Chapter 8


Bipolar disorders
Introduction Historical perspective Mania/manic episode Hypomania/hypomanic episode ‘Bipolar spectrum disorder’ Bipolar (affective) disorder (1)—classification Bipolar (affective) disorder (2) Bipolar affective disorder (3)—management principles Other issues affecting management decisions Hospital admission Treatment of acute manic episodes Treatment of depressive episodes Prophylaxis Psychotherapeutic interventions Cyclothymia Lithium Valproate/valproic acid Carbamazepine Oxcarbazepine Lamotrigine Atypical Antipsychotics



Bipolar affective disorder (once commonly known as manic depression or manic depressive illness) is one of the most common, severe, and persistent psychiatric illnesses. In the public mind, it is associated with notions of ‘creative madness’, and indeed it has affected many creative people—both past and present (see opposite). Appealing as such notions are, most people who battle with the effects of the disorder would rather live a ‘normal’ life, free from the unpredictability of mood swings. Dr. Jeckyll and Mr. Hyde-like in its presentation, the symptoms vary considerably from one person to the next, but are relatively consistent from one manic or depressive episode to the next within the same patient. The variety of presentations makes bipolar disorder one of the most difficult conditions to diagnose. More than in any other psychiatric disorder, the clinician needs to pay attention to the patient’s life history, including functional status during periods of well-being. Moreover, because of a patient’s tendency to confuse more functional, high-energy periods of hypomania with one’s best self, clinicians need to obtain third-party information from family and friends whenever possible. In the classical “couplet” presentation, relatively longer periods of depression alternate with shorter-lived periods of mania. The symptoms of mania characteristically include excessively elevated and/or irritable mood, a decreased need for sleep, pressured speech, increased libido, reckless behavior without regard for consequences, and grandiosity (see Mania/manic episode p. XXX). More severe manic episodes are typically characterized by thought disturbances and psychotic symptoms. On the basis of a single episode, it may be difficult to distinguish a manic episode with psychotic symptoms from schizoaffective disorder (see p. 228). The vast majority of people who experience mania also suffer from recurrent episodes of depression. Between these ‘highs and lows’, patients usually experience periods of full remission, which at times may extend for years or even decades. The diagnosis of Bipolar I disorder is used when an individual has experienced at least one clear-cut manic episode. The classic presentation of Bipolar I disorder appears, however, to be but one pole of a broader spectrum of mood disorders (see Bipolar affective disorder (1)—classification p. xxx). Some individuals experience only milder –hypomanic - episodes (see Hypomania/hypomanic episode p. xxx). The diagnosis


Bipolar illness 45

Bipolar II disorder is used when there is a history of hypomania and major depressive episodes; the diagnosis of cyclothymia (see Cyclothymia p. xxx) is used when there are oscillations between hypomania and briefer, subclinical depressive episodes. Full assessment should take account of issues including the number of previous episodes, the average length of episodes, the average time between episodes, the level of psychosocial and vocational functioning between episodes, previous responses to treatment (especially treatment of early depressive episodes), family history of psychiatric problems, and current (and past) use of alcohol and drugs. Although at the present time there is no cure for bipolar disorder, for most cases effective treatment is possible and can substantially decrease the associated morbidity and mortality, both from suicide and other causes such as heart disease. Over time, a significant minority of people with bipolar disorder develop severe and persistent functional impairments and warrant specific rehabilitative services. In general, however, the specific aims of treatment are to treat acute episodes as vigorously as needed to achieve remission and then to institute a preventive therapy plan to decrease the frequency, severity, and psychosocial consequences of mood episodes and to improve psychosocial functioning between such episodes.

