Posted by jrbecker on February 10, 2005, at 12:51:33
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 259-266
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2004.01.016
Copyright © 2004 Elsevier B.V. All rights reserved.
Preliminary communication
Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic–dysthymic temperament
J. Sloan Manning , a, , , Radwan F. Haykala, b, Pamela D. Connora, Patricia D. Cunninghama, W. Clay Jacksona and Stephanie Longaa From Mood Clinic, Family Medicine Department, University of Tennessee, Memphis, TN, USA
b From Psychiatry Department, University of Tennessee, Memphis, TN, USAReceived 28 May 2003; accepted 30 January 2004. Available online 26 April 2004.
Abstract
Background: The treatment of bipolar depression remains problematic. Lamotrigine has been shown in randomized controlled studies to be efficacious in preventing bipolar depression and rapid cycling states. Methods: Twenty-four women with cyclothymic temperament and refractory depression were recruited from four outpatient sites (three primary care and one psychiatric) and treated with lamotrigine in a naturalistic, open-label study. Temperament was determined by responses on the TEMP-A self-rating scale. Eighteen (75%) of these cyclothymic patients also scored high on the depressive temperament. Eighteen (75%) met DSM-IV criteria for bipolar II disorder. In two thirds of the cases, lamotrigine was add-on therapy to an antidepressant. Response to therapy was assessed using the DSM-IV Global Assessment of Functioning (GAF). Limitations: This study was naturalistic in design, without controls or blinds. Results: Of the 23 patients who remained in the study, 16 (70%) had significant, sustained responses. Of these 16, 12 (75% of responders, 52% of the total) had remissions (GAF>80) sustained longer than 12 months. Robust, sustained responses to lamotrigine monotherapy were seen in 4 patients (17%). Seven patients (30%) received no apparent benefit from lamotrigine. Conclusions: Lamotrigine induced prolonged illness remissions in a substantial number of female patients whose symptoms were both complex and refractory. Most manifested high scores on the cyclothymic and depressive temperaments, and prior refractoriness to multiple antidepressant and antidepressant/mood stabilizer combinations, before remitting with lamotrigine augmentation or monotherapy.1. Introduction
Lamotrigine, an antiepileptic drug (AED) originally developed for the treatment of partial epilepsy, also shows evidence of usefulness in the treatment of bipolar disorder. Open and controlled trials have revealed anti-manic activity (Ichim et al., 2000) and efficacy in bipolar depression (Calabrese et al., 1999 and Bowden et al., 1999). Additionally, lamotrigine has demonstrated efficacy in rapid cycling bipolar illness (Calabrese et al., 1996 and Calabrese et al., 2000).
Bipolar disorders are increasingly identified in psychiatric practice. Information on the phenomenology, pedigree, longitudinal course, and treatment response of bipolar illness has shifted previous conceptualizations of unipolar depression into the bipolar spectrum. In one large multicenter study in France, 40% of depressed psychiatric outpatients could be diagnosed as bipolar II based on expert questioning for mood lability and temperamental precursors and longitudinal observation (Allilaire et al., 2001).
This trend is also evidenced in primary care settings, where the prevalent subtypes of depressive illness were, on the basis of bipolar-insensitive, cross-sectional interviews, also thought to be overwhelmingly "unipolar." However, more recent observations have identified bipolar illness in as many as a third of depressed or anxious primary care outpatients (Manning et al., 1997 and Manning et al., 1999). Current estimates of bipolar illness in the general population are in the 3–5% range (Akiskal et al., 2000; Judd and Akiskal, 2003 and Hirschfeld et al., 2003), when bipolar II and related illness is taken into account. With perhaps only a third of these patients being seen in the specialty mental health sector, the treatment of the remaining two thirds is unaccounted. Since the primary care setting serves as the de facto US mental health services sector (Regier et al., 1993), a substantial number of these bipolar patients not currently under psychiatric care may be receiving such treatment in primary care settings.
