Psychiatry (Edgemont) 2010;7(5):27–32

Psychiatry (Edgemont) 2010;7(4):21–30

by Ashley B. Johnson, DO; Julie P. Gentile, MD; and Terry L. Correll, DO
Dr. Johnson is a Fourth Year Resident, Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, Ohio. Dr. Gentile is Associate Professor, Department of Psychiatry, Boonshoft School of Medicine, Wright State University. Dr. Correll is Assistant Professor, Department of Psychiatry, Boonshoft School of Medicine, Wright State University.

Psychiatry (Edgemont) 2010;7(4):21–30

Funding: There was no funding for the development and writing of this article.

Financial disclosure: The authors have no conflicts of interest relevant to the content of this article.

Editor’s note: All cases presented in the series “Psychotherapy Rounds” are composites constructed to illustrate teaching and learning points and are not meant to represent actual persons in treatment.

Key words: psychotherapy, bipolar disorder, borderline personality disorder, diagnostic dilemma

Abstract

The high prevalence of comorbid bipolar and borderline personality disorders and some diagnostic criteria similar to both conditions present both diagnostic and therapeutic challenges. This article delineates certain symptoms which, by careful history taking, may be attributed more closely to one of these two disorders. Making the correct primary diagnosis along with comorbid psychiatric conditions and choosing the appropriate type of psychotherapy and pharmacotherapy are critical steps to a patient’s recovery. In this article, we will use a case example to illustrate some of the challenges the psychiatrist may face in diagnosing and treating borderline personality disorder. In addition, we will explore treatment strategies, including various types of therapy modalities and medication classes, which may prove effective in stabilizing or reducing a broad range of symptomotology associated with borderline personality disorder.

Introduction

Borderline personality disorder (BPD) is a highly prevalent, chronic, and debilitating psychiatric problem characterized by a pattern of symptoms that may include chaotic and self-defeating interpersonal relationships, emotional lability, poor impulse control, angry outbursts, frequent suicidality, and self-mutilation.[1] It is not uncommon for the psychiatrist to see symptoms of both bipolar disorder (BD) and BPD, which creates a diagnostic dilemma that must be distinguished by the time of treatment initiation due to their diverging methods of approach. There are similar symptoms that may be seen in clinical presentations of both of these psychiatric disorders (Table 1 Table 2 Table 3 Table 4 Table 5).[2]

The treatment of choice for BPD remains psychotherapy.[1] In this clinical vignette, the authors will review some of the common issues that present themselves as the psychiatrist navigates this often challenging professional relationship.

Clinical Case

Brittany was a 22-year-old, single woman who presented for psychiatric consultation for ongoing management of BD.

Brittany was first diagnosed with BD as an unruly 16-year-old high school student. Subsequently, she had been seen by multiple psychiatrists for this disorder and had been prescribed multiple mood stabilizers, including gabapentin (Neurontin, Parke-Davis: Division of Pfizer Inc, New York), lamotrigine (Lamictal, GlaxoSmithKline, Research Triangle Park, North Carolina.), and valproic acid (Depakote, Abbott Laboratories, Abbott Park, Illinois). Most recently, she reported an overdose of valproic acid, which required a five-day stay in an intensive care unit; no subsequent inpatient psychiatric hospitalization was recommended. At the time of discharge, she assured the doctors that she was “fine,” that “it was a stupid thing to do,” and she verbally contracted that she would never try to overdose again.

During intake interview following the hospitalization, while she initially characterized her formative years as “good” with no report of any abuse, it became apparent that she had endured significant neglect from her parents, both of whom worked full-time to provide for the family.

Brittany described her symptoms of BD as starting at about the age of eight when she remembers it was necessary for her mother to seek full-time employment.

She remembered always having variable moods being “up and down,” which were consistently correlated with multiple relational triggers in her life. As an example, she described being “manic” after a boy showed interest in her at school. Her ‘manic’ episode included increased energy and excitement, texting her friends up to a couple hundred times a day, shopping tirelessly to find the right outfit to wear for him, and noticing an increased sexual drive; her family members commented on her energetic behavior. When peers would tease her about being “easy” or she suspected her boyfriend was flirting with another classmate, she would seemingly lose control by yelling obscenities in an angry, uncontrolled rant.

These “manic” episodes could occur frequently (up to several times daily) depending on how many good things happened in her life and typically would last several hours at a time.

During the first interview, Brittany’s speech was very rapid as she described her situation. The psychiatrist initially concluded that she was “pan-positive” on nearly every symptom of BD, but wanted additional time to consider possible axis II pathology. Psychotherapy had never been offered as part of the treatment recommendations; pharmacologic management had been the focus of her treatment thus far.

PRACTICE POINT

Diagnostic dilemma: BP versus BPD. BPD and BD, and particularly BD II, prove to be diagnostic dilemmas for practitioners due to the high occurrence of symptom overlap. Both disorders are associated with a considerable risk of suicide or suicide attempts, impulsivity, inappropriate anger, and unstable relationships.[3] However, many symptoms are particularly common in BPD to include self mutilation, self-injurious behavior without suicidal intent, and a stronger association to a childhood history of abuse. Insecure attachments, signified by an intense fear of abandonment, are hallmarks of BPD and not typical characteristics of BD.[3] Patients with BPD also demonstrate a higher level of impulsivity, hostility, and acute suicidal threats when compared to patients with BD.[3] Furthermore, Fiedorowwicz and Black[3] suggest careful history taking usually elicits a differing time course of mood lability: “Mood lability of BPD often is produced by interpersonal sensitivity, whereas mood lability in bipolar disorder tends to be autonomous and persistent.”[3]

Widiger and Mullins-Sweatt[4] delineate a time course of BPD symptoms over a lifetime. Early in life, patients are likely to have been emotionally unstable, impulsive, and hostile, although, thus far, research has not clearly defined childhood antecedents of BPD.[4] Normal adolescence often involves rebellion or identity diffusion problems; however, the development and intensity of BPD traits in an adolescent may precipitate involvement in rebellious groups.[4] These maladaptive traits may also contribute to the development of various axis I disorders including post-traumatic stress disorder and other anxiety disorders, eating disorders, substance-related disorders, attention deficit hyperactivity disorder (ADHD), and mood disorders.[4,5,12]

As the patient with BPD enters adulthood, he or she she may be hospitalized multiple times due to his or her impairment in impulse control, suicidality and quasipsychotic and dissociative symptomotology.[4,5] Patients with BPD decompensations account for 20 percent of psychiatric hospitalizations.[6] Comorbid mood disorder and substance-related disorder increase the risk of suicide, and as many as 10 percent of patients with BPD will have completed suicide by the age of 30.[4] Employment history may be wrought with multiple job losses or career changes, and interpersonal relationships are continually volatile.[6]

Fluctuations in gender identity, sexual orientation, and personal values may be common and likely stem from cognitive distortions and a fragmented sense of self.[6] Although a brief psychotic, dissociative, or mood disorder episode may recur, generally, by age 30, the patient’s affective instability and impulsivity begins to lessen.[4] However, establishing a relationship with a supportive and patient sexual partner or simply retreating to a more isolated life may contribute to earlier stabilization of disruptive emotional lability.[4]

Clinical Case, continued

Frequent and chronic feelings of depression were prevalent in Brittany’s life. Many triggers in her life instigated a depressed mood, but there were also instances when no precipitant was identified. Sometimes her depressed mood came “out of the blue.”

Additional historical information was collected during the first several psychotherapy sessions. She began reporting auditory hallucinations (hearing muffled voices calling her name) and visual hallucinations (seeing shadows) at age 12. She described one nonsuicidal self-injurious (NSSI) episode at the age of 13 when she scratched the word “alone” into her left forearm. She was subsequently very embarrassed about this as it forced her to wear long-sleeved shirts to hide it from others. She was very relieved when it healed completely, leaving no permanent scarring.

PRACTICE POINT

Treatment strategies for nonsuicidal self-injurious behavior in a psychotherapy setting. Acts of self harm may be suicidal or nonsuicidal, and both types are prevalent in BPD. It may be difficult for the psychiatrist to determine one from the other, as well as concluding the safest and least restrictive intervention to institute. The decision may be made to hospitalize the patient with nonsuicidal self harm since this behavior may be life threatening. If a patient is chronically suicidal, a psychiatrist may underestimate the severity and forego the decision to hospitalize. A decision to hospitalize may greatly affect a therapeutic relationship in a psychotherapy setting, especially if the patient disagrees with the need for hospitalization.

There are no pharmacologic interventions that are known to be specifically effective in the case of self harm. Psychotherapy remains the intervention of choice for BPD, and there is now evidence that dialectical behavioral therapy (DBT) in particular is promising.[1,7–9]

DBT relies upon principles of both cognitive behavioral therapy (CBT) and zen Buddist meditative philosophy to help patients with BPD regulate their emotions by overcoming suffering through acceptance.[4] The treatment assumes that maladaptive behaviors, including self injury, are attempts to manage intense affect. DBT strategies initially focus on reducing self harm until treatment-disruptive behavior is mastered.[4] The focus of treatment then shifts to teaching coping skills for emotional control and interpersonal relatedness, which is facilitated by an individual therapist as well as didactic skills-training groups. DBT emphasizes validation of a patient’s unbearably painful emotional experience along with acceptance that the patient is doing the best that he or she can at that moment.[4] The skills-training component focuses on mastery of four major areas: mindfulness, interpersonal effectiveness, distress tolerance, and emotion regulation.[10] Some specific therapeutic strategies include alternating between acceptance and change strategies, adding intuitive knowing to emotional experience and logical analysis, playing the devil’s advocate, exploring new points of view, turning problems into assets, extending the seriousness of the patient’s statements and advocating a middle path.[4]

Assessment of suicidality and NSSI behavior must be a top priority for the psychiatrist. Examples of NSSI behavior may include “deliberate, direct destruction of body tissue without conscious suicidal intent.”[9] The most common forms of NSSI behavior in a study by Lloyd-Richardson et al[9] included biting self, cutting/carving skin, hitting self on purpose, and burning skin.

Stanley et al[7] studied NSSI behavior, including cutting or burning, which is the most frequent reason for psychiatric visits to medical emergency departments.[7] The neurophysiology and the clinical implications of NSSI behavior are poorly understood, especially when there is no apparent suicidal intent. With a better understanding of the biological mechanisms involved in self injurious behavior (SIB), more effective pharmacologic regimens may be employed as well as accompanying psychotherapeutic interventions.[7] The NSSI group in the study by Stanley et al[7] had significantly lower levels of cerebrospinal fluid (CSF) beta-endorphin and met-enkephalin when compared with the non-NSSI group. Beta-endorphin is an opioid related to mediation of stress-induced analgesia; met-enkephalin is an opioid related to physical pain analgesia. Stanley et al[7] concluded that both opioids are thought to be involved in NSSI behavior; the severity of overall psychopathology was greater in the NSSI group. In this study, serotonergic and dopaminergic dysfunctions were not shown to have a relationship to NSSI behavior, but medications which act on the opioid system may still be implicated.

Nock et al[8] studied nonsuicidal- versus suicidal-related SIB in adolescents. Most of the adolescents assessed in this study were diagnosed with both axis I and axis II disorders, 62.9 and 67.3 percent, respectively. Overall, Nock et al[8] found that the vast majority of adolescents (70%) engaging in NSSI behavior reported a lifetime suicide attempt and more than half reported multiple attempts.[8] Some significant risk factors more closely associated with suicide attempts included a longer history of NSSI behavior, use of a greater number of methods, and absence of physical pain during NSSI behavior.[8]

Lloyd-Richardson et al[9] assessed the prevalence, associated clinical characteristics, and functions of NSSI behavior in a community sample of adolescents. This study found that the most common explanations for NSSI behavior were “to try to get a reaction from someone,” “to get control of a situation,” and “to stop bad feelings.”[9] The study found that adolescents in this community sample typically conducted the NSSI behaviors to influence behavior of others and to manage internal emotions. The psychiatrist working with patients who exhibit self harm should explore the etiology and antecedents of NSSI behavior and then institute as a goal of psychotherapy the reduction of these to the extent that is possible. The goals of the psychotherapy should also include building alternative coping strategies, increasing communication with the significant people in the patient’s life, and building on the patient’s social support system.[9]

Clinical Case, continued

Brittany reported chronic feelings of emptiness as well as worry that her loved ones would abandon her. She mentioned in a psychotherapy session an intense fear that a family member might even be taken from her by severe illness, such as influenza A (H1N1).

She had chronic thoughts of not wanting to be alive anymore and even hoped that she might be involved in a motor vehicle accident to end the “constant pain.” She had frequent thoughts of cutting herself to relieve her emotional pain, but fears of scarring prevented her from doing this.

Brittany occasionally heard muffled voices at times of maximal stress. These voices were always self deprecating, calling her fat, ugly, and stupid. Removing herself from stressful situations and being quiet helped calm the muffled voices.

Brittany: My bipolar is really out of control and none of the medications seem to work. My mood swings are all over the place and all I can think about is dying to end this misery. Doctors never help and always leave me when I need them the most. You’re the only one who really understands me.

Psychiatrist: It seems as though you’ve felt misunderstood and unable to find the help you need.

Brittany: Yes, I know I have bipolar disorder, everyone in my family has it, but my case manager asked me if I’ve ever been told I have borderline personality disorder. What do you think?

Psychiatrist: You’ve had a difficult, unpredictable childhood and because of that you’ve learned to deal with problems as best you can. However, the intense way in which you experience emotions sometimes causes you to react in ways that show others how impossible, hopeless, and painful your life seems at times.

