Amy T. Peters, BA, is Clinical Research Coordinator, Bipolar Clinic and Research Program, Massachusetts General Hospital; Andrew A. Nierenberg, MD, is Director, Bipolar Clinic and Research Program, Massachusetts General Hospital, and Professor of Psychiatry with Harvard Medical School; Thilo Deckersbach, PhD, is Director of Psychology, Bipolar Clinic and Research Program, Massachusetts General Hospital, and Assistant Professor of Psychology with Harvard Medical School.
Drs. Peters, Nierenberg, and Deckersbach have disclosed no relevant financial relationships.
This case follows a 32-year-old, married Hispanic male with a history of bipolar type I disorder and comorbid panic disorder with agoraphobia. Diagnosed with bipolar disorder at age 19 when he first had a manic episode, the patient exhibits a classic seasonal pattern, suffering from recurrent depressive episodes in the winter and periods of increased mood elevation in the spring. He had previously been a high-performing student. Now, due to comorbid panic disorder with agoraphobia, as well as social phobia, the patient resists going out in public for fear of having a panic attack and has difficulty tolerating uncertainty in social situations, including job interviews. These problems interfere with his educational and vocational performance.
Notably, the patient’s symptoms of anxiety have consistently acted as a trigger for episodes of mood elevation. When anxious, rumination and worry disrupt his sleep pattern so much that his inability to fall asleep develops into a decreased need for sleep. Decreased need for sleep is then associated with an increase in reward sensitivity, pleasurable activities and distractibility. Additionally, even at his best, the patient suffers from cognitive difficulties that impair his attention, focus, and ability to read and write.
His medical history is otherwise notable for chronic migraines, which have been treated for 5 years with topiramate (100 mg/d) which may, in part, be responsible for the problems in attention, focus, and memory. His cognitive impairments ultimately caused him to drop out of medical school, and currently interfere with his desired level of vocational functioning. He has been treated consistently by a psychiatrist and participated in cognitive behavioral therapy (CBT) for several years. The patient has benefited partially from the psychoeducation component of CBT, but has made only moderate efforts to change behavior.
The patient’s mood episodes have best been treated with olanzapine (10 mg/d) and lamotrigine 300 mg/d, and lithium 1,200 mg/d which, although successful in mood stabilization, caused intolerable weight gain. Additionally, the patient attributed his cognitive difficulties to treatment with olanzapine, and therefore, he stopped taking the medication. Previous neuroleptic trials included quetiapine, which made him too sedated and ziprasidone, which had no therapeutic or side effects at 80 mg twice daily.
After tapering off of olanzapine, the patient increased current treatment with lamotrigine from 300 mg/d to 400 mg/d and started aripiprazole at 20 mg/d. After this medication change, the patient began to experience symptoms of depressed mood and notice heel and leg pain. He also came to notice twitching, a decrease in balance and hand-eye coordination. Within a few weeks, he started to get a sense of buzzing and tingling, and then finally a tremor, most significantly in his hands, but also in his feet. After a month, his feet started throbbing and his thighs began to feel weak. The tingling and burning stopped, but severe musculoskeletal pain persisted. By the end of the following month, he could barely walk. The patient obtained a neurology consultation, wondering if his psychiatric medications were responsible for the pain. The neurologist referred the patient to an orthopedist for a suspected stress fracture, but the MRI came back negative. He used crutches for a few weeks, which helped the pain significantly, but when he resumed walking, the pain returned to its previous level.
After about 4 months, the patient decided to reduce the lamotrigine back to 300 mg/d. He reported that this helped the myoclonus and imbalance; however, the burning in his feet became worse. He had a single episode of tongue and chin numbness for 1 hour. He did not notice laterality, however, he eventually started feeling that the right side of his face was numb. He additionally experienced an increase in frequency of migraines. Migraines typically caused his eyes to hurt, although he came to experience eye pain more often and independent of the headaches.
One month later, he discontinued aripiprazole. He felt this reduced the leg tightness and weakness significantly. His heel pain also became much less prominent. Repeated attempts to restart aripiprazole continued to cause heel pain and he has not taken an adequate dose in several months. He maintains therapy with lamotrigine at 300 mg/d, lithium at 1,200 mg/d (blood level 0.7 meq/L), and topiramate at 100 mg/d, and takes minimal doses of aripiprazole for brief intervals (10 mg as needed) when his mood is particularly unstable.