DSM-IV (American Psychiatric Association, 1994) is relatively insensitive regarding bipolar II, the most common presentation of bipolarity, because it requires a minimum duration of 4 days for hypomania. In clinical practice hypomania typically lasts 1–3 days (Angst, 1998 and Wicki and Angst, 1991). In fact, these shorter, subtler forms of hypomania identify bipolarity without sacrificing diagnostic specificity (Benazzi, 2001). The DSM-IV emphasis on categorical criteria ignores the dimensional features that may be key to accurate and early diagnosis (Akiskal et al., 1995). Recently, Akiskal and Pinto (1999) suggested an expanded descriptive bipolar terminology that includes these dimensional features ranging from schizoaffective presentations to depressions arising from premorbid cyclothymic and hyperthymic (hypomanic) temperament. These affective temperaments have been operationalized using Kraepelin's (Kraepelin, 1899/1921) original conceptualizations and descriptions (Akiskal et al., in press).
As mixed temperamental presentations are common (Akiskal, 1992) in "soft" bipolar illness, we became interested in bipolar patients with cyclothymia (mood lability) around a dysthymic baseline. These "uneven" or "driven" dysthymics (Akiskal, 1996) retained the lifelong low self-esteem, pessimism, social anxiety, and lethargy of early onset dysthymia, but manifested an affective course punctuated by major depression and recurrent, albeit brief, escapes into energy, passion, socialization, and productivity that began and ended abruptly and were not experienced by patients as abnormal. This temperamental mixing and clinical presentation is common in our practice setting, and such patients, when treated for syndromal depressions, are prone to antidepressant resistance and treatment-emergent hypomania or mixed features (Akiskal, 1981). This presentation is properly viewed within the bipolar spectrum. One such patient with a modest response to paroxetine combined with divalproex was switched to a paroxetine–lamotrigine combination to avoid associated effects of weight gain and somnolence. The result (see case #1 below) was a robust, 36-month remission from illness that began the series of treatment attempts reported in this paper.
2. Methods
Twenty-four patients were included in the study. Twenty-one patients were seen in one of three ambulatory primary care sites in the University's Department of Family Medicine's residency training system while three were recruited from the private psychiatric practice of one of the Department of Family Medicine's clinical faculty members. All patients were Caucasian females, aged 37.5±9.5 (mean±standard deviation) years (range 22–55). Participating clinicians had previously established inter-rater reliabilities through prolonged contact with mentorship interaction including direct observation of interview and diagnostic skills in the department's Mood Disorder Clinics (MDC). These advanced teaching and patient care centers within a family practice residency exist to provide on-site expert consultation for primary care patients with mood disorders while retaining longitudinal contact and continuity of care. The development and operation of the MDC are described elsewhere (Manning et al., 1999).
The following measurement methods were used consistently at all sites. To be considered for this case series, patients must have been documented to have cyclothymic temperament by the TEMP-A operational criteria (Akiskal et al., in press) and diagnosed with mood disturbances refractory to one or more antidepressant and/or mood stabilizer interventions with proper therapeutic dosage and a treatment duration of at least 6 weeks (Souery et al., 1999). All patients presented in a depressed episode that met DSM-IV criteria for major depression and had illness characterized by chronic or recurrent major depression and long-lasting affective instability. In most cases, lamotrigine was added to a treatment regimen (usually antidepressant monotherapy) yielding only partial improvement in symptoms. DSM-IV diagnoses were made using a semi-structured interview (Manning et al., 1997). We used the International Mood Clinic (IMC) criteria devised by Akiskal and Pinto (1999) to identify the bipolar I1/2 (depression with protracted hypomania) and bipolar II1/2 (cyclothymic depressions) patients. Longitudinal, direct observation, supplemented where necessary by chart review and information from patient's significant others, was used to assign an initial and final GAF rating. Responses that yielded a final GAF score >70 were designated "significant". Responses with final GAF scores >80 were designated "robust" (remission). "Sustained" was defined as an absence of clinically significant depressed, expansive, or irritable mood during an observation period of at least 12 months.