Brittany: That may be true, but I seem to only drive people away. They are always leaving me and you probably will too. The hospital is the only place I’ve ever felt safe and cared for. If only someone who knew what they were doing could get my bipolar under control, then I wouldn’t have to live like this anymore!

Psychiatrist: Medications can be helpful; however, psychotherapy is the most important treatment for you. Would you be willing to discuss these frustrations on a weekly basis with me? Together, we could explore ways of coping that will give you the ability to better control how you experience your emotions and ultimately find the satisfaction you long for in relationships.

PRACTICE POINT

Making the diagnosis and choosing the type of psychotherapy. To arrive at an accurate diagnosis, information about presenting symptoms, past medical and psychiatric history, psychosocial history, current relationships, psychological functioning, and coping skills should be collected. Based on this information and other pertinent factors, a plan for treatment will be established.[11]

Marcinko et al[1] found that it is very important to evaluate possible comorbidity in diagnostic assessment of suicidal patients. The high prevalence of comorbid BD and BPD and some diagnostic criteria seen in both conditions present both a diagnostic and a therapeutic challenge. While pharmacotherapy is appropriate for the treatment of many psychiatric disorders, psychotherapy remains the treatment of choice for BPD. As mood stabilizers have been beneficial in the treatment of some patients with BPD, increasing attention has been given to the overlap between BPD and bipolar II disorder.[12] Although some individuals may present with BPD and comorbid BD, the majority of the evidence to date supports BPD as an independent diagnosis rather than an attenuated form of a mood disorder.[12] Furthermore, because of heterogeneity of the BPD, pharmacologic treatment has evolved to some particular dimensions of the BPD rather than the disorder in its entirety. The dimensions include affective instability, impulsive aggression, and identity disturbance. Effective medication management reduces the overall suffering of the patient and enables psychiatrists to make greater use of psychotherapeutic interventions, which are very important for BPD patients with and without BD comorbidity.

Choice of medications for patients with BPD is largely based upon the predominant axis I symptomotology, which may include anxiety, depression, hallucinations, delusions, and dissociation.4 However, it is important to consider that transient symptoms are common in the course of BPD recovery, especially in the context of often unrelenting crises. As such, pharmacologic treatment should not be disproportionately influenced by symptoms stemming primarily from the axis II diagnosis.[4] Widiger and Mullins-Sweatt[4] recommend that exploratory or supportive techniques should be utilized first in managing these symptoms. Conversely, unnecessary resistance to use of medications and relying excessively upon the psychiatrist’s own psychotherapeutic skills may extend periods of decompensation and cause more extensive suffering for the patient.[4]

The type of psychotherapy chosen is very important to the patient’s success. Psychodynamic psychotherapy is appropriate for the patient with the capacity for insight, the ability to modulate regression, and is in a stable environment.[11] For the patient with pragmatic thinking, a high degree of self control, and the need for direction and guidance, Novalis et al[11] recommends cognitive therapy. Finally, the patient with failure to progress in other types of therapies, who has real inadequacies, or who requires high levels of guidance (as in the case of an acute stressor) may be well suited for supportive psychotherapy.[11] It may be appropriate to change the type of therapy from time to time during treatment in the event that the acute needs of the patient are altered (Table 6).

Often patients with BPD will report initial, middle, and/or late insomnia. Plante et al[13] found that sleep disturbance is a common, yet poorly understood, phenomenon in BPD. Sedative-hypnotic medications were studied in patients with BPD and were used significantly more often for insomnia both as scheduled medications and “as needed” when compared to all other personality disorders. In fact, patients with BPD were four times more likely to use these medications. Plante et al[13] concluded that subjective sleep disturbance is a significant problem in BPD.[13]

Binks et al[14] completed a pharmacology study regarding treatment of BPD. BPD was found to be prevalent (2% in the general population, 20% among psychiatry in-patients) and has a significant impact on the healthcare delivery system; a complicating factor is that the patients will have frequent and recurrent crisis situations but are often nonadherent with recommended treatment options.[14] The current information available from Binks’s literature review indicates that the use of antidepressants may have a considerable positive effect in most patients.

Binks et al[15] also reviewed studies of psychological interventions and their success in patients with BPD. The definition of psychological treatments in this study included behavioral, cognitive-behavioral, psychodynamic, and psychoanalytic psychotherapies. After reviewing seven studies, Binks et al found that with DBT, some behaviors (including self harm or parasuicide) may decrease at 6 to 12 months, but there was no clear difference in hospital admissions. Another study showed a statistically significant decrease in suicidal ideation at six months for those receiving DBT.[15] Binks et al found no differences for outcomes of anxiety and depression, but those patients receiving DBT had milder symptoms than those in control groups. In summary, this review suggested that some of the problems frequently encountered by people with BPD may be amenable to psychotherapy and other behavioral treatments, especially when giving an extended course of treatment.[15]

Clinical Case, Continued

The course of treatment recommended at the end of the initial consultation was to begin psychotherapy (the treatment of choice for BPD) and initiate citalopram to address the many symptoms associated with the BPD. A slow taper of lamotrigine (Lamictal) over the course of the next several months was also planned, while continuing the full dose for the first six weeks while citalopram reached full therapeutic effect.

Over the next several weeks, Brittany agreed to adhere to medication recommendations and also engage in weekly psychotherapy sessions with her psychiatrist. Additional history revealed that Brittany had maintained a very chaotic relationship pattern throughout her early adulthood. She quickly developed feelings of attraction and dependency with multiple sexual partners. Though most partners found her sociable, supportive, and engaging, her low threshold for controlling her rage in common conflicts and disagreements typically evolved into abuse and ultimately abandonment. Moreover, her friends were frequently overwhelmed and annoyed by her intense feelings of hurt, anger, and depression. Brittany was, in turn, frequently deeply disappointed when her extreme reactions were not met with a consoling gesture.

Brittany: So I won’t be able to see you while you’re away next month?

Psychiatrist: No, but you will be able to contact the clinic in the case of an emergency. I will return for our regular session the following week.

Brittany: What if the other doctor doesn’t understand me like you do? Can I call you if I’m having a hard time?! I knew you’d eventually leave me like everyone else has! You’re a liar!

PRACTICE POINT

Abandonment issues processed from early developmental years and their persistence/significance in current relationships (including the psychiatrist in the room). According to Delgado and Songer,[5] absolute and unconditional love represents the core desire of patients with BPD. When others, including the psychiatrist, fail to embody these fantasies, affective storms may abound as they develop extreme hatred toward the imperfect person.[5] With an understanding of the patient’s early childhood experiences and family environment, the psychiatrist is able to interpret how these experiences have contributed to the development of the patient’s maladaptive coping style and its impact in relationships. A deficit in the capacity to recognize and tolerate loving and hostile feelings toward the same person simultaneously (object constancy) constitutes the foundation for his or her constant fear of abandonment. As a result, the patient persistently employs primitive or immature defense mechanisms (e.g. splitting, projection, acting out, dissociation). A therapeutic alliance represents the bedrock upon which a psychiatrist may achieve the ultimate goal of any psychotherapy: helping the patient achieve the ability to tolerate ambivalent feelings in a relationship by developing mature higher level defense mechanisms.[5]

As the treatment progresses, the therapeutic relationship between a psychiatrist and the patient with BPD can be as similarly volatile as the patients’ other significant relationships.[16] Feelings of anger or frustration toward the patient may spawn specific countertransference reactions that may include distancing, rejecting, or abandoning the patient. In addition, positive reactions may include fantasies of being the therapist who rescues or cures the patient, or romantic, sexual feelings in response to a seductive patient.[4] Proper management of these countertransference issues are best achieved through ongoing consultation with colleagues.[4] Furthermore, promoting a sense of secure attachment through frequent appointments (weekly or more frequently), communication between missed sessions or planned absences, setting limits on inappropriate or self-destructive behaviors, validation of suffering and abusive experience, helping the patient take responsibility for actions, and promotion of self reflection rather than impulsive action are key coping strategies to emphasize in the psychotherapeutic setting.[4,5]

CONCLUSION

BPD and BD symptom overlap represents a common diagnostic dilemma for psychiatrists. Carefully delineating the nature of attachments, suicidal and nonsuicidal acts, a time course of mood symptoms, role of interpersonal reactivity, and abuse history throughout childhood, adolescence, and adulthood can be especially helpful in arriving at a primary diagnosis. Chronic fears of abandonment and higher level of impulsivity, hostility, and acute suicidal threats are distinctive symptoms that can typically distinguish BPD from BD.

Aggressive pharmacologic treatment of sleep disturbance and comorbid axis I diagnoses in BPD can improve patients’ outcomes when used in combination with psychotherapy as the treatment of choice. Mood stabilizers, antidepressants, and antipsychotics have all shown efficacy in reducing the impact of common symptoms particular to the heterogeneous population with BPD, namely affective instability, impulsive aggression, and identity disturbance. Of course, careful attention must be given to the potential lethality of medications utilized in the treatment of BPD.

Choosing the appropriate modality of psychotherapy for BPD should be based on the patient’s core symptoms, cognitive abilities, need for guidance, ability to modulate regression, and level of psychological mindedness. Moreover, a psychiatrist must also be attuned to the acute needs of the patient as flexibility in changing the type of therapy in the midst of treatment may be necessary. Although DBT principles are specifically and effectively tailored to the hallmark symptoms of BPD, many other types of psychotherapy may be effective in reducing the severity of various BPD presentations. An accurate assessment of the patient’s level of functioning, mindfulness, interpersonal effectiveness, distress tolerance, emotion regulation, and strength of social support system are key elements that will lead the clinician to institute DBT, psychodynamic psychotherapy, interpersonal, CBT, and supportive psychotherapy, either individually or in combination.

Finally, building a therapeutic alliance with a patient with BPD may be a challenging task for a psychiatrist. However, understanding the common transference and countertransference reactions in a psychotherapeutic setting can equip the psychiatrist with essential foresight and knowledge to effectively facilitate the patient’s movement towards more fulfilling relationships and higher level defenses.

References
1. Marcinko D, Vuksan-Cusa B. Borderline personality disorder and bipolar disorder comorbidity in suicidal patients: diagnostic and therapeutic challenges. Psychiatr Danub. 2009;21(3):386–390.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision. Washington, DC; 2000.
3. Fiedorowicz JG, Black DW. Borderline, bipolar or both? Frame your diagnosis on the patient history. Curr Psychiatr. 2010;9 (1):21–30.
4. Widiger TA, Mullins-Sweatt SN. Personality disorders. In: Tasman A, Kay J, Lieberman J, et al, eds. Psychiatry, Third Edition. West Sussex: John Wiley & Sons, Ltd;2008:1733–1734.
5. Delgado S, Songer D. Personality disorders and behavioral disturbances. In: Gillig PM, Morrison AK, (eds.) More than Medication: Incorporating Psychotherapy into Community Psychiatry Appointments. West Chester, PA: Matrix Medical Communications; 2009:68–72.
6. National Institutes of Mental Health. Borderline Personality Disorder. 2001. http://www.nimh.
nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml#4. Accessed on February 10, 2010.
7. Stanley B, Sher L, Wilson S, et al. Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord. 2009 Nov 24. [Epub ahead of print]
8. Nock MK, Joiner TE Jr, Gordon KH, et al. Non-suicidal self-injury among adolescents: diagnostic correlates and relation to suicide attempts. Psychiatry Res. 2006;144(1),65–72.
9. Lloyd-Richardson EE, Perrine N, Dierker L, Kelley ML. Characteristics and functions of non-suicidal self-injury in a community sample of adolescents. Psychol Med. 2007;37(8):1183–1192.
10. Huffman, JC, Stern TA, Harley RM, Lundy NA. The use of DBT skills in the treatment of difficult patients in the general hospital. Psychosomatics. 2003;44: 421–429.
11. Novalis PN, Rojcewicz SJ Jr, Peele R. Clinical Manual of Supportive Psychotherapy, First Edition. Washington, DC: American Psychiatric Press, Inc.;1993.
12. American Psychiatric Association. Practice Guidelines for the Treatment of Patients with Borderline Personality Disorder: Guideline Watch. Washington, DC; 2005. DOI:10:1176/appi.books.
9780890423363.148718. Accessed on February 10, 2010.
13. Plante DT, Zanarini MC, Frankenburg FR, Fitzmaurice GM. Sedative-hypnotic use in patients with borderline personality disorder and axis II comparison subjects. J Pers Disord. 2009. 23(6):563–571.
14. Binks CA, Fenton M, McCarthy L, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005653.
15. Binks CA, Fenton M, McCarthy L, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005652.
16. Gunderson JG. Borderline Personality Disorder: A Clinical Guide. Washington, DC: American Psychiatric Press;2001.

Psychiatry (Edgemont) 2010;7(1):34-37

Psychiatry (Edgemont) 2009;6(10):12–15

Ms. Cascade is Vice President, Quintiles Inc./iGuard, Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Findling is Professor of Psychiatry and Pediatrics
Case Western Reserve University, Cleveland, Ohio.

Dr. Carroll is Associate Professor of Psychiatry, University of Cincinnati (Volunteer), Department of Veteran Affairs Medical Center, Chillicothe, Ohio; Dr. Kirkhart is Clinical Professor, Marietta College, Department of Veterans Affairs Medical Center, Chillicothe, Ohio; Dr. Ahuja is Consultant Psychiatrist and Honorary Clinical Lecturer, Northumberland, Tyne and Wear NHS Trust and Newcastle University, United Kingdom; Dr. Soovere is Staff Psychiatrist and Neurologist, Perry Point VAMC, Perry Point, Maryland; Dr. Lauterbach is Professor of Psychiatry, Neurology, and Radiology, Mercer University School of Medicine, Macon, Georgia (retired); Dr. Dhossche is Professor of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi; and Dr. Talbert is Clinical Pharmacist, Riverside Methodist Hospital, Columbus, Ohio.