Neuroleptic-Induced Akathisia in a Bipolar I Patient with Comorbid Anxiety, Cognitive Deficits
This case of bipolar I disorder is complicated by four unique and particularly challenging components: 1) comorbid panic agoraphobia and its tendency to induce and exacerbate symptoms of mania; 2) the burden of medical comorbidity and its capacity to complicate bipolar illness; 3) impairing cognitive difficulties that may be partially caused by chronic migraine treatment with topiramate; and 4) intolerability to the adverse effects of anti-psychotic medications.
Anxiety and Bipolar Disorder
Clinical and epidemiological studies have documented high rates of anxiety disorders among patients with bipolar disorder. Retrospective, cross-sectional, and prospective studies suggest greater bipolar illness severity among patients with anxiety disorders;1,2 poorer response to treatment;3 worse course of illness; longer time to recovery; lower quality of life; and sooner time to relapse after a period of recovery.4 Prospective studies also indicate a detrimental role for panic-related anxiety symptoms on the outcome of bipolar disorder.5,6 Of all anxiety disorders, panic disorder has been most closely identified with affective illness.7–9 On a treatment level, the behavioral care needs to help prepare not only for the typical warning signs of mania but also for the effects of anxiety on mood elevation. Given the portion of bipolar patients suffering from comorbid anxiety disorders in the bipolar population, treatment should focus on anxiety disorders and their link to both depression and mania.
Comorbidities of Bipolar Disorder
Medical comorbidity in psychiatric conditions is burdensome and frequently complicates the course of illness. People with serious mental illness die, on average, 25 years earlier than the general population, attributed largely to smoking, obesity, substance abuse, and inadequate access to medical care.10 Bipolar disorder, in particular, is associated with high rates of mortality from medical causes. The most common (and burdensome) medical illness in bipolar disorder is cardiovascular disease — most likely due to a combination of metabolic abnormalities associated with the pathophysiology of the disorder, side effects from medications, poor diet and lack of exercise.11–14 Research investigating the burden of cardiovascular disease has shown that bipolar patients with metabolic syndrome and/or obesity have more manic and depressive episodes; greater symptom severity; more psychiatric hospitalizations; are less likely to get well from a mood episode, are more likely to relapse (especially to depression), are more likely to have made a suicide attempt; and experience greater functional impairment.15–17
This patient suffers from chronic comorbid migraines. Annual estimates of migraine prevalence in the general population range from 3.3% to 21.9% for women and from 0.7% to 16.1% for men,18 but the rates are about twofold higher in patients with bipolar disorder, with higher rates among those with bipolar II and comorbid anxiety disorders.19–21 While cardiovascular disease may be the greatest medical risk factor in bipolar disorder, this case illustrates the complicating effect of recurrent migraines, highlighting the importance of managing medical risk factors and integrating medical and psychiatric care.
There is considerable evidence that patients with bipolar disorder exhibit cognitive difficulties during episodes of mania and depression,22–24 and that cognitive impairments persist in periods of euthymia.25,26 Cognitive impairments have been associated with poor functional outcomes.27 The current patient is treated with topiramate for recurrent migraines, which, while established as clinically effective in the treatment of migraine headache, places patients at a higher risk of experiencing cognitive difficulties. In a 6-month controlled study of topiramate for migraine prophylaxis, the proportion of patients who experienced one or more cognitive-related adverse events was 17% for topiramate 50 mg/day; 27% for 100 mg/day; 21% for 200 mg/day; and 12% for placebo.28 This case underscores the burden of cognitive difficulties on bipolar illness, as well as the possibility of exacerbation of such difficulties with standard pharmacological therapy. The benefit–risk ratio should be considered when offering these types of medications to bipolar patients.
