. Cognitive-behavioral therapy may offer an alternative to antidepressants, but has not received adequate study of its efficacy in postroke depression.24

 

Anxiety

Clinically significant anxiety is common in ischemic stroke patients, frequently co-occurs with depression, and may interfere with rehabilitation. Anxiety after stroke is usually in the form of generalized anxiety and appears to share risk factors with depression.25 Reported rates of prevalence of generalized anxiety disorder (GAD) after stroke range from 4% to 28%, with a higher percentage of patients experiencing anxiety symptoms.1

Poststroke anxiety may include posttraumatic stress symptoms, anticipatory anxiety about the risk of recurrence, and somatization. There is a lack of randomized controlled trial data to guide treatment of anxiety after stroke, but there is no reason not to apply the usual psychotherapeutic and psychopharmacologic treatments. When GAD is comorbid with poststroke depression, it appears to respond to antidepressant therapy.26

 

Emotional Incontinence

Emotional incontinence (also referred to as pathological crying or laughing, emotional diarrhea, emotional lability, pseudobulbar affect, or, more recently, involuntary emotional expression disorder [IEED]27) is a syndrome of uncontrollable episodes of emotional expression that occur after stroke and in a variety of other neurologic conditions. IEED is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. The crying or laughing are disinhibited and experienced by the patient as unwanted and a struggle to stop. In addition to stroke, this syndrome is common in patients with frontal lobe lesions due to traumatic brain injury, multiple sclerosis, pseudobulbar palsy, and amyotrophic lateral sclerosis.

Pathological crying or laughing can have a significant impact on individuals’ social functioning and their relationships with others. Unpredictable and uncontrollable outbursts of affect often cause severe embarrassment and avoidance of social interactions and may result in subsequent agoraphobia.

Treatment options include TCAs, SSRIs, dopamine agonists, and a combination of dextromethorphan and quinidine.28

 

Catastrophic Reactions

Catastrophic reactions are outbursts of frustration, dysphoria, and anger when confronted with a frustrating (usually cognitive) task, often appearing suddenly and unexpectedly, startling caregivers and relatives. Catastrophic reactions, emotional incontinence, and poststroke depression share some symptoms in common and often co-occur but are distinct clinical syndromes. One prospective study of patients with a first stroke identified catastrophic reactions in 12 of 326 patients within 48 hours from onset of the stroke, and were associated with nonfluent aphasias.29 Another study found that catastrophic reactions after acute stroke were significantly associated with depression, a personal and family history of psychiatric disorder, and subcortical lesions which were mostly located in the basal ganglia.30

 

Psychosis

Psychosis can be caused by stroke but is very uncommon, with an incidence of approximately 1%. Pre-existing cortical atrophy increases the risk for poststroke psychosis. Auditory hallucinations can be directly caused by acute stroke, mostly described after lesions of the brain stem, but rarely reported after cortical strokes. A cross-sectional study of 641 stroke patients identified four patients who developed postcortical stroke auditory hallucinations.31 All of them occurred after an ischemic lesion of the right temporal lobe, and all resolved without pharmacotherapy in a few months. Stroke can also cause delusions, which sometimes are persistent to the point of constituting a delusional disorder, eg, delusions of parasitosis.32 If psychotic symptoms appearing soon after stroke are mild and not distressing to the patient, drug treatment may not be necessary. Significant persistent or disruptive psychosis should usually be treated with antipsychotics since the risk of untreated psychosis usually is greater than the risk of increased mortality reported in some studies of patients with dementia receiving antipsychotics. However, long-term treatment may not be needed since most poststroke psychotic symptoms in patients without dementia will resolve.

 

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder has been reported after strokes, most often those affecting the basal ganglia or brainstem. Case reports suggest that both antidepressants33 and behavior therapy34 can be effective.

 

Hyposexuality

Decline in sexual interest and activity is common after stroke, with greater declines in those who are older or disabled. Psychological rather than physical aspects account for most of the decline in sexual activity in stroke survivors.35 Patients’ partners play a substantial role in the decline of sexual activity, related to their own anguish and anxiety over risk for recurrence of stroke. Patients and their partners can be counseled that sexual intercourse does not increase risk for stroke.36 Sexual dysfunction after stroke frequently occurs alongside depression; therefore, treatment for depression is likely to help restore normal sexual functioning37 unless the sexual dysfunction has been caused by an antidepressant. Patients with stroke may also have major medical comorbidities contributing to sexual dysfunction, including diabetes mellitus, peripheral vascular disease, and hypertension (with sexual dysfunction due to antihypertensives such as β-blockers).

 

Conversion Disorder and Stroke

Because some patients with conversion disorder present with acute onset of neurologic symptoms, they may be misdiagnosed as having transient ischemic attacks or strokes. In one study of 151 consecutive patients presenting to an emergency room initially diagnosed with stroke who received tissue plasminogen activator, four turned out to have conversion disorder instead.38 Careful neurologic examination and imaging studies permit distinguishing which patients really have strokes. The older the patient, the less likely it is that the diagnosis is conversion disorder. PP

 

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