Psychiatry (Edgemont) 2008;5(12):42–50

Disclaimer: This manuscript was developed by the authors and does not constitute research or opinions of the Department of Veterans Affairs.

Financial Disclosures: The authors have no financial conflicts of interest relevant to the contents of this manuscript.

Abstract

Modern psychiatric nosologies separate catatonia along the lines of presumed etiology: bipolar, major depression, schizophrenia, and/or due to a general medical condition. Catatonic signs have always possessed significant diagnostic, therapeutic, and prognostic value. Kahlbaum’s description of this syndrome in his monograph “Katatonia” included careful documentation of phenomenology. Kahlbaum selected the term katatonia to describe “tension insanity.” He felt that the neuromotor signs were more important than the content of delusions (e.g. megalomania). While he felt that he was describing a unitary illness, he did identify mood disturbance, psychosis, and medical factors in this new illness. In modern times, the term catatonia has become limited to describe a specifier of neuropsychiatric illnesses.

The authors of this article feel that the term katatonia should be used to describe a group of neuropsychiatric illnesses presenting with catatonic signs. This may prevent the misconception that “catatonia is schizophrenia” and improve the detection of katatonia in patients. Specifically, katatonia is also observed in mood disorders, general medical conditions, and pervasive developmental disorders. The literature also supports the view of Dr. Leo Kanner and his description for neuromotor and neuropsychiatric signs in autistic disorder. This scale is named in honor of Dr. Kanner. It was developed by the authors and includes some of Dr. Kanner’s core concepts. This paper will identify the clinical features of katatonia and introduce the KANNER scale (see APPENDIX 1) to improve conceptualization, detection, and measurement of this important clinical syndrome.

Key Words: catatonia, katatonia, stupor, Kahlbaum, bipolar disorder, schizophrenia, autism, KANNER

Introduction

Karl Ludwig Kahlbaum is best known for his description of catatonia. He presented his first description of catatonia in Innsbruck in 1869 and later wrote his monograph entitled Katatonia in 1873.[1] Since then, the presence of catatonic signs has always held diagnostic, therapeutic, and prognostic value.[2]

Kahlbaum’s description of this syndrome in his monograph included careful documentation of phenomenology. He selected the term katatonia to describe “tension insanity” and held that the neuromotor signs (e.g., waxy flexibility) were more important than the content of delusions (e.g., megalomania). While he was convinced that he was describing a unitary illness, he did identify mood disturbances, psychosis, and medical factors in this new illness.[2]

Kahlbaum described katatonia as a syndrome of motor abnormalities including mutism, negativism, stereotypies, catalepsy (waxy flexibility), and verbigeration.[1] Kraepelin included catatonia as belonging to the group of dementia praecox, but acknowledged that “catatonic morbid phenomena” occurred in different psychiatric disorders.[3]

In modern times the terms catatonic and catatonia have unfortunately become limited to describe specifiers for neuropsychiatric illnesses. The clinical term catatonia therefore holds minimal conceptual importance in clinical practice. For instance, Larner defines catatonia as a state of unresponsiveness with maintained immobility, posturing, mutism, and refusal to eat or drink. He lists several signs that may or may not be present (including incontinence).[4] Meanwhile Rogers has argued that catatonia is an extrapyramidal disorder.5 Fink and Taylor point out that in the two centuries since catatonia was first described, psychiatric terminology has changed many times.[6]

The authors propose that the term katatonia (with a “k”) be used to describe this cross-sectional clinical syndrome to avoid continuation of the more recent nosological confusion. In the published literature, katatonia has staged a remarkable comeback over the past 15 to 20 years, with several rating scales, brain imaging and genetic studies, and neurochemical theories that underscore the importance of this clinical entity.[6,7] However, research on katatonia has been limited by the lack of a psychopathological definition and clear conceptual understanding of the subject. This may explain why the existing catatonia rating instruments differ from each other in terms of the definition and number of individual symptoms.[7–11]

There is some variability of katatonia across various psychiatric disorders.[11] Thus, reexamination of the reliability and validity of catatonia rating scales across the various neuropsychiatric illnesses is recommended. Furthermore, the need for a new conceptual understanding of katatonia has been suggested because of the fluidity of the boundaries of the concept.[12] This review addresses the clinical concepts and attempts to describe katatonia over the past few decades. A new rating scale and a conceptual outline for this important clinical entity will be presented.

Research Criteria Defining Katatonia

Kanner’s autism. Kanner identified autism in 11 children between 2 and 8 years of age.[13–15] He described stereotypy, echolalia, and other neuromotor and neurodevelopmental signs. His classification was quickly adopted into the psychiatric nomenclature. Currently, autism (autistic disorder) has been placed as a subcategory of pervasive developmental disorders. Consequently, more emphasis has been placed on the social and emotional domains than the motor signs. There are several observations suggesting that catatonia and autism may have common underlying pathophysiology and treatment response.[16] The Autism Behavioral Checklist (ABC) does not define catatonic signs to the extent of detecting catatonic symptomatology in patients with autism. The autism rating scales fail to quantify items to show treatment response to the catatonic features. Consequently, we feel that there is a need for a new rating scale to assess katatonia in autism and pervasive developmental disorders. To date, there have been no studies of systematic ratings of catatonia in autism.

Lohr and Wisniewski (1987). Lohr and Wisniewski[17] proposed criteria for the catatonic syndrome, requiring one cardinal feature and two secondary features.[1] Northoff found that all patients who met this criteria scored at least 8 (>7) on the Northoff Catatonia Scale (NCS).[9] Catalepsy, positivism, or negativism (1 of these 3) must be present to meet Lohr and Wisniewski’s criteria.[17] Their criteria may not take into account immobility, excitement, and withdrawal (refusal to eat and drink) and may exclude a number of patients with catatonic symptomatology.

These criteria advanced the study of catatonia and highlighted important concepts that underlie catatonia. The clinician, however, may be challenged with some patients with katatonia who fail to meet this set of criteria but not others. Unfortunately, no rating scale was developed from these criteria.

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (1994). The development of DSM-IV brought about a new set of criteria for catatonia as a subtype of schizophrenia as well as a specifier for bipolar disorder and major depression. DSM-IV also included catatonia due to a general medical condition. DSM-IV catatonia criteria required 2 out of 5 signs, except for catatonia due to a general medical condition, where only 1 out of 5 was needed. We have previously pointed out the deficiencies of the DSM-IV and DSM-IV-TR (Text Revision) criteria.[18] There is currently no rating scale for DSM-IV or DSM-IV-TR catatonia criteria. Stompe et al[19] found that the sensitivity was greater for diagnoses with a higher number of items in katatonia criteria.

Rosebush et al (1990). Rosebush et al[20] described the Kahlbaum criteria with more than two cardinal features with more than one secondary feature. They used this criteria to identify catatonic features and measure treatment response. The Rosebush rating scale was proposed but it has never been published. Northoff examined this proposed rating scale and found it to have high correlation with other catatonia rating scales.[9] The Rosebush criteria do not take into account catatonic excitement and positivism (e.g., automatic obedience, mitgehen, ambitendency). This set of criteria is helpful but may exclude a number of patients with catatonic signs.

Rogers Scale (1991). The Modified Rogers Scale rates both extrapyramidal signs (EPS) and catatonic signs.[5] It contains several conceptual approaches to catatonia and catatonic signs. It is founded upon the concept that catatonic features are a form of EPS. Consequently the phenomenology is rated independent of presumed etiology and medications (e.g., antipsychotics). Rogers lists 36 motor signs and describes a neuropsychiatric motor examination. Each item is rated on a scale of 0 to 2 with scores ranging from 0 to 72. The Rogers scale has not been widely used in treatment. The Modified Rogers Scale provides definitions for gegenhalten, mitgehen, stereotypy, mannerism, echopraxia, bizarre gait, aprosodic speech, excitement, and negativism. It also describes overcompliance, iteration (the repetition of movements), and hypermetamorphosis. This scale has been used in institutional populations, including patients with mental retardation. It was also used by Starkstein et al[21] in a treatment study of catatonic features in patients with Parkinson’s disease and depression.

The Bush-Francis Catatonia Rating Scale (1996). The Bush-Francis Catatonia Rating Scale (BFCRS) was the first instrument constructed for the systematic, standardized, and quantifiable examination of catatonia using operationally defined signs and symptoms.[22] The BFCRS consists of 23 items accompanied by specific instructions to standardize the examination. Seventeen items are scored on a 0 to 3 scale while the remaining six are rated as either absent (“0”) or present (“3”). Selection of the items was based on a review of the classical and contemporary literature. The inter-rater reliability of BFCRS was established on 28 acutely ill patients presenting with catatonic syndrome that arose in the context of various psychiatric disorders. Catatonia ratings with the BFCRS predicted a high probability of treatment responsiveness to lorazepam.[23] Since its development, the BFCRS has been the most commonly used scale in research in catatonia. It is readily available for clinical use and has been translated into several languages. Our research team has used the BFCRS and considers it the gold standard compared to other scales.

The Northoff Catatonia Scale (1999). The Northoff Catatonia Scale (NCS) was based upon Kahlbaum’s descriptions of catatonia including 1) hypokinesias, 2) hyperkinesias, 3) affective symptoms, and 4) behavioral alterations. The NCS contains 40 items, rated from 0 to 2, with the scores ranging from 0 to 80. Northoff et al[9] performed extensive evaluation of the NCS and compared it to several rating scales. They found the NCS to be valid and reliable for rating catatonia. Also, hypokinesias and hyperkinesias were independent of antipsychotic medication. There was no significant difference between the NCS and the modified Rogers scale in the detection of catatonic patients. A score of >7 on the NCS separated catatonic from noncatatonic psychiatric patients. A factor analysis yielded four components that were characterized as 1) affective, 2) hypoactive, 3) hyperactive, and 4) behavioral.

In their editorial, Rosebush and Mazurek[7] pointed out that catatonia seemed to disappear from the landscape over the last century because psychiatry sought out verbal, introspective, and ‘interviewable’ patients. They expressed concerns regarding the affective and behavioral sections of the NCS because catatonic patients may be difficult to interview. These two sections may reduce the accuracy of the NCS in patients who are mute and exhibit negativism.[7]

The Braunig Catatonia Rating Scale (2000). Braunig, Kruger, and Shugar developed Catatonia Rating Scale (CRS)[10] for catatonia that has 21 items with possible scores of 0 to 4 (absent, minimal, moderate, marked, severe). These are defined by time intervals of observation during a 45-minute examination (<2 minutes, 2–10 minutes, 10–20 minutes, >20 minutes). The scores range from 21 to 84.

The scale is based on the work of several German language authors (Wernicke, Kraepelin, Kleist, Kahlbaum, Blueler, Meyer-Gross, and Leonhard). They group mitgehen and echophenomena under “abnormal suggestibility of will” (i.e., gegengriefen). This scale has been studied under factor analysis, but has not been used to measure treatment response.[10,11]

Fink and Taylor Criteria (2003). Fink and Taylor made a strong argument for a separate classification for catatonia (katatonia) in DSM-V.[6] They proposed a set of criteria for the detection and diagnosis of catatonia that is based on the earlier work of Taylor.[24] They did recommend the use of the BFCRS for research and clinical use. Consequently, the Fink and Taylor criteria (and the earlier version) have been used in screening for catatonia in at least two case series studies.[25,26]

Concerns over Catatonia Rating Scales

In spite of the classical history of catatonic signs, there is much confusion over the reference definitions for the terms used in these rating scales. Definitions tend to vary from one scale to the other.[27] These include mannerisms versus stereotypy, catalepsy versus waxy flexibility, and mitgehen versus mitmachen. Most North American psychiatry textbooks fail to adequately define these terms. Each rating scale has the support of its own research group leading to lack of uniformity in catatonia rating scales. In research and clinical institutions, there may be differing views regarding the weight of scale items. Consequently, most of these scales are not routinely used to measure treatment response. The BFCRS is most commonly cited for treatment studies in the North American publications. These scales may also not be sensitive enough to measure treatment response.[27]

In view of the variety of neuropsychiatric and general medical conditions that can manifest with catatonic features, a generic catatonia rating instrument would be insufficient to capture catatonia in specific patient populations and consequently would need modification.[6] Wong et al[28] tested the BFCRS in a sample of patients with chronic schizophrenia where catatonic features are frequently encountered. Using Rasch analysis, the authors constructed a 20-item scale from the BFCRS that was useful in their population of chronic catatonics. They suggested that rigidity, grasp reflex, and autonomic abnormality (and perhaps impulsivity) do not measure the same construct as other BFCRS signs in chronically ill patients with schizophrenia.[28] The BFCRS Revised version was shorter and simpler that the original BFCRS and better suited to identifying catatonic signs in patients with chronic schizophrenia.[28]

Treatment Response in Katatonia

Peralta et al[29] and Barnes et al[30] remind us that catatonia is found across a wide range of psychiatric, neurological, and medical disorders, and this generally supports Kahlbaum’s idea of a unitary phenomenology and pathology. The response to lorazepam or electroconvulsive therapy (ECT) does not follow the primary psychiatric diagnosis. In fact, it is katatonia that responds to these treatments. While some authors have noted a trend toward less favorable improvement for catatonic symptoms in schizophrenia as compared to mood disorders, this has not been consistently or conclusively demonstrated. Nonetheless, the presence of katatonia predicts a favorable response of these signs to interventions like intravenous amobarbital, lorazepam (and other benzodiazepines), and ECT. Katatonia seems to be associated with a favorable prognosis, when diagnosed and treated promptly. There is clinical evidence to suggest that failure to diagnose katatonia or provide effective psychiatric treatment may result in a poor outcome.[30]

Directions for Future Research

The KANNER scale should be compared against a gold standard. We propose testing the KANNER rating scale against the BFCRS. While other scales have merit, there is limited experience with these scales in North America. The KANNER scale has three components; each should be tested separately (APPENDIX 2 PT 1 , APPENDIX 2 PT 2 , APPENDIX 2 PT 3 , APPENDIX 3 , APPENDIX 4). It may be useful to call together a consensus panel to propose criteria, evaluate rating scales, and identify treatment standards. This has been done for other neuropsychiatric illnesses, such as Lewy body dementia. Furthermore, since the KANNER is a neuromotor examination, a training video or DVD with patients or simulation actors might be helpful to achieve improved understanding of katatonia and create a core standardization in the rating of katatonia (Table 1).

