12. Bipolar Disorders

8/12/2019 12. Bipolar Disorders

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Bipolar Disorders 6516. Opler LA, Klahr DM Ramirez PM : Pharmacologic treatment of delusions. Psychiatr Clin North Am17. Serreti A Lattuada E, Cusin C, Smeraldi E: Factor analysis of delusional disorder syrnptomatology. Comp r18. S toude mire A, Rieth er A: Evaluation and treatment of paranoid syndromes in the elderly. Gen Hosp19. Webb W Paranoid conditions seen in psychiatric medicine. Psychiatr Med 8 :37 -48 , 1990.

18:379-391, 1995.Psychiatry 40(2): 143-147, 1999.Psychiatry 9:267-274, 1987.

12. BIPOLAR DISORD ERSMarshall R. Thomas, M.D

1. What is bipolar disorder?How is it different from manic-depressive llness?Bipolar disorder encompasses a heterogeneous grou p of disorders characterized by cyclical dis-turbances in m ood, cognition, and behavior. The diagnosis requires a history of mania for at least 1week or hypomania for at least 4 days. Bipolar I disorder refers to patients w ho have had at leastone episod e of mania. Bipolar I1 disorder refers to patients with a history of hypo man ia and majordepressive episodes. Cyclothymia refers to patients with chronic (at least 2-year dur ation) moodswings that fluctuate between hypom ania and m inor but not m ajor depression.

M D Md M mD md D dM =Maaic EgisodeD =Major DepressiveEpisodc

=H y p d c pisoded =Minor Depnssivc Episodc

Modified from Goodwin F, Jamison K: Manic-Depressive Illness. New York, Oxford University Press 1990.

In 1921, the Germ an psychiatrist Emil Kraepelin introduced the term manic-depressive insanity,which included patients with recurrent unipolar depression as well as bipolar disorder and distin-guished both groups from schizophrenia, w hich he termed dem entia praecox. Kraepelin emphasized


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66 Bipolar Disordersthe similarities in course and outcome between patients with highly recurrent mood disorders, re-gardless of polarity. In 1962,Leonard introduced the term bipolar and emphasized differences be-tween unipolar and bipolar patients.Many researchers argue that modern adherence to Leonards bipolarhnipolar dichotomy, al-though clarifying certain issues, has caused clinicians to overlook the similarities between bipolarand many unipolar patients, who share a common pattern of recurrence, remission, and exacerba-tion. The modern concept of bipolar spectrum disorder encompasses patients with bipolar I and I1disorders, cyclothymia, hyperthymia chronic hypomania), and pseudounipolar depression.Pseudounipolar depressives are patients with a highly recurrent unipolar illness, a positive familyhistory for bipolar disorder, and a positive therapeutic response to antibipolar treatments.2. Describe the epidemiology of bipolar disorder.The lifetime risk for bipolar I disorder is 0.6-0.9% in industrialized nations, with no apparentgender differences; unipolar depression, however, is twice as common in women as it is in men.Differing criteria for what constitutes hypomania have made it difficult to determine the prevalence

of bipolar I and cyclothymic disorders. Bipolar I1 disorder is probably at least as common as bipolarI, and the lifetime prevalence of cyclothymia is estimated at 0.4-1.0%. Over the last 50 years, allmood disorders have increased in prevalence, with an earlier age of onset in each successive genera-tion-a phenomenon referred to as the cohort effect.Family studies find that if one parent has a major affective disorder the risk to the offspring is25-30 , whereas if both parents have an affective disorder the risk to the offspring may be as highas 5 6 7 5 . Suicide is common in untreated bipolar disorder; 25-50% of patients attempt suicide atleast once. Seasonal variations exist; depression is more common in the spring March through May)and autumn September through November), whereas mania is more common in the summer. Thepeak incidence of suicide occurs in May, with a second peak in October.3. How is mania recognized?Manic states range in severity from milder hypomania to psychotic or delirious manic states.The symptomatology evolves as the episode becomes more severe. The mood in mania may beelated or euphoric, but as severity increases the mood is more likely to become irritable, labile, anddysphoric. Thoughts may race; as mania progresses, thinking becomes disorganized, expansive, andgrandiose. Behavior increases from early physical hyperactivity, pressured speech, and decreasedneed for sleep to later manifestations of hypersexuality, increased impulsivity, and risk taking.