writer. musician Robert Downey. actor. Napoleon Bonaparte. 1944–1996. actor Robert Lowell. writer Graham Greene. Isaac Newton. philosopher. movie director Francis Ford Coppola. musician Stephen Fry. director Patricia Cornwell. poet Burgess Meredith. Marilyn Monroe. 1882–1941. 1913–1967. movie producer David Strickland. athlete (martial arts). 1876–1943. politician Axl Rose. writer Frances Lear. 1917–1977.. musician Ben Stiller. 1904–1991. musician. magazine publisher Connie Francis. F Scott Fitzgerald. Edgar Allen Poe. actor. Samuel Johnson. 1919–2002. Winston Churchill. TS Eliot. composer. 1905–1981. composer Jean-Claude Van Damme. 1963–1996. comedian Gordon Sumner (Sting). 1970–1999. writer Ilie Nastase. author. writer Virginia Woolf. astronaut Tim Burton. writer Ray Davies. Wolfgang Amadeus Mozart. actor. writer. writer Clifford Beers. director Spike Milligan. actor Tom Waits. actor Carrie Fisher. Plato (according to Aristotle). actor Kay Redfield Jamison. writer Other famous people who are thought to have had bipolar disorder William Blake. Victor Hugo. writer Don Simpson. editor. athlete (tennis). psychologist. arranger Famous people (deceased) who had a confirmed diagnosis of bipolar disorder Louis Althusser. St Theresa. Agatha Christie. composer Brian Wilson. women’s rights activist Vivien Leigh. humanitarian Neal Cassady. musician Linda Hamilton. comedian Stuart Goddard (Adam Ant). movie director Mary Jane Ward. actor Joseph Vasquez. artist. 1908–1963. Cary Grant. actor Larry Flynt. Jr. 1923–1996. St John. Abraham Lincoln. 1918–1990. actor.46 ATYPICAL ANTIPSYCHOTICS Famous people who have publicly stated they have bipolar disorder Buzz Aldrin. musician. 1926–1968. Rod . writer. writer Theodore Roethke. musician. comic actor. Robert E Lee. St Francis. 1908–1997.

Hippocrates described such people as ‘amic’ and ‘melancholic.’ Proposed connections between melancholia and mania are described in the writings of Aretaius of Cappadocia (c. Walt Whitman. hopes were high that understanding of the pathophysiology of mental illness might be within reach.’ with melancholia caused by excess of ‘black bile’ and mania by excess of ‘yellow bile’. Robert Louis Stevenson. It was his view that the mood disorders ‘represented manifestations of a single morbid process. Tennessee Williams. it was not until the middle of the 19th Century before this connection was more widely accepted. and in the same year an effective treatment was developed by Paul Ehrlich using arsenic compounds. they at least agreed that the illness was characterized by alternating periods of melancholia and mania. Alfred. Theories of psychopathology at that time were based in the ‘humors. Despite the view of some clinicians in the 18th Century that melancholia and mania were interconnected (e. one of the most common causes of severe (often mania-like) psychiatric symptoms (‘general paralysis of the insane’).CHAPTER 8 Bipolar illness 47 Steiger. Vincent van Gogh. Historical perspective The condition now referred to as bipolar affective disorder has been described since ancient times. often separated by periods of normal mood. who claimed that he had been teaching students at the Salpetrière about la folie circulaire for 10 years. Lord Tennyson. closely followed two weeks later by a paper in the same journal by Jean-Pierre Falret (1794– 1870). Robert James. Although the two men were to continue arguing about who originated the idea. Emil Kraepelin comprehensively described ‘manic-depressive insanity’ in the 6th edition of his textbook Psychiatrie: Ein Lehrbuch für Studirende und Ärzte. In 1854 Jules Baillarger (1809–1890) published a paper in the Bulletin of the Imperial Academy of Medicine describing la folie à double forme.150 BC) and Paul of Aegina (625–690). 1705–1776).e. the mood disorders). the German microbiologist August Wassermann discovered a method of detecting syphilitic infection in the CNS. Syphilis was. In 1906. In 1899. In the 5th edition he had already divided severe mental illnesses into those with a ‘deteriorating’ course (i. schizophrenia and related psychoses) and those with a ‘periodic’ course (i.e. Reliably diagnosing and .’ At the turn of the 20th Century. Mark Twain. at that time.g.