Proposal

We propose the KANNER scale as a unifying instrument for quantifying katatonic core features (a) across the broad range of neuropsychiatric illnesses and (b) in the specific contexts of autism and pervasive developmental disorders. The KANNER scale is named after Leo Kanner (1894–1981), who described the neuromotor and neurodevelopmental features of autism, which are also features of katatonia.[13–15] We feel it is necessary to identify katatonia in patients with other neuropsychiatric illnesses, including schizophrenia and mood disorders, and due to general medical conditions (Table 1).
Based on our review and analysis from a large body of literature, the clinical signs for a possible and a probable diagnosis of catatonia are contained within the KANNER scale. Since there is no true gold standard for diagnosis, the sensitivity and specificity of this scale cannot be easily ascertained. Because the KANNER scale is based on an exhaustive and comprehensive review, we propose that it be adopted and tested prospectively for its clinical utility, sensitivity, and specificity.

Acknowledgment
This work is dedicated to the late Tressa D. Carroll who provided conceptual input.

References
1. Kahlbaum KL, Levij Y, Pridon T, trans. Catatonia. Baltimore, MD: Johns Hopkins University Press, 1973.
2. Carroll BT. Kahlbaum’s catatonia revisited. Psychiatry Clin Neurosci. 2001;55:431–436.
3. Kraepelin E. Dementia Praecox and Paraphrenia. (Barclay RM, trans) Edinburgh: E and S. Livingstone, 1919.
4. Larner AJ. A Dictionary of Neurological Signs, Second Edition. New York, NY: Springer Science Business Media, Inc. 2006;67–68.
5. Rogers D. Motor disorder. In: Rogers D (ed). Psychiatry Towards a Neurological Psychiatry. New York, NY: John Wiley & Sons, Inc.,1993;11–19.
6. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. New York: Cambridge University Press, 2003.
7. Rosebush PI, Mazurek MF. Catatonia: re-awakening to a forgotten disorder. Mov Disord. 1999;14:395–397.
8. Lund CE, Mortimer AM, Rogers D, McKenna PJ. Motor, volitional and behavioral disorders in schizophrenia. I. Assessment using the Modified Rogers Scale. Br J Psychiatry. 1991;158:323–327.
9. Northoff G, Koch A, Wenke J, et al. Catatonia as a psychomotor syndrome: a rating scale and extrapyramidal motor symptoms. Mov Disord. 1999;14:404–416.
10. Braunig P, Kruger S, Shugar G, et al. The catatonia rating scale I: development, reliability, and use. Compr Psychiatry. 2000;41:147–158.
11. Kruger S, Bagby RM, Hoffler J, Braunig P. Factor analysis of the Catatonia Rating Scale and catatonic symptom distribution across four diagnostic groups. Compr Psychiatry. 2003;44:472–482.
12. Ungvari GS, Carroll BT. Nosology of catatonia. In: Mann SC, Francis A, Fricchione GL (eds). Catatonia: From Psychopathology to Neurobiology. Washginton, DC: American Psychiatric Press, Inc., 2004.
13. Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943;2:217–250.
14. Neumarker KJ. Leo Kanner: his years in Berlin, 1906–24. The roots of autistic disorder. Hist Psychiatry. 2003;14:205–218.
15. Kanner L. Follow-up study of eleven autistic children originally reported in 1943. J Autism Child Schizophr. 1971;1:119–145.
16. Dhossche D, Carroll BT, Carroll TD. Is there a common neuronal basis for autism and catatonia? In: Dhossche D, Wing L, Ohta M, Neumarker K (eds). Catatonia in Autism Spectrum Disorders. St. Louis, MO: Elsevier/Academic Press, Inc. 2006;(72):151–162.
17. Lohr JB, Wisniewski AA. Movement Disorders: A Neuropsychiatric Approach. New York, NY: Guilford Press, 1987.
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Press, Inc., 1994.
19. Stompe T, Ritter K, Schanda H. Catatonia as a subtype of schizophrenia. Psychiatr Ann. 2007;37(1):31–36.
20. Rosebush PI, Hildebrand AE, Furlong BG, Mazurek MF. Catatonic syndrome in a general psychiatric population: frequency, clinical presentation and response to lorazepam. J Clin Psych. 1990;51:357–362.
21. Starkstein SE, Petracca G, Tesón A, et al. Catatonia in depression: prevalence, clinical correlates, and validation of a scale. J Neurol Neurosurg Psychiatry. 1996;60:326–332.
22. Bush G, Fink M, Petrides G, et al. Catatonia I: Rating scale and standardized examination. Acta Psychiatr Scand. 1996;93:129–136.
23. Bush G, Fink M, Petrides G et al. Catatonia II: Treatment with lorazepam and electroconvulsive therapy. Acta Psych Scand. 1996;93:137–143.
24. Taylor MA. Catatonia: a review of a behavioral neurologic syndrome. Neuropsychiatry Neuropsycholand Behav Neurol. 1990;3:48–72.
25. Carroll BT, Spetie L. Catatonia on the consultation-liaison service: a replication study. Int J Psych Med. 1994;24:329–337.
26. Cottencin O. Catatonia and consultation-liaison psychiatry study of 12 cases. Prog Neuropsychopharmacol Biol Psychiatry. 2007;15;31(6):1170–1176.
27. Kirkhart R, Ahuja N, Lee J, et al. Detection and measurement of catatonia. Psychiatry (Edgemont) 2007;4(9):52–56.
28. Wong E, Ungvari GS, Leung S-K, Tang W-K. Rating catatonia in patient with chronic schizophrenia: Rasch analysis of the Bush-Francis Catatonia Rating Scale. Int J Methods Psychiatric Res. 2007;16:161–170.
29. Peralta V, Cuesta MJ, Serrango J, Mata I. The Kahlbaum syndrome: a study of its clinical validity, nosological status and relationship with schizophrenia and mood disorder. Compr Psychiatry. 1997;38:61–67.
30. Barnes MP, Sunders M, Walls TJ. The syndrome of Karl Ludwig Kahlbaum. J Neurol Neurosurg Psychiatry. 1986;49:991–996.
31. Carroll BT, Thomas C, Jayanti K, et al. Treating persistent catatonia when benzodiazepines fail. Current Psychiatry. 2005;4:56–64.

Psychiatry (Edgemont) 2008;5(10):37–41

Financial Disclosure
The authors have no financial conflicts of interest with the material presented in this study.

Abstract
Objective: A tremendous increase in the diagnosis of bipolar disorder in pediatrics raises questions about current diagnostic practices. Even though researchers are providing initial follow-up data about rigorously diagnosed bipolar youth versus youth with severe nonbipolar mood symptomatology, not much is known about these different patient groups in the community. This study used standardized assessment tools to evaluate if meaningful differences emerge between different mood disorder types in children.

Design: The Mini International Neuropsychiatric Interview and the Child/Adolescent Symptom Inventory were used to classify patients as having bipolar disorder or mood disorder not otherwise specified (NOS) according to criteria set forth by the National Institute of Mental Health. A retrospective chart review followed back the treatment for eight months.

Setting: A community mental health clinic.

Participants: 41 pediatric patients between six and 18 years old.

Measurements: Global Assessment of Functioning scale and Clinical Global Impression scales were compared pre- and post-treatment.

Results: Patients with bipolar disorder improved significantly more than mood disorder NOS patients, despite similar levels of care. Meaningful differences in diagnostic and treatment variables were apparent at baseline and at endpoint.

Conclusion: Standardized assessments in community clinics are feasible and lead to the identification of meaningful differences between “similar” patient groups. Improving diagnostic practices across different psychiatric settings appears paramount.

Introduction

Recently, there has been a significant increase in the diagnosis of bipolar disorder in youth.[1] Within the last decade, this diagnosis in children and adolescents has more than doubled.[2] There are a number of possibilities explaining this dramatic increase. Perhaps an unknown biological variable, causing an actual increase of bipolarity in the pediatric population, exists. Perhaps this change is due to a more comprehensive understanding of the disorder. Or, perhaps the surge of diagnoses is due to a combination of diagnostic confusion and poor diagnostic practices.

Often determining which disorders plague a child can be challenging due to a variety of factors, including comorbidity (i.e., a series of disorders frequently occurring simultaneously, such as attention deficit hyperactive disorder [ADHD], oppositional defiant disorder, and bipolar disorder).[3] In community practices today, there seems to be a habit of categorizing a series of similar, yet fundamentally distinct, disorders under the heading of bipolar disorder.[4] However, with the advancements of psychiatry in the modern era, including new medications and new diagnostic classifications, it is more important than ever to differentiate between disorders. Conditions in youth can continue into adulthood with complicated symptoms; therefore, it is essential to diagnose properly from an early age. Furthermore, the imperfections of medications and their often serious side effects strengthen the desire to avoid intensive use if not critically necessary. Thus, on these two counts, the correct diagnosis and treatment is vital in psychiatric practice.

More specifically, in the case of pediatric bipolar disorder, it is crucial to distinguish between severely mood disordered youth and actual bipolar disordered youth. Data from the National Institute of Mental Health (NIMH) clearly delineate the importance of diagnostic differentiation between these two conditions. The data underscore this necessity by suggesting that severely mood disordered, but not bipolar disordered, youth may be significantly at risk for developing unipolar depression in adulthood, but not adult bipolar disorder.[5]

Leibenluft describes a series of four phenotypes of “bipolarity” in the pediatric population.[6] The phenotypes range from the Diagnostic and Statistical Manual of Mental Disoders, Fourth Edition, Text Revision (DSM-IV-TR) definition of bipolar disorder to severely mood disordered youth. These latter patients are characterized by hyper-arousal and severe irritability, but not by core manic symptoms of euphoria, grandiosity, decreased need for sleep, hypersexual behavior, and racing thoughts. Phenotype I matches both the symptomatic and duration criteria of the DSM-IV-TR for bipolar disorder. Phenotype II matches the symptomatic criteria but not the duration criteria. Phenotype III does not match the symptomatic criteria for mania or hypomania, but cycling is present with irritability as the predominant mood. And, finally, phenotype IV references youth without symptomatic criteria and without cycling, but with chronic severe irritability. Patients in the latter groups are considered to be severely mood disordered, yet not bipolar.

Often in clinical practice, all of the phenotypes are deduced to be bipolarity, though this certainly may not be the case, as evidenced by the NIMH study. Unfortunately, there is little data in community practice highlighting the differences between bipolar disorder and severely mood disordered pediatric patients. Therefore, this study is an initial pilot study to look at two samples, one with bipolar disorder and one with severe mood disordered symptomatology, to see if any meaningful differences emerge. In this paper, Leibenluft’s phenotypes I and II will be referenced as pediatric bipolar disorder, while phenotypes III and IV will be referenced as mood disorder not otherwise specified (NOS).

Methods

A retrospective chart review included all patients, five to 18 years of age, who underwent a psychiatric evaluation between September 2004 and September 2007, and were diagnosed with bipolar disorder or mood disorder NOS. A psychiatric evaluation by a board-certified child and adolescent psychiatrist in this clinic includes the administration of the Mini International Neuropsychiatric Interview for Children and Adolescents[7] to the patient and the completion of the Child/Adolescent Symptom Inventory[8] by the parent. Patients were diagnosed with bipolar disorder I or II when they fulfilled full DSM-IV-TR criteria and with bipolar disorder NOS when they showed discrete episodes of core hypomanic/manic symptom clusters, such as euphoria, grandiosity, decreased need for sleep, hypersexual behavior, and racing thoughts, for at least four hours duration, at least once per week.[9] Patients were diagnosed with a mood disorder NOS when they showed a significant mood disturbance of severe irritability, cyclical or not, and did not have discrete episodes of core hypomanic/manic symptoms, even though they may have had sporadic, isolated core hypomanic symptoms.[6] Figure 1) provides an example of a patient diagnosed with a bipolar disorder and a patient diagnosed with a mood disorder NOS.

Patients were included if they returned for at least one follow-up visit after the start of pharmacotherapy. In general, patients were started on pharmacotherapy immediately after the initial evaluation, were scheduled for a return visit one month later, and were subsequently seen for follow-up visits every two to three months. Follow-up visits included both patients and parents to review progress, side effects, mental status, and the medication regimen. As part of every follow-up visit, a Global Assessment of Functioning (GAF) score was determined. Data were documented in a standardized chart format.

Patients were treated with mood stabilizers/anti-aggression medications, most commonly aripiprazole.[10] The decision to treat with mood stabilizers was made with informed consent/assent of the parent and the patient.