Manic E pisode: Diagnostic CriteriaDistinct period of elevated, expansive, or irritable mood:A t least 1 weekOr hospitalized

Inflated self esteem or grandiosityDecreased need for sleepPressured speechFlight of ideas or thoughts racing

Three of the following: four if mood only irritable:DistractibilityIncreased activityExcessive involvement in pleasurable activitieswith high risk of painful consequencesMarked impairment, psychosis, or hospitalizationNot due to direct effect of substance or medical conditionFrom American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.Washington,DC, American Psychiatric Association, 1994,with permission.

Hypomanic Episode: Diagnostic CriteriaDistinct period of elevated, expansive, or irritable mood at least 4 days)Three additional symptoms: four if mood only irritableUnequivocal change in functioningChange observable by others Table continued on ollowing page


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Bipolar Disorders 67Hypomanic Episode: Diagnostic Criteria Continued)

Episode not severe enough to cause:Marked impairmentHospitalizationPsychosisNot due to direct effects of a substance or general medical condition

~ ~~From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.Washington, DC, American Psychiatric Association, 1994,with permission.4. What is a mixed state?A m ixed state is diagnosed w hen the patient simultaneously m eets criteria for m ania and m ajordepression. M ixed states are common , occurring in approximately 40% of manic patients. Mixedstates are sometimes difficult to distinguish from or are m isdiagnosed as agitated depressions a ndborderline con ditions. Mixed states are mo re com mo n in patients with substance abuse and neuro-

logic disor ders (e.g., head injury) and are assoc iated with increased suicidality, chronicity, andpoorer response to lithium.5. What is the clinical significance of bipolar I1disorder?Bipolar I1 (BP 11 disorder is diagnosed in patients w ith e pisod es of hypomania interspersedwith episodes of major depression. Clinically, patients usually present during periods of depression.Often the diagnosis is not clear, because both hypomania and depression may be associated w ith ir-ritability, and the psychom otor symptom s of hypom ania may be subtle. B P I disorder is morecommon in women. BP I1 tends to run in families (breeds true), and patients wh o present as BP I1tend to stay in the sam e category; they have subsequent episodes of hypom ania but not mania.Bipolar I disorder should not be viewed as a minor form of BP I, because psychosocial morbid-ity, substance abuse, and suicide attempts are at least as common in BP 11 What constitutes the besttreatment co urse for patients with BP needs further study. Patients with BP I1 show a predominanceof depression, but antidepressant treatments may induce rapid cycling and mixed states, as they do inBP I disorder. Patients with BP I1 also may be biologically heterogeneous. For exam ple, severe envi-ronmental stressors such as prolonged abuse o r neglect may cause forms of m ood disregulation thatphenotypically resemble BP I1 (referred to as bipolar ZZphenocopy) n patients without family histo-ries of affective disorders.6. How are bipolar and unipolar depression differentiated?About 10-20% of hospital first admissions for depression later develop a bipolar disorder.

Careful scrutiny of the patients history for episodes of mania o r hypomania m ay help to m ake the di-agnosis in some cases. The clinical course of bipolar depression is characterized by premo rbid cy -clothymic temperament; recurrences; and early-age, rapid, and postpartum onsets. Symptomaticallybipolar depressives are more likely to demonstrate psychosis, hypersomnia, anergia (low energy), andsevere shut-down depressions that are immobilizing. Bipolar depressives also are more likely to havefamily histories of bipolar disorder and familial loading for affective disorders in general. In the ab-sence of a premorbid history of mania hypomania or cyclothymia no single associated finding ispathognomonic for bipolar disorder, but clusters of such factors make the diagnosis more likely.7. Describe the course of illness issues in bipolar disorder.