Lamotrigine was dosed at the discretion of the clinician. Most titrations corresponded to the manufacturer's recommended schedule for patients not on another anticonvulsant, with dose increases of 25–50 mg every 2 weeks. Increases or decreases in the lamotrigine dose were permitted to maximize clinical effect or minimize an adverse effect.
3. Results
Twenty-four patients with cyclothymic temperament and refractory mood states were identified and then placed on lamotrigine (Table 1). Patient demographics are summarized in Table 2. All but three patients were recruited from the family practice setting. Doses of lamotrigine were 181.25 mg±S.D. 41.2 mg/day (range 100–250 mg). One patient developed a benign, unexplained rash during the initiation of therapy and discontinued lamotrigine (4%). Of the 23 patients, 16 (70%) experienced at least a significant sustained response; 12 of these 16 (75%) had a GAF >80 longer than 12 months. This means that 12 of 23 (52% of total sample) experienced a sustained robust response. Lamotrigine yielded no benefit to seven patients (30%). Of these seven, one had a robust response, then relapsed into cocaine abuse. Three other patients discontinued lamotrigine before a clinical effect could be observed. We conservatively added all these four patients to the other three non-responders. The three patients who exhibited a pure cyclothymic temperament type (as recorded by the TEMP-A) were all among the non-responders. By contrast, all three cyclothymic/hyperthymic patients experienced a robust (GAF>80) sustained response to lamotrigine. The rest of the patients (75%) manifested a mixed cyclothymic/dysthymic TEMP-A pattern.Lamotrigine monotherapy was given to 4 patients (17%), while concomitant medications were used in 20 of 24 patients (83%). Lithium was used in 4 (17%) and antidepressants in the others. Multiple prior antidepressant failures were common in those studied (Table 3). No particular pattern of response related to differing medications could be discerned. Comorbid medical conditions are listed for descriptive purposes and include diabetes mellitus Type II b, essential hypertension, or mild persistent asthma. In no instance was the general medical comorbid condition or its treatment judged to be a factor in treatment resistance.
4. Discussion
Our results add to the body of literature (Calabrese et al., 2000 and Calabrese et al., 2003) suggesting that lamotrigine is an effective medication in the management of bipolar disorder. Our report is unique in a least four respects.
First, we report on the efficacy of lamotrigine in a largely primary care setting and demonstrate that clinical material is abundant there and warrants more sophisticated interventions for bipolar spectrum illness.
Secondly, we focus in this sample on the most prevalent manifestation of bipolarity—that of "soft" or non-manic bipolar illness. These patients often experience abrupt shifts in mood, usually in the downward (depressive) direction, that respond poorly to antidepressant therapy. They are at high risk for dysfunction in academic, occupational, and interpersonal pursuits. The use of the TEMP-A permitted a quick, reliable, and clinically relevant assessment of affective temperaments, expanding the diagnosis of bipolarity beyond the narrow categorical approach of DSM-IV.
Thirdly, most of the patients included in this study simultaneously met operational criteria for two temperament subtypes, 21 of 24, and the majority of cases (18 of 24) manifested a mixed cyclothymic/dysthymic pattern. In-depth clinical interviews and follow-up suggest that this mixture, corresponding to Kretschmer's cycloid personality (Kretschmer, 1936), heavily influenced the life pursuits and clinical presentation of the illness. Dysthymics are typically guilt-ridden, gloomy, socially anxious pessimists with a tendency to hypersomnia. Their sub-bipolar core traits are well described in clinical cohorts (Akiskal et al., 1980 and Haykal and Akiskal, 1999). Cyclothymics tend to shift abruptly every few days from such a low-energy state to one characterized by enthusiasm, social interaction, and novelty-seeking with a noticeably decreased need for sleep (similar to that of hyperthymic individuals) in a biphasic pattern (Akiskal et al., 1977). That this abrupt shifting can alternate around or coexist with a dysthymic baseline mood might explain why the phases of higher energy and subsequent hypomanias are so easily missed in these temperamentally mixed patients. Such individuals switch or cycle "up" to "normal", but they gain little benefit from this pseudo-normalcy because it is short-lived. However, the consequences of decisions made while motivated by these upward shifts can be significant. Importantly, such individuals often suffer prolonged, disabling major depressions, with only brief respites. Extension of the temperamental and clinical presentation into prolonged states of irritability is also common (Akiskal et al., 1977 and Koukopoulos and Koukopoulos, 1999). Many of these patients may manifest "borderline" personality features (Akiskal, 1981). Mood stabilizers like lamotrigine may be an effective intervention for borderline personality disorder whether or not DSM-IV criteria for a major mood disorder are met (Pinto and Akiskal, 1998); the same appears to be true for divalproex (Frankenburg and Zanarini, 2002).