The chart review included historical information obtained during the initial evaluation and “followed back” the treatment course until either the patient dropped out of treatment or until the last visit within the first year after the initial evaluation. As such, data were only obtained for a maximum of one year of treatment. Information extracted from the records included age at initial evaluation, gender, DSM-IV-TR diagnoses, including initial GAF, family history of bipolar disorder, number of prior psychiatric hospitalizations, highest level of care ever required (1=outpatient psychotherapy, 2=wraparound or family-based therapy, 3=partial hospitalization program, 4=residential care/hospitalization), previous number and type of medications used, risk factors for suicidality routinely collected in this clinic (e.g., past or present suicidal ideation, past or present suicidal behavior, family history of suicidal behavior, exposure to suicidal behavior, history of physical or sexual abuse, history of psychiatric hospitalization, and substance use), medications prescribed after the evaluation, changes made in the prescription, number of medications used during the treatment, and final GAF. A Clinical Global Impression-Improvement Score (CGI) was extracted from the report of the last treatment visit, compared to the initial evaluation.

Statistical comparisons were done with Student’s t-test for continuous variables and Chi-square test for categorical variables. Tests were two-tailed and significance was put at the 0.05 level.

Results
Twenty-two patients were identified as having been diagnosed with mood disorder NOS and 19 patients with bipolar disorder. Characteristics of both groups are listed in Table 1). Patients with bipolar disorder were about four years older, had more risk factors for suicidality (63% of patients with past suicidality versus 45%), more inpatient hospitalizations (53% of patients vs. 41%), and had more past medication trials. Patients with mood disorder NOS had more ADHD diagnoses (82% vs. 58%), more overall diagnoses, and more family histories of bipolar disorder (64% vs. 58%). The only statistically significant difference between the two groups was in age.

After approximately eight months of follow-up, patients diagnosed with bipolar disorder improved significantly more as manifested by their endpoint GAF. Even though not statistically significant, their CGI and change in GAF were much better as well. Patients were treated with an average of 2.5 medications, while their highest level of care did not differ. Table 2) summarizes these findings. In Table 3), the medications to treat the primary disorder, initially and at endpoint, are listed. The overwhelming majority was treated with atypical antipsychotic monotherapy for the mood problems, although many were prescribed anti-ADHD medications as well (mood disorder NOS: seven treated with stimulants and seven with atomoxetine; bipolar disorder: two treated with stimulants and five with atomoxetine).

Discussion
The results of this study need to be interpreted in light of its limitations. Sample sizes were small, which more than likely reduced the statistical power to find significant differences. Treatment was uncontrolled and data were collected retrospectively. Adherence to treatment was unchecked. Many patients received concomitant psychosocial treatments.

On the other hand, these real-world patients were diagnosed with standardized assessment tools, enhancing diagnostic accuracy. The authors believe that this latter issue goes to the heart of the current controversy in youth bipolar disorder. In many settings, where diagnostic accuracy is less than desirable, numerous patients may be diagnosed with bipolar disorder without clearly meeting pre-established criteria. The explosion in bipolar disorder diagnoses in youth is probably in large part related to inadequate diagnostic workups. Emerging data show that it will be important to increase diagnostic precision, since, among other things, diagnosis predicts prognosis.[5] Researchers are starting to show that the longitudinal course, family history, and pathophysiology of bipolar disorder versus mood disorder NOS is quite different.[11,12] The present study also shows that it is important, in real-world settings, to differentiate both conditions: Patients with mood disorder NOS improved significantly less than patients with bipolar disorder, despite similar treatment intensity and pharmacotherapy.

In this clinic, bipolar disorder patients were significantly older. Both groups had comorbidity, although ADHD was much more common in mood disorder NOS patients, a finding that is also discussed in research studies.13 These latter two observations, the age difference and the comorbidity difference, may be related: Mood disorder NOS patients are reported to have a high comorbidity with ADHD and oppositional defiant disorder, both of which have an earlier onset than bipolar disorder.[13]

Patients with bipolar disorder appeared to have a more significant past histories, including more risk factors for suicidality, more medication trials, and more psychiatric hospitalizations. As such, they looked more like adults with bipolar disorder. Despite these factors, they improved much better under the current treatment conditions. One wonders if this finding is related to a better understanding of the treatment needs of bipolar patients compared to severely mood disordered patients. In this regard, upon reviewing the specific medications, it is of note that, at endpoint, there were significant differences in the pharmacotherapy of the two conditions: Many more patients with bipolar disorder were taking anticonvulsant mood stabilizers (42% versus 5%), while 14 percent of mood disorder NOS patients received no longer mood stabilization (0% in bipolar group).

One finding, contrary to research results, was the increased incidence of a family history of bipolar disorder in mood disorder NOS patients. This finding, however, is difficult to interpret without direct evaluation of the family members. Indeed, in real-world settings, not only youth but also adults may be overdiagnosed with bipolar disorder, as such inflating the reported family histories.

In summary, this study shows the feasibility of putting standardized assessment tools into place in a busy clinic setting. In doing so, guidelines for diagnosing youth with different mood problems can be followed. This has led to the identification of significant differences in the outcome between patients with bipolar disorder and mood disorder NOS.

References
1. Blader JC, Carlson GA. Increased rates of bipolar disorder diagnoses among US child, adolescent, and adult inpatients, 1996–2004. Biol Psychiatry. 2007; Feb 16 (ePub).
2. Youngstrom EA, Birmaher B, Findling RL. Pediatric bipolar disorder: validity, phenomenology, and recommendations for diagnosis. Bipolar Disorders. 2008;10:194–214.
3. Weller EB, Calvert SM, Weller RA. Bipolar disorder in children and adolescents: diagnosis and treatment. Curr Opin Psychiatry. 2003;16(4):383–388.
4. Kuehn BM. Scientists probe child bipolar disorder. JAMA. 2007;297:1181.
5. Brotman MA, Schmajuk M, Rich BA, et al. Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biol Psychiatry. 2006;60:991–997.
6. Leibenluft E, Charney DS, Towbin KE, et al. Defining clinical phenotypes of juvenile mania. Am J Psychiatry. 2003;160:430–437.
7. Sheehan DV, Lecrubier Y, Sheehan K, et al. The validity of the Mini International Neuropsychiatric Interview (MINI), according to the SCID-P and its reliability. Eur Psychiatry. 1997;12:232–241.
8. Gadow KD, Sprafkin J. Adolescent Symptom Inventory-4. Stony Brook, NY: Checkmate Plus LTD, 1997.
9. Geller B, Zimmerman B, Williams M, et al. Phenomenology of prepubertal and early adolescent bipolar disorder: examples of elated mood, grandiose behaviors, decreased need for sleep, racing thoughts and hypersexuality. J Child Adolesc Psychopharmacol. 2002;12:3–9.
10. Bastiaens L. A non-randomized, open study with aripiprazole and ziprasidone for the treatment of aggressive behaviors in youth in a community clinic. Comm Ment Health J. 2008, in press.
11. Rich BA, Schmajuk M, Perez-Edgar KE, et al. Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation. Am J Psychiatry. 2007;164:309–317.
12. Brotman MA, Kassem L, Reising MM, et al. Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation. Am J Psychiatry. 2007;164:1238–1241
13. Carlson GA. Who are the children with severe mood dysregulation, a.k.a. “rages”? Am J Psychiatry. 2007;164:1140–1142.

Ms. Cascade is Vice President, Quintiles Inc./iGuard, Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Weisler is an Adjunct Professor of Psychiatry at the University of North Carolina, Chapel Hill and Adjunct Associate Professor of Psychiatry at Duke University, Durham, North Carolina.

Financial Disclosures

Dr. Weisler is or has been a consultant to, on the speakers bureaus of, and/or received research support from the National Institute of Mental Health, Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cephalon, Ciba Geigy, CoMentis, Corcept, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil Pharmaceuticals, Medicinova, Merck, Neurochem, New River Pharmaceuticals, Novartis, Organon, Otsuka America Pharma, Pfizer, Pharmacia, Saegis, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Shire, Solvay, Synaptic, TAP, UCB Pharma, Validus, Vela, and Wyeth; and has been or is a stockholder in Bristol Myers Squibb, Cortex, Merck, and Pfizer.

Abstract

In this article, we identify commonly prescribed anticonvulsant medications and characterize central nervous system (CNS) reasons for use. Primary care physicians prescribe 37 percent of all anticonvulsant medications in the US. Psychiatrists are the second highest prescribers with a 19-percent share, and neurologists account for 16 percent of all anticonvulsant medication prescriptions. The top three agents prescribed by psychiatrists are clonazepam, lamotrigine, and divalproex; neurologists most commonly prescribe topiramate, gabapentin, and levetiracetam. Anticonvulsant medications most commonly prescribed by psychiatrists are primarily used for bipolar disorder and anxiety. In contrast, these indications account for less than 10 percent of uses for the top products commonly prescribed by neurologists.

Key words

anticonvulsant medication, seizure medication, clonazepam, lamotrigine, divalproex, topiramate, gabapentin, levetiracetam, carbamazepine, bipolar disorder, anxiety, epilepsy, migraine, pain
Introduction

Although there are more than 30 medications available today for the treatment of seizures, the profile of these agents and utility in other disease areas vary widely. In this article, we identify commonly prescribed anticonvulsant medications and characterize central nervous system (CNS) reasons
for use.

Methods

We obtained data from two different sources: 1) total retail prescriptions of anticonvulsant medications in 1st Quarter 2008 from Vector One National (VONA), which captures nearly half of all prescription activity in the US; and 2) annual data from Verispan’s Prescription Drug and Diagnosis Audit (PDDA) database regarding reasons for use of each anticonvulsant medication. PDDA captures data on disease states and associated therapies from 3,100 office-based physicians representing 29 specialties across
the US.

Results

As seen in Figure 1, primary care physicians prescribe 37 percent of all anticonvulsant medications in the US. Psychiatrists are the second highest prescribers with 19-percent share, and neurologists account for 16 percent of all anticonvulsant medication prescriptions. The remaining 27.7 percent of anticonvulsant medications are prescribed by a variety of specialties with no one group accounting for more than five percent. The top three agents prescribed by psychiatrists are clonazepam, lamotrigine, divalproex. In contrast, neurologists most commonly use topiramate, gabapentin, and levetiracetam.

Figure 2 contains a breakdown of reasons of use for the top anticonvulsant medications prescribed by psychiatrists and neurologists. As seen in Figure 2, anticonvulsant medications most commonly prescribed by psychiatrists are primarily used for bipolar disorder and anxiety, making up 68 percent of the reasons for use for clonazepam, 69 percent of lamotrigine, and 58 percent of divalproex by psychiatrists. These indications, however, account for less than 10 percent of uses for the top products prescribed by neurologists, which include topiramate, gabapentin, and levetiracetam. Instead, medications commonly prescribed by neurologists are used to treat seizures, migraines, and pain, making up 73 percent of the reasons for use for topiramate, 77 percent of gabapentin, and 92 percent of levetiracetam by neurologists.

Commentary

by Richard H. Weisler, MD

The data presented in this article, as highlighted in Figure 2, clearly reveal that clinicians have embraced some of the uniqueness of each of the included seizure medications.

While all of the seizure medications reported on are effective in helping to control seizures, some, like divalproex and carbamazepine (not included in this article’s data), are also very effective for controlling mania acutely.[1] Divalproex and carbamazepine are probably also effective as maintenance agents in preventing episodes of mania, though this later use has yet to be clearly proven. On the other hand, clinicians generally have realized that lamotrigine is better at treating depressive symptoms in bipolar disorder than divalproex and perhaps carbamazepine, although they each help ameliorate depressive symptoms to some degree. In contrast, divalproex and carbamazepine in numerous trials have been shown to be more effective at treating manic symptoms than lamotrigine, although lamotrigine also helps prevent manic symptoms to some degree as noted in lamotrigine’s FDA approval indication.

The presented data analysis in this article reveal that gabapentin and topiramate are still being used by a relatively small percentage of clinicians to treat bipolar disorder, though the clinical trial data clearly show that neither is effective for treating either mania or depression. Some clinicians perhaps may be taking advantage of topiramate’s ability to decrease both appetite and weight or help with alcohol abuse and dependence, as those conditions are frequently comorbid in bipolar patients. Gabapentin can also help control anxiety and pain symptoms, and perhaps clinicians have taken advantage of gabapentin being an effective treatment for these symptoms in some bipolar patients because of the abuse liability of benzodiazepines, opiates, and other pain medications.[2–4]

Neurologists and some psychiatrists have also taken advantage of pregabalin (not included in this article’s data), another FDA-approved an alpha 2-delta-ligand, to ameliorate pain and anxiety symptoms in a similar fashion. Not surprisingly, pregabalin, like gabapentin, does not appear to be effective in treating either manic or depressive symptoms, though several studies have shown that it is effective in some anxiety disorders. As a very large percentage of bipolar patients are being treated with multiple medications, let’s hope that gabapentin, pregabalin, and topiramate are used only in rare exceptions by clinicians as standalone treatments for bipolar disorder due to their lack of efficacy for mania or depression.

Clonazepam can, in some cases, be used to treat seizures. Far more commonly, clonazepam is used like the other benzodiazepine class members to rapidly and effectively control anxiety symptoms as reflected in the prescribing patterns. Clonazepam’s speed of response makes it a very useful drug in generalized anxiety disorder as well as panic disorder and social phobia.[5] Clonazepam relieves anxiety symptoms rapidly even without chronic dosing, which is consistent with it frequently being used on an as-needed basis by clinicians in these situations. Clonazepam as a monotherapy treatment is clearly not an effective treatment for mania, and it can even exacerbate depression in some cases. This suggests that clonazepam is being used by psychiatrists to control pure or comorbid anxiety symptoms and perhaps as a sleep aide. Clonazepam also carries some abuse risks. Unlike the other seizure medications in this article’s data, abrupt discontinuation of clonazepam, even in patients without epilepsy, can lead to withdrawal seizures after regular use.