In the past there has been a tendency to underestimate the rate of recurrence and to overestimatethe age of onset of bipolar disorder. Many bipolar adolescents are misdiagnosed as conduct-disor-dered or schizophrenic, because they may demonstrate lab ile mood, abnorm al thinking, an d dis-turbed behavior several years before their first recognizable major affective episode. For bipolarpatients, the mean age of first impairment due to psychiatric sym ptom s is 18.7 years; the mean ageof first treatment is 22 years; and the mean age of first hospitalization is 25.8 years. The lag betweenage offirst impairment and age ofjirst treatment is causefor concern in light of data suggesting thatearly intervention and treatment may prevent the development of a more malignant course of illness.


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68 Bipolar DisordersTh e rate of cycling increases with each successive episode. The average free interval betweenthe first and second ep isode is 5 years, but by the fourth episode cycles are occurring at least yearly.Although duration of episodes demonstrates interindividual variability, the average untreated manicepisode lasts 4 months an d the average depressive episod e 6-9 months. M anic episodes often begin

abruptly over hours to days. Bipolar d epressions usually take weeks to develop, but they still have amore rapid onset than unipolar depression.Approximately 20% of bipolar patients dem onstrate rapid cycling. Rapid cycling is morecommon in women, patients with B P 11, and patients who have received antidepressant treatments.Rapid cyclers may have a poorer response to lithium and a higher rate of hypothyroidism.In clinical cohorts, another 20% of bipolar patients have a ch ronic course with no free intervalbetween episodes. A history of chronicity, substance abuse, and mixed states is associated withpoorer outcome.8. Describe the relationship between stress and onset of affective episodes in bipolar disorder.At times it is difficult to sort out w hether stress has led to an episod e, or the prodromal symp-toms of an episode have led to the stress. Investigations su ggest that stressors are statistically m orelikely to be associated w ith the onset of episod es early in the course of illness. This finding , alongwith the finding of inc reasing cycling, have suggested that the illness may kindle itself and becomeincreasingly endogenous over time. In kindling, a model borrowed from neurology, a subthresholdstimulus applied at a regular interval over time becomes capable of inducing seizure activity.Interpersonal and w ork difficulties are comm on precipitants associated w ith mood destabiliza-tion. Sleep reduction may b e a final common pathway that leads to m ania in a variety of situations,including stress-induced sleep disruption, parturition, and travel. There also is a high rate of bipolar-ity in patients whose m oods d emo nstrate seasonal variation.9. List medical conditions that may cause mimic or exacerbate bipolar disorder.Organic factors can cause or exacerbate both m ania and depression. Th e DSM-IV provides aseparate diagnostic category fo r organically derived mood disorders: m ood disorder du e to . [indi-cate the general medical condition]. Historically, the term secondary mania has been used to des-ignate manic states that arise from neurologic, endocrinolog ic, metabolic, infectious, or othermedical conditions. Many organic factors may contribute to depression or mania individually, butfew can engender a true bipolar synd rome with cycling between two states.

Organic Causes o Bipolar Mood SyndromesDrugs Isoniazid, steroids, disulframNeurologic factorsMetabolic factorsInfection AIDS dementia, neurosyphilis, influenza

Mu ltiple sclerosis, closed head injury, CNS tumors, epilepsy,Thyroid disorders, postoperative states, adrenal disorders, vitamin

Huntingtons disease, cerebrovascular accidentB 12 deficiency, electro lyte abnormalities

Modified from Goodwin F Jamison K: Manic-Depressive Illness. New York Oxford University Press 1990.Patients with an organic affective disorder are less likely to have a positive family history andmay respond to treatment of the underlying condition. Other organic affective syndromes, such as

those associated with brain trau ma and m ultiple scleros is, are not reversible but benefit from an-tibipolar treatments. Patients with a genetic predisposition to bipolarity may have a lower thresholdfor developing organ ic affective syndrome secondary to organic stressors.10. What psychiatric conditions are commonly comorbid with bipolar disorder?Bipolar disorder is the axis I disorder most l ikely to be associated with com orbid substanceabuse or dependence; 60% of bipolar patients dem onstrate abuse or dependence in on e form or an-other. A study by the National Institutes of M ental Health (N IMH ) found that 46% of bipolar patients


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Bipolar Disorders 69abused or were dependent on alcohol, and 41 abused or were dependent on marijuana, cocaine,opiates, barbiturates, or hallucinogens. All forms of substan ce abuse are more com mon in manic ormixed phases of the illness. Comorbid substance abuse is associated with significantly poorer o ut-com es and increased rates of suicide.