Lastly, we excluded from our series male patients with similar temperamental underpinnings. While this limitation removed only a few patients from consideration [since bipolar II appears to be more common in females (Perugi et al., 1990)], their exclusion left the study population undiluted by a male population less at risk for the highest cycle rates and without the premenstrual worsenings of affective symptoms that plague many female bipolars. However, our anecdotal experience with lamotrigine use in bipolar II males is similarly encouraging. We did not report on rapid cycling vs. non-rapid cycling in the analysis because the term "rapid cycling" loses its usefulness in bipolar II1/2, in which one or two hypomanic episodes per month are often the norm.
The inclusion of the additional descriptive labels proposed by Akiskal and Pinto (1999) helps in two ways. It allows differentiation of a larger segment of the DSM-IV bipolar II population with brief hypomanias from a smaller segment with bipolar I genetic underpinnings and longer (weeks to months) hypomanias (bipolar I1/2). These subtypes may not be demonstrating full manic episodes because of incomplete penetrance or because of attenuation of episodes of expansive mood by treatment prior to full expression. The progression of bipolar II to bipolar I is uncommon (Coryell et al., 1995). The newer proposal of Akiskal and Pinto (1999) also permits patients with early-onset or recurrent pseudo-unipolar conditions to be more naturally (and, many maintain, more correctly) grouped with others who share similar affective temperamental roots. It also facilitates the communication of a recognizable pattern of morbid and temperamental phenomenology to assist interested clinicians and peer review. In the descriptive nosology of Akiskal and Pinto (1999), bipolar II1/2 also differs from bipolar II in that the required duration of hypomania is 2 days. Such a 2-day criterion for hypomania correlates well with NIMH prospective data on mood lability and bipolar II outcome and recent investigations documenting a 1- to 3-day mean modal duration of hypomania.
All three patients with a "pure" cyclothymic temperament were poor responders. It is well known that underlying cyclothymia is a destabilizing and poor prognostic factor in bipolar II treatment outcome (Akiskal et al., 2003). By contrast, the three patients with a mixed cyclothymic/hyperthymic temperament had a superior response to lamotrigine augmentation. This may imply that the temperamental predominance of hypomania rather than depression may have a better prognosis. It also may mean that lamotrigine is efficacious in eradicating depressive symptoms while preserving features of hyperthymia. If so, lamotrigine would be an "ideal" mood stabilizer. In comparison of patients with bipolar II and those with bipolar II1/2, the patterns of response to treatment were similar. This similarity is a reaffirmation that bipolar subcategories beyond bipolar II still behave clinically like the more strictly defined bipolar II of DSM-IV. From a pragmatic treatment perspective, they are well embedded in the bipolar spectrum.
It cannot be determined from our data whether more patients might have obtained responses to lamotrigine monotherapy. All patients were kept on their concomitant medications during remission. However, the fact that four patients experienced such robust remissions on lamotrigine alone makes this an intriguing possibility. There is also the question of the value of lamotrigine monotherapy in antidepressant naive patients compared to its potential benefit in those with demonstrated antidepressant resistance. This suggests that a randomized study of lamotrigine (as a single agent possessing both mood-stabilizing and antidepressant properties) is warranted in bipolar II. In such a study, particular attention should be directed to response in groups controlled for past treatment attempts and/or combination therapies.