Neurologists diagnose and treat many more patients for their epilepsy than psychiatrists and this is reflected in their prescribing patterns.[6,7] Neurologists also treat far more patients for migraines than psychiatrists. Not surprisingly, neurologists use more topiriamate and, to some degree, divalproex for migraine headaches as both compounds have FDA disease indications for migraines.[6] Neurologists have recognized that levitracetam is a very effective and generally well-tolerated anticonvulsant. Trials seem to suggest though that levitracetam is not very effective in treating anxiety or mood disorders. Apparently, clinicians have adopted this view of levitracetam as well with wide usage by neurologists for epilepsy and little use outside of that disease area.[8]

All of the seizure medications in Figure 2 are also being used in a substantial minority of cases for other uses. Fibromyalgia, I am certain, represents one of the “other” common indications for gabapentin and pregabalin.[9] These “other uses” may also reflect the breadth of action for antiepileptics and/or the many still unmet clinical needs that clinicians are attempting to address.

As a class, existing and future seizure medications are likely to continue to be very widely used and to remain attractive compounds both for neurologists and psychiatrists. My personal belief is that many other very exciting uses for seizure medications have yet to be identified. Kanner recently reviewed the evidence for the bidirectional link between depression and epilepsy.[10] And one shouldn’t forget that neurologists and psychiatrists share a common organization for board certification for a reason, though each specialty has their own focus of practice. Unmet clinical need will likely drive this clinical exploration of new uses for antiepileptics. For example, additional and more effective treatments for posttraumatic stress disorder (PTSD),[11,12] affective disorders, and traumatic brain injuries (TBI) are desperately needed at this time. A recent Rand Corporation mental health survey of recently returned troops from Iraq and Afghanistan (N=1,965)[13] estimates that of these 1.64 million war veterans, currently about 300,000 (18.5 %) meet criteria for PTSD or depression, about 320,000 (19.5 %) report experiencing a probable TBI, and 120,000 (7.3 %) report having PTSD or depression and experiencing probable TBI. Will some antiepileptics ultimately turn out to be of help for these soldiers and others with affective, anxiety, and cognitive problems like those who have been injured in motor vehicle accidents or assaults? In 1993, in desperation, I first tried the then unapproved drug lamotrigine under a compassionate use exemption for two very refractory patients based only on my clinical hunch and Robert Post’s anti-kindling theory. My two patients, their families, and I were pleasantly shocked a few short weeks later when lamotrigine dramatically lifted their severe unremitting depression and controlled their mood cycling. In 2003, lamotrigine was approved for bipolar disorder by the FDA.[14] I know there will be more stories of new uses like this one for “seizure medications” in the future.

References
1. Weisler RH, Cutler AJ, Ballenger JC, et al. The use of antiepileptic drugs in bipolar disorders: a review based on evidence from controlled trials. CNS Spectr. 2006;11(10):788–799. Review.
2. Rosenberg JM, Salzman C. Update: new uses for lithium and anticonvulsants. CNS Spectr. 2007;12(11):831–841. Comment in: CNS Spectr. 2008;13(2):109–110; author reply 110.
3. Zwanzger P, Eser D, Rupprecht R. [Anticonvulsants in the treatment of anxiety—an alternative treatment option?] Nervenarzt. 2007;78(11):1274–1282.
4. Van Ameringen M, Mancini C, Pipe B, Bennett M. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy. Drugs. 2004;64(19):2199–2220.
5. Nardi AE, Perna G. Clonazepam in the treatment of psychiatric disorders: an update. Int Clin Psychopharmacol. 2006;21(3):131–142.
6. Wilby J, Kainth A, Hawkins N, et al. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess. 2005;9(15):1–157, iii–iv.
7. Otoul C, Arrigo C, van Rijckevorsel K, French JA. Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy. Clin Neuropharmacol. 2005;28(2):72–78.
8. Mulleners WM, Chronicle EP. Anticonvulsants in migraine prophylaxis: a Cochrane review. Cephalalgia. 2008;28(6):585–597
9. Goldenberg DL. Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;21(3):499–511.
10. Kanner AM. Depression in epilepsy: a complex relation with unexpected consequences. Curr Opin Neurol. 2008;21(2):190–194.
11. Berlin HA. Antiepileptic drugs for the treatment of post-traumatic stress disorder. Curr Psychiatry Rep. 2007;9(4):291–300.
12. Davidson JR. Pharmacologic treatment of acute and chronic stress following trauma: 2006. J Clin Psychiatry. 2006;67 Suppl 2:34–39.
13. Tanielian T, Jaycox LH, (eds). Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: RAND Corporation, MG-720-CCF, 2008:492.
14. Weisler RH, Calabrese JR, Bowden CL, et al. Discovery and development of lamotrigine for bipolar disorder: a story of serendipity, clinical observations, risk taking, and persistence. J Affect Disord. 2008;108(1-2):1–9. Epub 2007 Nov 14. Review.

Funding

This study was supported by funding from Shire Development Inc.

Financial Disclosures

Dr. Weisler has received research support from, has been a speaker for, and/or has been a consultant to Abbott, the Agency for Toxic Substances and Disease Registry/Centers for Disease Control and Prevention, AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, CoMentis, Corcept, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson and Johnson, Lundbeck, MediciNova, Merck, the National Institute for Mental Health (NIMH), New River, Novartis, Organon, Pfizer, Saegis, Sanofi-Synthelabo, Schwabe, Shire, Solvay, Synaptic, TAP Pharmaceutical Products, UCB Pharma, Vela, and Wyeth, and holds or has held stock in Bristol-Myers Squibb, Merck, and Pfizer; Dr. Kalali is a consultant to Shire Pharmaceuticals; Dr. Cutler has received research grants, is a consultant to, or is a speaker for Abbott Pharmaceuticals, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Dalnippon Sumitomo Pharma, Eli Lilly & Co., Forest Labs, GlaxoSmithKline, Janssen Pharmaceutica, JDS Pharmaceuticals, Johnson & Johnson PRD, Memory Pharmaceuticals, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceuticals, Pfizer, Sanofi-Synthelabo, Sanofi-Aventis, Seprecor, Shire Pharmaceuticals, Solvay Pharmaceuticals, Supernus Pharmaceuticals, Vanda Pharmaceuticals, and Wyeth Pharmaceuticals; Dr. Gazda is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Janssen, Johnson and Johnson, Pfizer, Sanofi-Aventis, and Shire Pharmaceuticals; and Dr. Ginsberg has received research support from and is a consultant to Shire Pharmaceuticals.

Abstract

Objective: To evaluate the safety and efficacy of carbamazepine extended-release capsules (CBZ-ERC) in combination with other psychotropic medications for the treatment of bipolar I disorder.

Design: In this Phase IIIb, open-label, eight-week, observational, polypharmacy study, adult subjects were started on CBZ-ERC 200mg and titrated over four weeks to optimal dose (1600mg/d maximum). Concomitant lithium and atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole) were permitted. Safety assessments included adverse events, laboratory parameters, physical examination, medication history, vital signs, and electrocardiogram. Efficacy measures included the Young Mania Rating Scale (YMRS), Hamilton Rating Scale for Depression (HAM-D), Montgomery-Åsberg Depression Rating Scale (MADRS), and Clinical Global Impressions Scale–Bipolar Version (CGI-BP). All data were summarized using descriptive statistics.

Results: Overall, 45 (84.9%) subjects reported treatment-emergent adverse events (TEAEs); most were mild or moderate in severity. The most commonly reported TEAEs were somnolence (n=14, 26.4%), sedation (n=12, 22.6%), dizziness (n=11, 20.8%), headache (n=9, 17.0%), and nausea (n=7, 13.2%). There were no clinically significant changes in vital signs, including weight. Mean changes in laboratory parameters were small, with values that were within the normal range for the majority of subjects. Few changes relative to screening for other safety parameters occurred. Mean total YMRS score decreased from baseline at each study visit. HAM-D and MADRS scores decreased from baseline at Weeks 4 and 8, and all three CGI-BP components (overall bipolar disorder, mania, and depression) improved during the study.

Conclusion: CBZ-ERC appears to be safe and effective for use in combination with atypical antipsychotics and lithium for treatment of bipolar I disorder.

Key Words

carbamazepine, extended release, bipolar disorder
INTRODUCTION

Current options for the treatment of bipolar disorder include the Food and Drug Administration (FDA)-approved mood stabilizers (e.g., lithium, valproate, lamotrigine, and carbamazepine extended-release capsules [CBZ-ERC]) and antipsychotics (e.g., chlorpromazine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). While these agents have been shown in double-blind trials to be effective for the management of acute mania,[1–11] bipolar disorder is a lifelong disorder with frequently recurring symptoms.[12] It has been estimated that 37 percent of patients who have a manic episode suffer a recurrence within one year, and 73 percent experience a recurrence within five years.[13] Further, a long-term follow-up estimate of the lifetime outcome of bipolar disorder determined that only 16 percent of patients had recovered with treatment, while recurrence was observed in 52 percent of patients.[14]

It has long been recognized that long-term treatment of bipolar disorder with monotherapy is not always the most successful approach;[15] therefore, switching therapies or combining therapies is often used to manage bipolar episodes.[16–18] Several recent studies suggest that greater therapeutic benefit is achieved with combination therapy compared with monotherapy,[19–23] and recent studies have reported that, while 18 percent of patients with bipolar disorder receive monotherapy,[24] approximately 30 to 50 percent are treated with three or more agents concurrently.[18,24,25]

In general, polypharmacy is recognized as potentially placing patients at increased risk for adverse events (AEs), as well as creating the potential for drug-drug interactions.[26,27] However, although there is an increased potential for drug-drug interactions with concomitant therapies, polypharmacy also can, at times, decrease the incidence of AEs when the dosage of each drug in the combination regimen is lower than that of the monotherapy regimen.[28] In addition, the total cost of medications is higher with polypharmacy; nevertheless, by improving medical outcomes when appropriately prescribed, polypharmacy has been shown, in the management of other chronic medical conditions, to decrease the overall cost of healthcare.[29,30] The adverse event burden may be less for some patients with combination therapy, because lower doses can often be used to obtain the same effect. The improved efficacy of carbamazepine in combination with lithium compared with the use of either agent alone in bipolar disorder—especially in patients with a history of rapid cycling—has been demonstrated in a double-blind study.[31] The safety of CBZ-ERC in combination with commonly used mood stabilizers and antipsychotic agents was demonstrated in a recent clinical trial.[32] The purpose of this open-label study is to explore further the safety and efficacy of CBZ-ERC in combination with other psychotropic medications in the treatment of bipolar I disorder.

METHODS

This Phase IIIb, open-label, observational, polypharmacy study was conducted in accordance with current applicable regulations, the International Conference on Harmonisation (ICH), and local ethical and legal requirements. Before site initiation, protocols, informed consent documents, and relevant supporting and patient recruitment information were submitted to and reviewed and approved by a centralized Institutional Review Board (IRB), BioMed IRB. All subjects provided informed consent before they completed any study-related procedures.

Subjects. Otherwise healthy male or nonpregnant female outpatients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)[33] criteria for bipolar I disorder (most recent episode: manic or mixed) based on medical records were eligible for the study if they met the following criteria: one or more prior manic or mixed episode; Young Mania Rating Scale (YMRS)[34] score of 16 or more; and currently receiving treatment with an antipsychotic (e.g., olanzapine, risperidone, quetiapine, or aripiprazole) as either monotherapy or in combination with a mood stabilizer (e.g., lithium, valproate, or lamotrigine), and currently changing medication to improve efficacy or side-effect profile. Female subjects had agreed to adhere with acceptable forms of contraception throughout the study.

Subjects who had a history of a lack of therapeutic response to an adequate trial with carbamazepine for the treatment of bipolar I disorder; who met DSM-IV-TR criteria for ultra-rapid cycling (i.e., >6 mood episodes per year);33 who were judged by the investigator to be acutely at risk for suicidal or violent behavior; or who had histories of serious suicide attempts requiring medical intervention were excluded from study participation. Additional exclusion criteria included histories of or presence of clinically significant hepatic or renal disease or any other disease that could affect the action, absorption, or disposition of the study drug or assessments; bone marrow depression; seizure disorder (other than a single childhood febrile seizure); myocardial infarction within six months of screening; borderline or antisocial personality disorder or any nonaffective psychotic disorder or mental disorder caused by a general medical condition; current hospitalization for the treatment of psychiatric symptoms; the presence of any other primary Axis I disorder not specifically allowed by the protocol; the presence of any condition that could confound interpretation of the study results or that represented an inappropriate risk to the subject; and a history of hypersensitivity or intolerance to CBZ-ERC.

Study periods. The study comprised three study periods—screening, open-label titration, and observation—and a 30-day follow-up. Subject eligibility was determined during the 2- to 10-day prestudy screening period. Baseline safety and efficacy assessments were performed at the beginning of the four-week titration period, and CBZ-ERC treatment was initiated in all subjects. [The starting dose of 200mg/d was followed by 200mg increases every 3 to 4 days—as tolerated and clinically indicated—to a target dose of 800mg/d BID (maximum dose, 1600mg/d) (Table 1). Dosage adjustments were stopped when the subject’s optimal dose was achieved, and downward titration was permitted at any time during treatment to improve tolerability or for safety reasons. Mood stabilizers, with the exception of lithium, were discontinued with a slow downward titration while CBZ-ERC was gradually titrated upward. Lithium (when appropriate) and carbamazepine serum levels were obtained at Weeks 1, 2, 4, and 8 or early termination (ET) (final visit), and were monitored throughout the observation period. At each study visit, safety, adherence, and concomitant medication data were collected and the YMRS[34] was administered. Other efficacy rating scales—(Clinical Global Impressions Scale–Bipolar Version [CGI-BP],[35] Hamilton Rating Scale for Depression, 21-item version [HAM-D21],36 and Montgomery-Åsberg Depression Rating Scale [MADRS])[37]—were administered at baseline (Week 0) and Week 4. Subjects continued their CBZ-ERC optimal dose during the four-week observation period; however, the dosage might have been reduced at any time during the treatment period to improve tolerance. All efficacy rating scales were administered, and safety, adherence, and concomitant medication data were collected at the final visit (Week 8/ET). Follow-up to collect information on new or ongoing AEs was conducted 30 days after the last dose of the study drug was given.