and the work of many psychiatrists.48 ATYPICAL ANTIPSYCHOTICS treating such a condition was a huge step forward. The idea that they could be understood and treated only if the traumatic childhood events. the FDA’s approval of lithium salts in 1970 led to a dramatic increase in the diagnosis of bipolar disorder in the United States. caused by disruptions in biological functioning. including Mogens Schou in Denmark and Ronald Fieve in the US. Basic to this classification scheme are the concepts of the manic episode (see p. the pervasive ‘new’ psychodynamic theories regarded functional illnesses (i. Bipolar disorders in the DSMIV-TR DSM-IV-TR provides a categorical classification of the bipolar affective disorders through dividing them into types based on criteria sets with defining features. It was not until specific drug treatments for these ‘functional illnesses’ were found. Although some still maintained it was a physical illness. XXX). not the brain. but it took nearly three decades. or interpersonal conflicts were uncovered. to develop better treatments. influenced psychiatric thinking for over half a century. and new life was breathed into the old search for biological mechanisms. The quest had begun to understand the biological mechanisms and. Equally significant was the observation by Ronald Kuhn that when patients with ‘manic-depressive psychosis’ were treated with imipramine they could switch from depression to mania. Indeed. however. the stage was set for classifying psychiatric disorders in line with their presumed differing etiologies. in doing so. repressed sexual feelings. before lithium would become the mainstay of treatment for manicdepressive illness. based on an incorrect animal model). the hypomanic episode . that psychiatry came full circle again. With different pharmacological agents treating different psychiatric disorders. In 1949 John Cade published a report on the use of lithium salts in manic patients (curiously.e. schizophrenia and manic-depressive illness) as illnesses of the mind. That this did not occur in most patients with depression suggested that there was a different biological mechanism underlying depressive illness compared to manic-depressive illness. In cases of manic-depressive illness. neuropathologists failed to find any structural brain abnormalities.

BIPOLAR DISORDER NOT OTHERWISE SPECIFIED Prominent bipolar symptoms that do not clearly meet the criteria for any of the above bipolar disorders or that have an indeterminable etiology. each uniquely defined by a specified criteria set of symptoms.CHAPTER 8 Bipolar illness 49 (see p. although may also have hypomanic or major depressive episodes. DSM-IV-TR also includes very rapid mood cycling (not meeting minimal episode duration criteria) and manic or mixed episodes superimposed on primary psychotic disorders within this category. MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION WITH MANIC or MIXED FEATURES Prominent manic or mixed symptoms arising as a direct physiological consequence of a medical condition as evident from labwork. and etiology (if known) of the manic. hypomanic. and/or depressive symptoms present: BIPOLAR I DISORDER (p XXX) Occurrence of at least one manic or mixed episode. BIPOLAR II DISORDER (p XXX) Occurrence of one or more major depressive episodes and at least one hypomanic episode. duration. they are divided into the following types by the number. the mixed episode (see p. XXX). While all bipolar affective disorders are defined by the occurrence of at least some manic or hypomanic symptoms. but no manic or major depressive episodes. XXX). physical exam or history. . mixed. and the major depressive episode (see p. SUBSTANCE-INDUCED MOOD DISORDER WITH MANIC or MIXED FEATURES Prominent manic or mixed symptoms arising during or within 1 month of substance intoxication or withdrawal or otherwise etiologically related to medication use. XXX). CYCLOTHYMIA (p XXX) Occurrence of numerous periods of hypomanic symptoms and numerous periods of depressive symptoms.