The responses induced by lamotrigine in these patients were sustained over long periods of time, suggesting a high level of effectiveness. The robustness of the majority of those responses allowed noticeable improvements in functioning that permitted patients to recover skills, acquire new ones, and experience substantial gains in quality of life, documented in a global fashion. The following clinical vignettes will serve as illustrations.
4.1. Case #1
Mrs. A. was a 29-year-old woman presenting with a recurrent episode of major depression with atypical features. She had suffered from some level of depression since early adolescence and had been treated unsuccessfully with three different serotonin specific reuptake inhibitors (SSRIs), each at adequate doses for at least 8 weeks. At the time of presentation, she was receiving paroxetine prescribed by another physician, but deriving only modest benefit from it. Mrs. A. described herself as "a person in search of herself" whose gloomy pessimism made her husband's life difficult, stating, "I don't know why he's stayed with me this long." She was employed at a local museum, but found getting along with co-workers and her supervisor difficult because of her self-described low self-esteem and rejection sensitivity. She described her family as "totally crazy," with her father and many female members of his family being alcoholic or having "nerve problems." No formal diagnosis of bipolar disorder in a family member had been made. She experienced what she described as periods of "being normal" once or twice a month. On these "normal" days, she would typically wake up feeling the need to "get as much done as possible while the energy lasted," knowing that in a day or so she would be too tired to function. During these bursts of energy, she experienced racing thoughts, conjugal interest (rare for her), and the desire to clean house, rearrange furniture, or work on craft projects often until 2 or 3 a.m. At times this energy would be largely irritable, resulting in arguments with her husband and threats of divorce. Mrs. A. met criteria for bipolar II1/2, and a trial of divalproex added to the paroxetine evened her moods significantly, but without improving her sense of fatigue, low self-esteem, and lack of motivation. It also resulted in a 15-lb weight gain, prompting her request to discontinue the medication. A gradual switch to lamotrigine caused a noticeable improvement in mood and mood stability when the dose reached 100 mg/day. On the third visit for follow-up, her husband joined her to express thankfulness for her "dramatic turnaround." At her most recent visit, years later, she requested information on pregnancy and drug-related risks, offering, "I never considered having children before, but after nearly 3 years of feeling well, I want to know what it is like to be a mother."
4.2. Case #2
Mrs. B. was a 42-year-old woman who presented with complaints of anxiety and depression that she believed might be related to perimenopause, though a variety of hormone preparations (single and combined) had failed to provide improvement. She was employed as a real-estate broker who used her job to "avoid her husband." She found handling her two teenage daughters difficult and described her home as "full of women with continuous premenstrual syndrome (PMS)." She had experienced at least four previous major depressions beginning at age 17, with two episodes following the birth of her children, and a fourth ostensibly triggered by a period of marital discord. Two previous trials of antidepressant treatment with SSRIs and one trial with bupropion failed to improve consistently her depression. She commented, "Antidepressants never really worked for me. I would feel pretty good for several weeks, but the depression would always come rushing back." Mrs. B. experienced regular and abrupt shifts to expansive moods that lasted 7–10 days. During these usually elated times, she spent money frivolously and indulged herself and her daughters in spur-of-the-moment vacations to the mountains to ski or to the coast to sunbathe. On one or two occasions during these expansive moods, she participated in sexual trysts that caused profound guilt after her mood "crashed." Mrs. B. met DSM-IV criteria for bipolar II and was begun on lamotrigine as a monotherapy, producing a very satisfying "evenness" that has been maintained for over 2 years. She now wonders how her life would be different, if she had experienced stable euthymia in past years. She suspects her "wreck of a marriage" could have been avoided.
Overall, our data cohere very well with the current literature on lamotrigine's efficacy profile in bipolar II, rapid-cycling, and so-called "borderline" patients. While this paper was under review, two pivotal studies demonstrated the lfficacy of lamotrigine in bipolar I, with greater specificity for preventing the depressive phase (Calabrese et al., 2003 and Bowden et al., 2003).
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