Study drug. CBZ-ERC (Equetro™) is a three-bead (immediate-, extended-, and enteric-release) capsule formulation of carbamazepine. In this open-label study, all subjects were in a single treatment group, so no blinding was required. CBZ-ERC 200mg capsules (lot number ODV040203) were used during the titration period, and 200mg and 300mg capsules (lot number ODV040202) were used during the observation period. Study medication was administered BID, with the morning and evening meals.

Concomitant use of lithium was permitted, provided that a stable dose had been maintained for two weeks before screening; other mood stabilizers (valproate and lamotrigine) were discontinued during the titration period. In addition, concomitant use of benzodiazepines for agitation or sleep as well as the following antipsychotics were permitted: olanzapine, risperidone, quetiapine, and aripiprazole. The dosage of concomitant medications was adjusted, if needed, after the optimal dose of CBZ-ERC had been achieved. Concomitant use of antipsychotics other than those listed above, long-acting, injectable antipsychotics, antidepressants, and clozapine was not permitted. Subjects who needed alternative treatments (e.g., electroconvulsive therapy [ECT], mood stabilizers, or antipsychotics that were not present at baseline) were withdrawn from the study.

Evaluation criteria. Safety assessments. Safety assessments, the primary study outcome, included the recording of AEs, laboratory parameters, a physical examination, and medication history (including all medications taken during the course of the study and those taken for three months prior to screening), vital signs, and an electrocardiogram (ECG). In addition, the total number of days on treatment was summarized for the safety population to determine the extent of study drug exposure.

AE information—defined as any unfavorable and unintended sign, symptom, disease, or exacerbation of a pre-existing condition temporally but not necessarily causally associated with the use of the investigational agent—was collected and recorded from the time of signed informed consent and for 30 days after treatment ended. AE intensity (mild, moderate, or severe) was assessed; the outcome (resolved, unresolved, resolving, resolved with sequelae, death, or unknown) was recorded; and the causal relationship between the AE and study drug was categorized. Serious AEs were those that resulted in death; were life-threatening; required inpatient hospitalization or prolongation of existing hospitalizations; resulted in persistent or significant disability or incapacity; or resulted in a congenital abnormality or birth defect. A treatment-emergent AE (TEAE) was defined as an AE that occurred on or after the first day of double-blind dose of study medication; a treatment-related AE was defined as a TEAE considered by the investigator to be causally related to the study drug.

Laboratory assessments—collected under nonfasting conditions—included biochemistry, hematology, urinalysis, urine pregnancy test, thyroid stimulating hormone (TSH), and serum lithium and carbamazepine levels. The following biochemistry parameters were assessed: sodium, potassium, calcium, urea, creatinine, albumin, total protein, lactic dehydrogenase (LDH), aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin, glucose, and cholesterol. Hematology parameters included hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), total and differential white blood cell (WBC) count, and platelet count. Urine was analyzed for glucose, blood, protein, and pH, and a drug screen was performed. Biochemistry, hematology, urinalysis, and TSH samples were obtained at screening, at Week 4, and again at Week 8/ET. The drug screen was performed at screening and Week 8/ET; serum lithium and carbamazepine levels were measured at screening and Weeks 1, 2, 4, and 8/ET. A urine pregnancy test was performed on all females of childbearing potential at screening and Weeks 0, 4, and 8/ET.

A full physical examination was performed at screening and Week 8/ET; height was measured at screening only, and weight was recorded at each study visit. Vital signs—pulse rate and blood pressure (BP)—were measured at each study visit after the subject had been in a sitting position for five minutes. Blood pressure was measured using the same method and the same arm throughout the study. Clinically significant changes from screening in the physical examination and/or vital signs were noted as AEs. A 12-lead ECG was performed with the subject in the supine position; this was read and interpreted by a cardiologist at screening and at Weeks 4 and 8/ET.

Efficacy assessments. The clinician-administered efficacy assessments—administered in this study by qualified raters— included the YMRS,[34] HAM-D21,[36] MADRS,[37] and CGI-BP;[35] these are standard measuring instruments used in clinical studies of bipolar disorder. The YMRS, the primary efficacy variable, is an 11-item scale designed to assess the severity of symptoms associated with the manic state of bipolar disorder.[34] Scored on a scale of 0 to 60, with higher scores indicating greater disease severity, the YMRS was administered at screening, baseline, and Weeks 1 through 8/ET. The secondary efficacy variables (HAM-D, MADRS, and CGI-BP) were administered at baseline and Weeks 4 and 8/ET.
The first 17 items of the HAM-D21, a 21-item instrument designed to detect the presence and severity of depression in adults,[36] were included in the score analysis. Four assessed items that were not included in the score analysis are diurnal variation of symptoms, depersonalization and derealization, paranoid symptoms, and obsessional and compulsive symptoms. Scoring of the MADRS,[37] a 10-item instrument designed to detect the presence and severity of depression in adults, was based on a clinical interview. The CGI-BP measures the severity of (CGI-BP-S) and changes in (CGI-BP-C) mania, depression, and overall bipolar illness.[35] The CGI-BP-S measures severity of mania, depression, and overall bipolar illness on a scale ranging from 1 (normal, not ill) to 7 (very severely ill), and the CGI-BP-C evaluates change from the Baseline assessment for each phase of the illness was determined, with grading options ranging from 1 (very much improved) to 7 (very much worse). As with the YMRS, higher scores indicated greater disease severity for all three secondary efficacy assessments.
Statistical methods. All data were summarized using descriptive statistics; no inferential analyses were performed for the safety or efficacy assessments in this study. The number of observations, mean, standard deviation (SD), median, minimum, and maximum values are presented for the numerical variables, and categorical variables are summarized using frequencies and percentages. Calculation of the extent of study drug exposure was determined by converting the number of days of treatment for each subject into weeks, and then summarizing the data continuously as mean number of weeks, and categorically by the number of weeks of drug exposure.

Patients were evaluated based on the safety and intention-to-treat (ITT) populations. The safety population comprised all patients who received one or more doses of the study drug, and served as the basis for the safety evaluation; the ITT population comprised all enrolled patients who received one or more doses of study drug, had a baseline YMRS evaluation, and one or more postbaseline YMRS evaluations, and served as the basis for the efficacy evaluation.

Results
This study was conducted at 11 sites in the United States between March 8 and October 19, 2005.

Subject disposition. Among the 53 subjects enrolled, 35 (66%) completed the trial and 18 (34%) terminated early (Table 2). The most common reasons for early termination were lost to follow-up (7 subjects [13.2%]) and the occurrence of an AE (9 subjects [17.0%]); one subject withdrew due to lack of efficacy. In addition, one subject who reported a serious AE (abdominal pain) withdrew from the study; however, because the subject did not return to the site for end-of-study procedures, the investigator considered “lost to follow-up” the most appropriate reason for study termination. The safety population comprised 53 (100%) enrolled subjects, and the ITT comprised 52 (98.1%) subjects; one subject was excluded from the ITT population because no postbaseline YMRS data were available.

Subject demographics. The majority of subjects in the safety population were female (64.2%) and white (58.5%), and the mean age was 38.8 years. The subjects’ mean weight, 194.7 lbs, was high in both groups, and there were no notable demographic differences between the safety and ITT populations. Mean baseline disease characteristics are summarized in Table 3. The most recent bipolar episode reported was a mixed episode in the majority of subjects (62.3%), and 45.3 percent reported more than 10 previous manic/mixed episodes. All concomitant psychiatric conditions reported at screening were categorized as “history and not active.”

Previous medications reported by greater than 10 percent of subjects included antidepressants (96.2%), antiepileptics (28.3%), antihistamines for systemic use (11.3%), and sex hormones and genital modulators (11.3%). All subjects were receiving concomitant antipsychotic medications during the study, including olanzapine (11.3%), risperidone (13.2%), quetiapine (50.9%), and aripiprazole (28.3%). In addition, 24.5 percent were receiving concomitant mood stabilizers, including lithium (7.5%), valproate (15.1%), and lamotrigine (1.9%).

Safety evaluations. Drug exposure. The total number of days on treatment was summarized for all subjects included in the safety population. The number of days for each subject was converted into weeks, and the data were summarized continuously as mean number of weeks, and categorically by the number of weeks exposed. The aggregate number of patient years on drug was then computed across all subjects. Overall patient exposure to CBZ-ERC was 6.3 patient years, with subjects receiving concomitant antipsychotic medications exposed for 5.8 patient years, and those receiving both antipsychotics and lithium exposed for 0.6 patient years. Mean study drug exposure was slightly longer for subjects who received antipsychotics with lithium (7.54 weeks) compared with those who received concomitant antipsychotics without lithium (6.27 weeks). A majority of the subjects in the overall safety population (63.5%) and in the antipsychotic group (62.5%) were exposed to CBZ-ERC for seven or more weeks; among four subjects in the antipsychotic plus lithium group, three were exposed to CBZ-ERC for more than eight weeks, and one was exposed between two and three weeks. The most common CBZ-ERC dosages administered during the study were 400mg (46 subjects; mean exposure duration 1.95 weeks) and 800mg (42 subjects; mean exposure duration 3.02 weeks). The mean CBZ-ERC daily dose was 696.3mg overall—694.0mg in the antipsychotic group and 723.9mg in the antipsychotic plus lithium group.

Adverse events. Treatment-emergent adverse events (TEAEs) were summarized for the overall safety population, and for subsets of subjects receiving the following concomitant medications: antipsychotics (n=49), antipsychotics with lithium (n=4), olanzapine (n=6), risperidone (n=7), quetiapine (n=27), and aripiprazole (n=15). Subjects receiving antipsychotics plus lithium (4) were excluded from the data summaries of those receiving concomitant antipsychotics because the numbers were insufficient for a meaningful analysis.

In the overall safety population, 84.9 percent of subjects reported TEAEs during the study (Table 4). The most commonly reported TEAEs (≥10% of subjects in the safety population) were somnolence (26.4%), sedation (22.6%), dizziness (20.8%), headache (17.0%), and nausea (13.2%). Weight gain was reported as an AE for three subjects (5.7%), with the maximum weight increases from screening ranging from 7.1 to 12.2 percent. The subject with the greatest increase in weight withdrew from the study because of an AE of weight gain; this subject was receiving concomitant valproate and quetiapine.

AEs were reported by 83.7 percent of subjects who received concomitant antipsychotics and by 100 percent of subjects receiving concomitant antipsychotics plus lithium. The distribution of the most commonly reported TEAEs among subjects receiving concomitant antipsychotics was similar to that of the overall safety population; however, it differed among those who were on concomitant antipsychotics plus lithium. None of the subjects in this group reported dizziness or sedation, which were among the most commonly reported AEs in subjects in the overall safety population; however, it was not possible to assess the importance of this finding due to the small number of subjects in this subgroup. Further, AEs differed among subjects receiving different antipsychotics. All subjects receiving concomitant olanzapine (n=6) or risperidone (n=7) reported AEs; 81.5 percent receiving quetiapine (n=27) and 80 percent receiving aripiprazole (n=15) reported AEs. The most commonly reported TEAEs in the safety population (somnolence, sedation, dizziness, headache, and nausea) were also reported in subjects receiving antipsychotics, with the exception of nausea, dizziness, and headache, which were not reported in subjects receiving olanzapine.

Most AEs were mild or moderate in severity, with eight subjects (15.1%) experiencing severe AEs. Overall, 31 (58.5%) TEAEs were rated as mild and 24 (45.3%) as moderate. With the exception of the 15 subjects who received concomitant aripiprazole, more than 50 percent of TEAEs in subjects receiving antipsychotics and/or lithium were rated as mild in intensity. Among subjects receiving aripiprazole, 10 (31.3%) of the TEAEs were rated as mild, 18 (56.3%) moderate, and four (12.5%) severe. No severe TEAE was reported by more than one subject. The distribution of severe TEAEs among subjects in the antipsychotic subgroups was as follows: lithium (0); olanzapine (0); aripiprazole (thrombocytopenia, diarrhea, asthenia, and sedation); quetiapine (nausea, influenza-like illness, priapism); and risperidone (dizziness). AEs leading to study discontinuation were reported in 10 subjects. Among the AEs leading to study discontinuation, only rash and sedation were reported by more than one subject and were considered to be study-drug related. Serious AEs were reported by three subjects: one subject withdrew from the study due to abdominal pain that was considered unrelated to the study drug; one subject reported priapism that was considered possibly related to the study drug; and one subject was hospitalized for increased bipolar symptoms that had begun during screening, so the subject was not administered the study drug. No deaths were reported during the study.

