Olivia Lee and Lawrence Robbins, MD
Introduction to Bipolar Disorder
The broadening concept of the bipolar spectrum has evolved over the years. We no longer view bipolar primarily as characterized by mania. Bipolar disorder is a chronic psychiatric illness that is broadly categorized in the DSM-V into several subtypes – bipolar I and bipolar II – depending on the presence of depressive, manic, or hypomanic features. It may occur in at least 4.4% of the population, but this number is likely to underestimate the true prevalence.1 There are major issues in identifying the milder bipolar presentations.2 Bipolar disorder often co-occurs with other psychiatric illnesses, creating innumerable patient presentations that may not fit neatly into the boxes of the two subtypes. The word “bipolar” is misleading and creates a stigma of severe mental illness. There certainly is underdiagnosis for the milder forms. Most patients do not suffer from classic manic symptoms. The milder “hypomanias” are subtle and mild in comparison to true mania. For most patients there is a significant lag time from the onset of milder bipolar symptoms and diagnosis.
The classic mania that defines bipolar I is easily recognized. Symptoms of mania include euphoric mood, grandiosity, distractibility, flight of ideas, thoughtlessness or risk-taking, and excessive involvement in pleasurable activities (i.e., sex, gambling, spending). Patients in the midst of a manic episode may also take on an excessive number of activities and exhibit pressured speech, excessive speech, irritability, and insomnia.3 These behaviors cause serious impairment to daily functioning and often last for several days or longer. Acutely manic patients are also high risk for harm to themselves or others.4
Milder hypomania is less likely to impair everyday functioning. However, it is also hypomania that is more commonly missed for a variety of reasons.4 Hypomania and the milder end of the bipolar spectrum have various presentations, complicating the diagnosis. These patients may have persistently agitated personalities, with frequent depression or excessive energy but not meeting the classic diagnostic criteria for bipolar I or bipolar II. Brooding, irritable pessimism may be a manifestation of the milder end. They often have a family history of bipolar disorder or depression. Many do not identify or remember a clear hypomanic episode. Diagnosing and treating these patients greatly improves quality of life and reduces mortality risk from suicide. The clinical stakes for missing bipolarity are enormous.
Speaking with a “significant other” is vital for teasing out mild hypomanic symptoms.4 Most patient simply complain of depression. Signs of mild bipolar disorder may include a history of early onset depression(prior to age 18), severe bouts of depression, rapid onset depression for no apparent reason, poor response to trials of antidepressants (including complaints of being up all night, mind racing, etc.), agitation, anger, high anxiety, hypersomnia or (less likely) insomnia, and irritability. Family history of severe depression, hospitalization, and other bipolar traits is helpful. The “bipolar reaction” to antidepressants may give insight into underlying bipolar disorder.4 Family history of a bipolar reaction to antidepressants may also be a clue. An opposite reaction to other drugs may be present, such as being anxious or wired from benzodiazepines or sleeping pills. Depression is often the primary problem in bipolar II disorder; it is much more pervasive than are the highs of hypomania. Comorbid moderate or severe anxiety may further compound impairment seen in bipolar depression and increase suicidal tendencies by up to 35%.5 Suicide and substance abuse are commonly found among those with untreated bipolar.
Comorbidity of Chronic Pain and Bipolar Disorder
Bipolar disorder patients who also suffer from chronic pain are challenging. Almost 24% of bipolar patients may present with chronic pain.6 The comorbid pain decreases quality of life. Patients with bipolar disorder and chronic pain often respond poorly to treatment and have an increased risk of suicide.6 One study that assessed the relationship between pain and bipolar disorder recommended a pain assessment as part of the routine care for patients suffering from bipolar.6 It requires a multidisciplinary approach to adequately treat these patients. Other than the pain physician/provider, psychotherapists constitute a vital part of the team.