Anxiety symptoms axis I1 disorders and certain psychotic conditionsare found m ore com-monly in patients with bipolar disorder. During m ixed manic states and depressive episodes, bipolarpatients m ay experience extreme anxiety that may rem it with control of the affective disorder. Somebipolar patients may appear character-disordered (borderline or narcissistic), because their mooddisorder is inadequately treated, whereas others dem onstrate a comorbid axis I1 diagnosis in the ab-sence of mood disregulation. Up to 50 of bipolar patients have psychotic symptoms such as delu-sions or hallucinations a t some point in the course of their illness.The presence of psychotic symptoms only during periods of prominent mood disturbance dis-tinguishes psycho tic affective disorders fro m schizop hrenia and schizoaffective disorder, in whichpsychotic sym ptom s exist outside of periods of m ood disturbance.11. What are the advantages and disadvantages of using lithium in the treatment of bipolardisorder?Advantages: Lithium has been in clinical use for over 40 y ears. It appears to be highly effectivefor mild m anic sym ptom s and classic euphoric mania. Although lithium is less effective in treatingbipolar depression, approximately 50 of bipolar patien ts with mild-to-moderate d epression re-spond to treatment if given enoug h time. Lithium appears m ore effective in treating with m ania-de-pression-interval (M DI) as opposed to depression-mania-interval (DM I) sequences. On e distinctadvantage of lithium for some patients is the fact that its standard preparations are significantly lessexpensive than other antimanic drugs.Disadvantages: Despite lithiums remarkable efficacy in euphoric man ia, 30-50 of bipolar pa-tients either are unab le to tolerate or fail to respond to lithium . Even for patients who benefit the rateof response is slow: 10-14 days for mania and 4-8 weeks for depression. Gastrointestinal distress,cognitive dullness, polyuria, and tremor represent co mm on acute effects. Weight gain is a commoncause of discontinuation over the long term; 25 of patients gain 10 pounds or more. Approximately10%of patients develop hypothyroidism. E lderly patients w ith comprom ised renal function requirecareful dosage adjustment. Patients with mixed states, severe mania, psychosis, substance abuse, anda history of neuro logic insults are less likely to respond to lithium m onotherap y.12. What are the advantages and disadvantages of using anticonvulsants in the treatment ofbipolar disorder?

Althoug h lithium is considered by many clinicians to be the first-line dru g in the treatment ofmania and bipolar m ood cycling, many patients either are unable to tolerate or fail to respond tolithium. As a result, in the last 15-20 years, there has been increasing interest in the use of anticon-vulsants, particularly valproic acid and carbam azepine, to treat bipolar m ood disord ers. Controlledtrials have demonstrated the efficacy of both drugs in acute mania, and studies of valproic acid havesuggested a more rapid onset of antimanic action compared with lithium. Valproic acid, like lithium,is FDA-approved for the treatment of acute m ania. M ore recently, investigators and clinicians havelooked at the use of lamohigine, gabapentin, and topiramate for patients with bipolar disorder.The disadvantages of these agents are mainly related to side effects. Valproic acid usually iswell tolerated, although weight gain is an issue of concern fo r some patients. Rapid loading at 500mg 3 timeslday can be accomplished in hospital settings for many acutely agitated patients.Carbamazepine is more difficult to dose and requires a more gradual upward titration.Carbamazepine a lso autoinduces its own metabolism and heteroinduces the metabolism of otherdrugs. As a result, careful dru g level monitoring is required, and other drugs, such as antipsychoticsand birth control pills, may be rendered less effective unless dosage adjustments are made.Lamotrigine is associated with a potentially life threatening rash, especially in pediatric patients.Gabapentin is relatively well tolerated, but is of questionab le efficacy. com mo n side effect of topi-ramate is weight loss, which is an advantage for som e patients.