Akathisia is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is generally well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics.29 The matter of bipolar disorder as a risk factor for antipsychotic-induced movement disorders is still inconclusive; however, a review of studies on antipsychotic-induced extrapyramidal side effects in bipolar and schizophrenia suggests that bipolar patients, especially for those having an acute depressive episode, are more vulnerable to acute anti-psychotic-induced movement disorders than those with schizophrenia.30
Additionally, a recent study looked at the subjective experience of akathisia and found that akathisia was significantly correlated with subjective cognitive dysfunction.31 The possibility of akathisia is of particular concern now that second-generation antipsychotics are a mainstay of treatment for bipolar depression. So far, the established treatments for neuroleptic-induced akathisia include beta-adrenergic blockers, anticholinergic, and antiadrenergic drugs, (though these were not utilized in this particular case), in addition to reducing the dose of the antipsychotic if possible.28,32 A recent review on the evidence of anticholinergics in neuroleptic-induced akathisia, however, concluded that there was insufficient data based on good quality research to support the use of anticholinergics.33 It is still possible that some could respond to anticholinergic drugs to treat akathisia, as several preliminary trials have demonstrated positive outcomes.34,35 Low-dose mirtazapine is another possible but underutilized treatment for akathisia.36
This case encapsulates the complexity of bipolar disorder and its treatment as well as that of comorbid anxiety, comorbid medical conditions, cognitive impairment, and akathisia. Each of these complications can exacerbate not only the primary mood disorder but also exacerbate each of the other complications. It is a challenge to find treatments that can help bipolar patients achieve long-term stability for their dynamic constellation of multiple problems.
In this case, the patient currently reports he is well, although he continues to experience brief periods of mood elevation. In the wake of his physical pain, he has recently become more compliant with behavioral interventions, although he still suffers from robust cognitive difficulties in attention and memory.
- McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420–426. doi:10.1176/appi.ajp.158.3.420 [CrossRef]
- Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161(12):2222–2229. doi:10.1176/appi.ajp.161.12.2222 [CrossRef]
- Henry C, Van den Bulke D, Bellivier F, Etain B, Rouillon F, Leboyer M. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003;64(3):331–335. doi:10.4088/JCP.v64n0316 [CrossRef]
- Otto MW, Simon NM, Wisniewski SR, et al. STEP-BD Investigators. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br J Psychiatry. 2006;189:20–25. doi:10.1192/bjp.bp.104.007773 [CrossRef]
- Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157(6):956–962. doi:10.1176/appi.ajp.157.6.956 [CrossRef]
- Frank E, Cyranowski JM, Rucci P, et al. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry. 2002;59(10):905–911. doi:10.1001/archpsyc.59.10.905 [CrossRef]
- Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. Am J Psychiatry. 1995;152(2):280–282.
- Kessler RC, Rubinow DR, Holmes C, Abelson JM, Zhao S. The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med. 1997;27(5):1079–1089. doi:10.1017/S0033291797005333 [CrossRef]
- Fogarty F, Russell JM, Newman SC, Bland RC. Epidemiology of psychiatric disorders in Edmonton. Mania. Acta Psychiatr Scand Suppl. 1994;376:16–23. doi:10.1111/j.1600-0447.1994.tb05787.x [CrossRef]
- Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42. Epub 2006 Mar 15.
- Soczynska JK, Kennedy SH, Woldeyohannes HO, Liauw SS, Alsuwaidan M, Yim CY, McIntyre RS. Mood disorders and obesity: understanding inflammation as a pathophysiological nexus. Neuromolecular Med. 2011; 13(2):93–116. doi:10.1007/s12017-010-8140-8 [CrossRef]
- Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care. 2007;13(7):S170–7.
- Sylvia LG, Kopeski LM, Mulrooney C, Reid J, Jacob K, Neuhaus EC. Does exercise impact mood? Exercise patterns of patients in a psychiatric partial hospital program. J Psychiatr Pract. 2009;15(1):70–8. doi:10.1097/01.pra.0000344923.81898.53 [CrossRef]
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- Kemp DE, Gao K, Chan PK, Ganocy SJ, Findling RL, Calabrese JR. Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome. Bipolar Disord. 2010;12(4):404–13. doi:10.1111/j.1399-5618.2010.00823.x [CrossRef]
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- McIntyre RS, Konarski JZ, Wilkins K, Bouffard B, Soczynska JK, Kennedy SH. The prevalence and impact of migraine headache in bipolar disorder: results from the Canadian Community Health Survey. Headache. 2006;46(6):973–982. doi:10.1111/j.1526-4610.2006.00469.x [CrossRef]
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