Comorbidity of Migraines and Bipolar Disorder
The comorbidity of migraine with mood disorders has been well documented. There have been a number of clinic based studies as well as epidemiologic samples from community populations.7 Migraine and depression share some of the same pathophysiology. Antidepressants or mood stabilizers may alleviate both conditions. In the majority of migraine patients who suffer from depression, anxiety is a complicating factor. The anxiety disorder often precedes the age of onset of migraine, with depression following afterward. Migraine or other pain may exacerbate depression, and depression fuels migraine and pain. This is in addition to the shared environmental and genetic factors linking migraine and depression.
Emerging data is identifying the relationship between bipolar disorder and migraine. From 25 to 35% of bipolar patients suffer from migraine as well.6 This association may be due to shared pathophysiologic mechanisms.
Treatment Approaches for Bipolar Disorder
It may take some time to find the effective medication, or medications, for a given patient. Mood stabilizers often are the mainstay of treatment, and sometimes help the headaches. The anticonvulsants, lithium, and the atypicals constitute the 3 classes of mood stabilizers. Lamotrigine is the most commonly used antiepileptic for bipolar, but does not help headaches. Lamotrigine may be beneficial for some with neuropathic pain. Divalproex sodium is effective for mania, hypomania, depression associated with bipolar disorder, and for migraine prevention. Divalproex has been well studied for these conditions and is one of the most commonly used migraine preventives. Carbamazepine and oxcarbazepine are antiepileptics that have utility as mood stabilizers, but not for migraine prophylaxis. They may alleviate neuropathic pain. Oxcarbazepine is somewhat safer than the original carbamazepine. Gabapentin has been effective in high doses for some patients with milder bipolar symptoms. Gabapentin is effective for certain pain syndromes, but not for migraine.
Lithium carbonate is an underutilized mood stabilizer. Low doses of lithium do not usually cause hypothyroidism or irritate the kidneys. With appropriate monitoring these risks can usually be avoided. Lithium sometimes alleviates cluster headaches. Lithium has also been evaluated for conditions such as multiple sclerosis and Alzheimer’s.8
Divalproex sodium, carbamazepine, and oxcarbazepine may produce teratogenic effects. Divalproex is more likely than the others to result in birth defects, particularly at doses above 500mg daily. Lamotrigine may be the best choice of an antiepileptic during pregnancy. Lithium taken during pregnancy is fetal cardiac anomalies, but this is rare. Lithium may be indicated for bipolar during pregnancy disorder under appropriate circumstances.8–10 For women who were stable on lithium prior to pregnancy, discontinuation during pregnancy may lead to relapse.10
Atypical antipsychotics are also a mainstay for bipolar symptoms.11 These agents include the general categories of “pines”, “dones”, “pips” and “rips”. These include clozapine(the first atypical), olanzapine, quetiapine, risperdone, lurasidone, brexpiprazole, aripiprazole, and cariprazine.These are efficacious in treating mania and are prescribed as monotherapy or in combination with another mood stabilizer.12 The atypical side effects are many and varied. These include metabolic syndrome (insulin resistance, dyslipidemia, hypertension), weight gain, fatigue, “brain fog”, and extrapyramidal symptoms (akathisia, acute dystonia, dyskinesia/parkinsonism, and tardive dyskinesia).13 Patients on atypical antipsychotics should receive routine bloodwork. Signs of EPS may go unnoticed by some patients, rendering it important to ask specific questions. There certainly are concerns about the atypical antipsychotics during pregnancy, but in low doses these have resulted in minimal problems in the newborns.
As previously mentioned, lamotrigine is a very commonly prescribed mood stabilizer for bipolar disorder. It is one of the only effective medications for bipolar depression.14 Initiating a patient on lamotrigine requires a slow titration due to the rare (1:3,000: according to the German rash registry) but lethal side effects of Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).15 SJS/TEN are variants of the same hypersensitivity reaction, differentiated by the percent of skin surface area that is affected (<10% in SJS, >30% in TEN). This rare rash is characterized by painful blisters, peeling skin, and tissue necrosis. The SJS rash often occurs in unusual areas, such as the palms of the hands, soles of the feet, or mucous membranes. A “regular” drug rash may occur in up to 10% of patients. Signs of SJS/TEN typically occur within 8 weeks of initiation and warrant immediate discontinuation of lamotrigine.15 Many of the anticonvulsants carry the risk of SJS/TEN, such as divalproex, carbamazepine, and oxcarbazepine.