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7 Bipolar Disorders13. How does stage of illness affect treatment strategy in bipolar disorder?The treatment strategy in bipolar disorder de pen ds on the current stage of the illness, dimen-sional assessment of the illness, and know ledge of past treatment. T he treatment of acute mania (de-scribed in Chapter 49) includes the use of antimanic drugs and, depending on the severity of illness,adjunctive agents such as sedative-hypnotics, benzodiazepines, and an tipsychotic agents. The treat-ment for acute depression (discussed in more detail in the controversies section below) is compli-cated in bipolar patients by the need to minimize the use of antidepressant agents.Preventive treatment w ith antibipolar agents usually is indicated, because bipolar disorder almostalways is recurrent. Th e high rate of su icide attempts in all phases of illness dictates an ongo ing assess-men t of safety issues throughout the course of treatment. Recent studies suggest that many patientsmay do better long-term with antibipolar combination treatments (e.g., lithium plus va lproic acid) in-stead of m ore traditional antimanic monotherapy strategies (e.g., lithium or valproic acid used alone).

CONTROVERSIES14. What is the treatment for bipolar depression?Issue.All antidepressants appear capable of inducing mania, mixed states, and mood cycling,thus worsening the long-term course of the illness.Discussion.Patients with mild-to-m oderate bipolar depression m ay respond to antimanic agentssuch as lithium alone, although there is often a significant lag time of u p to 8 weeks before a full an-tidepressant response. Tricyclic antid epre ssants (TC As) shou ld be avoided, because they may b emore likely than other antidepressants to indu ce cycling and also appear to b e marginally effective inthe treatment of bipolar depression. Bupropion also can ind uce m ania, at least in som e patients.Recent data suggest that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertra-line, and paroxetine, may be less likely to induce m ania and hypo mania than TC As and m onoamineoxidase inhibitors (MAO Is). MAOIs appear to be particularly effective in patients w ith anergic de-pressions or atypical sym ptom s (mood reactivity, hypersomnia, hyp erphagia, leaden fatigue, and re-jection sensitivity), many of wh om may b e bipolar.Currently, most clinicians attempt to treat mild-to-mo derate bipolar depression without an anti-depressant. So m e clinicians prefer augm entation with a second antiman ic agent before adding an an-tidepressant. If an antidepressant is required, a short-acting SSR I (sertraline or paroxetine) orbupropion is the first choice. If these are ineffective, an M A 0 1 or electroconvulsive therapy may beused. Patients with rapid cycling dep ressions or mixed states of man ia and concurrent depression re-quire cessation of antidepressant agents and treatment with anticonvulsant com bination strategies.15. What is the role of antipsychotic agents in the treatment of bipolar disorder?Issue. Traditional antipsychotic agents (neuroleptics) frequently have been prescribed to pa-tients with bipolar disorder. Many patients begin these agen ts when hospitalized for acute m ania, butthen continue on antipsychotics post hospital discharge after the acute sy mptom s have resolved.Clinicians should avoid unnecessarily ex posing patients to these a gents since the older class of an-tipsychotics is asso ciated with risks of drug-induced extra pyramidal sym ptoms, neuroleptic-in-duced dysphoria, and potentially irreversible tardive dyskinesia.Discussion.60% of patients with bipolar disorder experience psychotic sym ptoms a t some timeduring the cou rse of their illness. The high h istorical use of antipsych otic agents in bipolar patientsmay relate to the fact that clinicians and patients have fo und that an tipsychotic agents are helpful inobtaining and maintaining a clinical response. The sid e effects of the older antipsycho tic agents, how-ever, mean t that this therapeutic advan tage was purchased at a potentially high co st to the patients.In recent years, a new generation of antipsychotics has been developed that is much less likelyto cause drug-induced parkinsonism and tardive dyskinesia. The newer atypical antipsychoticagents, which include clozapine, risperidone, o lanzapine, and quetiapine (with additional agents inthe pipeline) com bine HT 2 post synaptic antagonism with D, recep tor blockade. In addition tofewer neurologic side effects, these newer agents have positive effects on m ood, anxiety, impulsivity,and aggression.