Laboratory evaluations. Laboratory evaluations, vital signs, and ECG data were summarized for the overall safety population, and for subsets of subjects who received antipsychotics alone or combined with lithium. Overall, mean changes in hematology parameters from screening to Week 8/ET were small, with values reported within the normal range for the majority of subjects. Greater than 10 percent of subjects had abnormal WBC counts at Week 8/ET; three subjects had abnormally low WBC counts and two had abnormally high WBC counts. The mean change in WBC count from screening to Week 8/ET was -0.646×103/µL. Most subjects with abnormal hematology results at Week 8/ET were from the subgroup receiving antipsychotic medications. Among those receiving antipsychotics plus lithium, one had a decreased RBC count and one had abnormal hemoglobin. Clinically significant abnormalities were reported for four subjects, as follows: one low neutrophil (1.15×103/µL) and WBC (2.4×103/µL) counts; one low neutrophil (1.11×103/µL) and WBC (2.7×103/µL) counts with elevated lymphocytes (1.72×103/µL); one low WBC (2.9×103/µL) count; and one elevated lymphocyte (6.21×103/µL) count. Among these four subjects, three had abnormal values at screening. Two (2) subjects discontinued the study drug because of hematologic abnormalities (thrombocytopenia [1]; decreased neutrophil count [1]).

Despite the fact that fasting was not required for clinical chemistry samples, mean changes in chemistry and electrolyte values from screening to Week 8/ET were small in most subjects. However, more than 10 percent of subjects with laboratory data at Week 8/ET had abnormally high results for the following parameters: GGT (n=15, mean increase 33.514U/L); cholesterol (n=7, mean increase 16.595mg/dL); glucose (n=5, mean increase 8.757mg/dL); ALT (n=5, mean increase 0.649U/L); AST (n=4, mean increase 1.351U/L); ALP (n=4, mean increase 8.4U/L); and TSH (n=4, mean increase 0.4µIU/mL). Most subjects with abnormal serum chemistry results at Week 8/ET were from the subgroup that received antipsychotics, and most of them received quetiapine (the most commonly prescribed antipsychotic in this study). Abnormalities in clinical chemistry results in subjects receiving antipsychotics plus lithium included elevated glucose, decreased glucose, and elevated GGT (1 subject each).

A total of 33 subjects had serum CBZ levels outside of the normal range during at least one study time point. Approximately half of the abnormal values occurred during the first or second week of the study, and in most cases these values were abnormally low during the study medication titration period. Clinically significant serum chemistry/ electrolyte abnormalities were reported in 15 subjects after the first dose of study drug; among these subjects, 10 were receiving concomitant quetiapine. The most common clinically significant abnormality in chemistry parameters was TSH (n=7); six of these subjects received concomitant quetiapine and two had abnormal results at screening. Although clinically significant GGT abnormalities were reported in four subjects, no other liver function test parameters were clinically significant in any subjects. Among the four subjects with clinically significant elevated glucose, three had a medical history of type 2 diabetes. One (1) subject discontinued the study drug because of hyponatremia (122mmol/L). Concomitant medications other than quetiapine taken by subjects who developed clinically significant serum chemistry abnormalities included olanzapine (increased potassium [1 subject] and increased GGT [1 subject]); aripiprazole (increased glucose [1 subject]); aripiprazole and lithium (increased glucose [1 subject]); and olanzapine and aripiprazole (increased GGT and TSH [1 subject]).

Clinically significant abnormal urinalysis results included elevated urine glucose (n=3) and blood in the urine (n=1). All three subjects with abnormal urine glucose had type 2 diabetes at screening, and the subject with blood in the urine was female, suggesting menstrual blood contamination. Serum carbamazepine values outside therapeutic range (4.0–10µg/mL) were reported at least once during the study in 33/53 (62.3%) of subjects. Most of these were abnormally low levels, and approximately half occurred during the first two weeks of the study. Among the four subjects receiving concomitant lithium, three maintained therapeutic serum carbamazepine levels (0.6–1.2mEq/L) throughout the study, while one had consistently low levels.

Few changes relative to screening were reported for other safety parameters. On the physical examination, changes in rash were reported in two subjects and skin redness was reported in one; other skin changes included superficial ulcerations of both feet in one subject. No clinically significant mean changes from baseline were observed in vital signs (pulse rate, blood pressure, temperature, and weight) at Week 8/ET. The mean change in weight in the overall safety population was 1.2 lbs; in the subgroup receiving concomitant antipsychotics it was 1.1 lbs, and in the subgroup receiving antipsychotics plus lithium it was 1.5 lbs. At screening, 64.2 percent of subjects had normal ECGs, and none of the remaining 35.8 percent had clinically significant abnormalities. One subject in the antipsychotic plus lithium subgroup had an abnormal and clinically significant ECG at Week 4. At the end of the study, 49.1 percent of subjects had normal ECGs, and there were no clinically significant abnormal findings.

Efficacy results. There was a mean decrease in the total YMRS score from baseline at each study visit, indicating improvement in the severity of manic symptoms. As illustrated in Figure 1, the mean decrease from baseline was progressively greater at each postbaseline visit, with the mean (SD) decrease -6.7 (6.13) points at Week 1 and -12.9 (6.43) points at Week 8/ET.

There also was a mean decrease from baseline at Weeks 4 and 8/ET in the secondary efficacy variables, HAM-D and MADRS, indicating improvement in the severity of depression (Figure 2). The mean (SD) HAM-D score at baseline was 11.2 (6.84), and the mean decrease from baseline at Week 4 was -4.4 (6.11) and at Week 8/ET -5.1 (6.39). Similarly, the mean (SD) MADRS score at baseline was 14.5 (8.92). and the mean decrease from baseline was -6.2 (8.77) at Week 4 and -7.4 (7.97) at Week 8/ET.
Each of the three CGI-BP components—mania, depression, and overall bipolar disorder—improved during the study, demonstrating reduced severity of bipolar illness. For overall bipolar disorder, the percentage of subjects rated as “moderately ill” or “markedly ill” at baseline (n=40, 77.0%) on the CGI-BP-S decreased at Week 4 (n=10, 21.7%) and at Week 8/ET (n=7, 17.9%). Further, the percentage rated as “improved” (“very much improved” or “much improved”) on the CGI-BP-C increased over time (Week 4, n=24 [52.2%]; Week 8/ET, n=23 [60.5%]), while the percentage rated as “not improved” (“minimally improved,” “no change,” “minimally worse,” “much worse,” and “very much worse”) decreased over time (Week 4, n=22 [47.8%]; Week 8/ET, n=15 [39.5%]). Similar findings were reported for the mania and depression components of the CGI-BP. For the mania component, the percentage rated “moderately ill” or “markedly ill”on the CGI-BP-S at baseline (n=38, 73.1%) decreased at Week 4 (n=5, 10.9%) and at Week 8/ET (n=5, 12.8%), the percentage rated as “improved” on the CGI-BP-C increased over time (Week 4, n=27 [58.7%]; Week 8/ET, n=23 [60.5%]), and the percentage rated as “not improved” on the CGI-BP-C decreased over time (Week 4, n=19 [41.4%]; Week 8/ET, n=15 [39.5%]). For the depression component, the percentage of subjects rated as “moderately ill” or “markedly ill” on the CGI-BP-S at baseline (n=19, 36.5%) decreased at Week 4 (n=9, 19.6%) and at Week 8/ET (n=7, 17.9%), the percentage rated as “improved” on the CGI-BP-C increased over time (Week 4, n=13 [28.3%]; Week 8/ET, n=11 [29.0%]), and the percentage rated as “not improved” on the CGI-BP-C decreased over time (Week 4, n=33 [71.7%]; Week 8/ET, n=27 [71.0%]). Figure 3 summarizes the percentage of improvement at Week 4 and Week 8/ET on the three components of the CGI-BP-C.

DISCUSSION

Based on current trends in the management of bipolar disorder,[18,24,25] it is anticipated that CBZ-ERC will be used as combination therapy, and subjects were, therefore, allowed to continue on lithium and/or antipsychotics (e.g., olanzapine, risperidone, quetiapine, and aripiprazole) in the present study to evaluate CBZ-ERC in a “real-world” setting. Results showed the agent to be safe and generally well tolerated when administered as combination therapy, with the majority of TEAEs rated as mild or moderate in severity, and only eight (15.1%) subjects experiencing AEs rated as severe. The most commonly reported TEAEs (≥10%) were somnolence, sedation, dizziness, headache, and nausea; these were also the most commonly reported AEs in previously published clinical trials with CBZ-ERC as monotherapy for the acute treatment of bipolar disorder in an inpatient setting in which a more aggressive dose titration strategy was used.[4,5] All reports of severe TEAEs were in the subjects in the subgroup treated with concomitant antipsychotics; however, none of these were in the subjects who had received olanzapine or lithium. Ten subjects discontinued the study drug because of AEs; rash and sedation—commonly occurring AEs with CBZ—were the only events leading to study discontinuation in more than one subject. In general, changes in laboratory test results were small and not clinically significant, and there were no notable changes in the other safety assessments (e.g., physical examination, vital signs, and ECG), although one subject on concomitant valproate and quetiapine withdrew from the study because of weight gain. The mean reduction from baseline in the YMRS score was -6.7 points after one week and -12.9 points after eight weeks, indicating improvement in the severity of mania. HAM-D and MADRS total scores also showed mean reductions, indicating patient improvement in depressive symptoms as well, and all three components of the CGI-BP-S and CGI-BP-C improved during the study, indicating overall improvement in the symptoms of bipolar disorder.

Carbamazepine has been widely used for many years in psychiatric and neurologic settings, and its AE profile is well-defined.[16] An early study of CBZ in bipolar disorder reported AEs consistent with those observed when it was used for treatment of other conditions (>10% experienced dizziness, ataxia, clumsiness, drowsiness, slurred speech, diplopia).[38] Recent studies with the FDA-approved, extended-release formulation (CBZ-ERC) have supported its general tolerability in patients with bipolar disorder.[4,5]

The high rates of overweight and obesity that have been reported in patients with bipolar disorder are problematic[39,40] and are considered sufficiently bothersome by patients and physicians to interfere with medication adherence.[41,42] In addition, it has been shown that some FDA-approved agents for bipolar disorder—especially atypical antipsychotics—are associated with metabolic effects (e.g., weight gain, diabetes, hyperlipidemia),[43] which may contribute to an already high rate of metabolic syndrome among patients with bipolar disorder.[44] Among the atypical antipsychotics permitted in this study, weight gain was most common with olanzapine, followed by risperidone and quetiapine;[43,45] aripiprazole is associated with only negligible weight gain.[46] Among the mood stabilizers, weight gain is most often seen with valproic acid, followed by lithium; CBZ has not been associated with clinically significant weight gain.[4,5,45]

Although total cholesterol levels increased from baseline in subjects on concomitant atypical antipsychotic agents in this study, the implications of this trend with regard to development of metabolic syndrome is unknown, as other lipids were not measured and the use of concomitant agents confound the results. Metabolic syndrome is therefore not considered a significant issue with CBZ-ERC monotherapy,[47] and combination treatment with anticonvulsants and lithium has been reported to have the most favorable AE profile.[26]

This study was designed with a gradual four-week titration period, beginning with a low CBZ-ERC dose of 200mg/d, which represents half the starting dose used in the acute inpatient trials.[4,5] Beginning treatment with a modest dose, followed by gradual upward titration (200mg every 3 to 4 days, as tolerated), has been suggested by other investigators as one way to improve the tolerability of combination regimens used in the treatment of bipolar disorder.[26] As anticipated, CBZ-ERC tolerability showed a trend toward improvement compared with that in previous clinical trials with monotherapy, with the overall incidence of TEAEs (84.9%) lower compared with approximately 90 percent reported with a more rapid (7-day) titration period.[4,5,48] In addition, in a pooled analysis of two inpatient trials, AEs occurred most frequently during dose titration, with their incidence markedly decreasing over the three-week study duration, lending further support to the theory that the improvement in the incidence of AEs in this study can be explained by the longer, more gradual titration period.[48]

This study had several limitations. First, it is difficult to assess the clinical impact of safety data specific to CBZ-ERC in patients who are receiving concomitant therapy; however, because the data in this study demonstrated an AE profile that was, for the most part, similar to that of previous trials with CBZ-ERC monotherapy, it was concluded that CBZ-ERC is generally well tolerated in combination therapy. Although no overall safety trends were seen with concomitant therapies, the small numbers in the risperidone, olanzapine, and lithium subgroups make it difficult to assess the impact of concomitant therapy with these two agents. Another limitation in the interpretation of the safety results is that blood was collected in the nonfasting state, so clinical chemistry values must be viewed accordingly. Finally, interpretation of the efficacy results in this study is limited by the lack of a randomized, double-blind, placebo-controlled study design. These limitations signal the need for a more systematic evaluation of specific combination therapies compared with monotherapy in the management of bipolar disorder.[12]

CONCLUSIONS

The results of this study generally support the safety and efficacy of CBZ-ERC for patients with bipolar disorder who require combination therapy. CBZ-ERC was safe and generally well tolerated by patients with bipolar I disorder when it was administered concomitantly with other mood stabilizers and atypical antipsychotic medications. Its safety profile appears to be comparable to previous safety profiles for CBZ, with the most frequently reported TEAEs similar to those most often reported in previous studies of CBZ-ERC in patients with bipolar disorder, and these findings suggest a trend toward improved tolerability compared with studies that used faster titration rates.

Changes in laboratory test results were generally small, not clinically significant, and comparable to those that had been reported in previous CBZ-ERC trials. Improvements in the efficacy assessments—also consistent with those of other studies—indicated improvement in symptoms of bipolar disorder with CBZ-ERC administered BID. Further study of CBZ-ERC as a component of a combination regimen in a larger population of patients with bipolar disorder is needed to confirm these findings.

ACKNOWLEDGMENT

The author wishes to acknowledge Craig S. Ornstein, PhD of Advogent for his contributions to this manuscript.

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