Patients with bipolar spend the vast majority of their time in depression rather than in mania. Many of these patients require combination therapy to target depressive symptoms. Lamotrigine and quetiapine are two of the atypicals that may be effective in managing depressive episodes.16 While lithium is a first line therapy for mania, it has also shown efficacy in preventing relapse of depressive episodes and decreasing suicidality.16 Combination therapy of olanzapine and fluoxetine has been approved by the FDA for treating depression associated with bipolar I disorder.16 Lurasidone is an atypical that has shown promise for the depression.4,17 Antidepressants usually result in either no effect, or the typical “bipolar” response (up all night, wired, mind racing). Occasionally they are helpful. Emerging therapies include, among others, ketamine, TMS, and microdosing (primarily psilocybin).16
It is crucial to recognize psychiatric disorders in our pain patients. Patients with unrecognized personality disorders or bipolar disorder often suffer from poor outcomes. Patients with the milder end of the bipolar spectrum frequently are diagnosed and treated as if they suffer from “regular” depression. They generally do not do well on antidepressants. Patients with psychiatric comorbidities, such as bipolar, require a multidisciplinary approach. The medications that treat psychiatric conditions may also be helpful for the pain conditions as well.
ABOUT THE AUTHORS
Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an associate professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 390 articles/abstracts and written 5 books (on headache). Address correspondence to Lawrence Robbins at email@example.com.
- Harvard Medical School. National Comorbidity Survey (NSC).; 2007.
- Kessler RC, Wai TC, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C: American Psychiatric Press; 2013.
- Culpepper L. The diagnosis and treatment of bipolar disorder: Decision-making in primary care. Prim Care Companion J Clin Psychiatry. 2014;16(3). doi:10.4088/PCC.13r01609
- Amuk OC, Patel RS. Comorbid Anxiety Increases Suicidal Risk in Bipolar Depression: Analysis of 9720 Adolescent Inpatients. Behav Sci (Basel). 2020;10(7). doi:10.3390/BS10070108
- Stubbs B, Eggermont L, Mitchell AJ, et al. The prevalence of pain in bipolar disorder: A systematic review and large-scale meta-analysis. Acta Psychiatr Scand. 2015;131(2):75-88. doi:10.1111/acps.12325
- KR M, DE S. Comorbidity of migraine and psychiatric disorders. Neurol Clin. 1997;15(1):115-123. doi:10.1016/S0733-8619(05)70298-X
- L L, B C, A N, et al. Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis. Clin Neuropharmacol. 2020;43(5):158-161. doi:10.1097/WNF.0000000000000407
- Jones SC, Jones I. Pharmacological Management of Bipolar Disorder in Pregnancy. CNS Drugs. 2017;31(9):737-745. doi:10.1007/s40263-017-0452-x
- Yacobi S, Ornoy A. Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci. 2008;45(2):95-106.
- JR C, PE K, W M, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360. doi:10.1176/APPI.AJP.162.7.1351
- Canadian Agency for Drugs and Technologies in Health. Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features: A Review of Clinical and Cost-Effectiveness and Guidelines.; 2016. https://pubmed.ncbi.nlm.nih.gov/27831672/. Accessed August 15, 2021.
- Stroup TS, Gray N. Management of Common Adverse Effects of Antipsychotic Medications. doi:10.1002/wps.20567
- Ng F, Hallam K, Lucas N, Berk M. The Role of Lamotrigine in the Management of Bipolar Disorder. Vol 3.; 2007.
- Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Saf. 1998;18(4):281-296. doi:10.2165/00002018-199818040-00004
- Yalin N, Young AH. Pharmacological treatment of bipolar depression: What are the current and emerging options? Neuropsychiatr Dis Treat. 2020;16:1459-1472. doi:10.2147/NDT.S245166
- Ostacher M, Ng-Mak D, Patel P, Ntais D, Schlueter M, Loebel A. Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis. World J Biol Psychiatry. 2018;19(8):586-601. doi:10.1080/15622975.2017.1285050