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Depressive Disorders 71Clozapine, olanzapine, and, to a lesser extent, risperidone have all been studied in patients withbipolar mo od disord ers. Clozapine appears to have a powerful anti-manic and mood stabilizingeffect and is useful in treatment resistant bipolar d isorder. Olan zapin e and risperid one may h avestronger anti-depressant effects, but appear to indu ce mania in som e patients. Nevertheless, c on-

trolled trials of olanzapine have shown its efficacy in treatment of acute mania and have resulted inFDA approval for use in acute mania.BIBLIOGRAPHY

1 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.2. Baldessarini RJ, et al: Pharmacological treatment o f bipolar disorder throughout the life cycle. In Shulman3. Calabrese JR, et al: Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J4 Freeman MP, Stoll AL: M ood stabilizer combinations: A review of safety and efficacy. Am J P sychiatry5. Ghaemi S, et al: Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: Review of the6. Goodwin F, Jamison K: Manic-Depressive Illness. New York, Oxford University Press, 1990.7. McElroy S, et al: Clinical and research implications for the diagnosis of dysphoric and mixed mania or hy-8. Nathan P E, Gorrnan JM (eds): A Gu ide to Treatments that Work. New York, Oxford U niversity Press, 1998.9. Post RM, et al: A history of the use of anticonvulsants as mood stabilizers in the last two deca des of the 20th10. Schou M: Th e effect of prophylactic lithium treatment o n m ortality and suicidal behavior: A review for clin-11. Tohen M, et al: Olanzapine versus placebo in the treatment of acu te mania. Am J Psychiatry 156(5):702-709,

Washington, DC, American Psychiatric Association, 1994.KI, Tohen M (eds): Mood Disorders Across the Life S pan. New York, Wiley-Liss, 1 996 , pp 299-338.Psychiatry 156(7):1019-1 023,1999.155 I :2-21, 1998.empirical literature. Clin Psychopharm acol 19(4):354-361, 1999.

pomania. Am J Psychiatry 149:1633, 1992.

century. Neuropsychobiology 38(3): 152-166, 1998.icians. J Affective Disorders 50(2-3):253-259, 1998.1999.

13. DEPRESSIVE DISORDERSLawson R. Wukin, M . D

1. What are the seven secrets of depression?Depression is 1) common, 2 )often m issed, 3 ) not hard t o diagn ose if you look for it, 4) ftensevere, 5 ) often recurrent, (6) costly, and 7) highly treatable. These facts are secrets in the sensethat they are not w ell understood by the American public or by many physicians.Depression is am ong the five most comm on disorders seen in a primary care physicians office.Unrecognized an d untreated depression has been acknow ledged as a major public health problem inthe United S tates for the past 20 years. As many as half of the cases of depressive disorders go un-recognized by the patient or the doctor, and am ong those recognized mo st will remain untreated. Thereasons for such neglect include stigma, misunderstandings about the seriousness and treatability ofdepression, and preferential attention by patient and doctor to somatic complaints.The disability caused by depressive disorders rivals that of coronary artery disease an d is greaterthan the disability resulting from chronic lung disease or arthritis, according to the MedicalOutcomes Study.I5 The cost of depressive disorders in terms of treatment, work missed, and loss offunction approximates 43 billion annually in the U.S. Depression is associated with 80% of sui-cid es. Yet it is highly treatable, wit h 80 of p atients responding to antidepressant therapy, psy-chotherapy, or both, when treated by qualified professionals. The cost of diagnosis and treatment issmall, relative to other com mo n severe medical disorders, whereas the cost of not treating a depres-sive disorder is great.

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12. Bipolar Disorders