lasting at least 1 week (or any duration if hospitalization is necessary) B. or irritable mood.50 ATYPICAL ANTIPSYCHOTICS Mania/manic episode DSM-IV-TR lists the specific diagnostic criteria set for a manic episode and includes additional criteria/descriptors to allow the clinician to further qualify the current or most recent episode (see p XXX). Psychotic symptoms In its more severe form.g. or there are psychotic features.e. electroconvulsive therapy. Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g. During the period of mood disturbance.. light therapy) should not count toward a diagnosis of Bipolar I Disorder. three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: (1) inflated self-esteem or grandiosity (2) decreased need for sleep (e. engaging in unrestrained buying sprees.. mania may be associated with psychotic symptoms (usually mood-congruent. sexual indiscretions. expansive. a drug of abuse.. at work or school. or sexually) or psychomotor agitation (7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e. attention too easily drawn to unimportant or irrelevant external stimuli) (6) increase in goal-directed activity (either socially. a medication. or to necessitate hospitalization to prevent harm to self or others. but may also be incongruent): .. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others.g. medication. The symptoms are not due to the direct physiological effects of a substance (e. feels rested after only 3 hours of sleep) (3) more talkative than usual or pressure to keep talking (4) flight of ideas or subjective experience that thoughts are racing (5) distractibility (i. DSM-IV-TR Criteria for Manic Episode A. or other treatment) or a general medical condition (e.g. The symptoms do not meet criteria for a Mixed Episode..g. A distinct period of abnormally and persistently elevated.. E. or foolish business investments) C. hyperthyroidism).

Irritability and aggression may lead to violent behavior. related to identity or role (with ‘special powers’ or religious content).’ .CHAPTER 8 Bipolar illness 51 . . . and inability to maintain adequate living conditions. .Grandiose ideas may be delusional. to the point of not eating or drinking.Preoccupation with thoughts and schemes may lead to self-neglect.Total loss of insight.Pressured speech may become so great that clear associations are lost and speech becomes incomprehensible. . .Suspiciousness may develop into well-formed persecutory delusions.Catatonic behavior—also termed ‘manic stupor. .

Depression plus over-activity/pressure of speech .g. or other treatment) or a general medical condition (e.B.. light therapy) should not count toward a diagnosis of Bipolar I Disorder.. a medication. .. Typical presentations of a mixed episode can include: .g. or there are psychotic features. B. or to necessitate hospitalization to prevent harm to self or others.Dysphoria plus manic symptoms (with exception of elevated mood) . Also included are additional criteria/descriptors to allow the clinician to further qualify the current or most recent episode (see p XXX).Mania plus agitation and reduced energy/libido . DSM-IV-TR Criteria for Mixed Episode A. ‘Ultrarapid’ cycling refers to the situation when fluctuations are over days or even hours. The symptoms are not due to the direct physiological effects of a substance (e. a drug of abuse.Rapid cycling (fluctuating between mania and depression—4 or more episodes/yr) N. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others. medication. Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g. C. hyperthyroidism). Hypomania/hypomanic episode Finally. electroconvulsive therapy. DSM-IV-TR lists the specific diagnostic criteria set for a hypomanic episode and includes additional criteria/descriptors to allow the clinician to further qualify the current or most recent episode (see p XXX). The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period.52 ATYPICAL ANTIPSYCHOTICS Mixed episode DSM-IV-TR characterizes a mixed episode as the cooccurrence of the specific criteria sets for a manic episode and a major depressive episode (see p XXX).

or other treatment) or a general medical condition (e. A distinct period of persistently elevated. or to necessitate hospitalization.g. feels rested after only 3 hours of sleep) (3) more talkative than usual or pressure to keep talking (4) flight of ideas or subjective experience that thoughts are racing (5) distractibility (i. a medication. hyperthyroidism). bizarre. The episode is not severe enough to cause marked impairment in social or occupational functioning. or it can be seclusive. E. or sexually) or psychomotor agitation (7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g. and there are no psychotic features. expansive. expansive. the person engages in unrestrained buying sprees. and seductive. Thinking can range from florid psychosis. F. B. During the period of mood disturbance. and feelings. three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: (1) inflated self-esteem or grandiosity (2) decreased need for sleep (e. to retardation so profound that no meaningful mental activity can occur. The symptoms are not due to the direct physiological effects of a substance (e. sexual indiscretions.e. Cycles of fluctuating moods and energy levels serve as a background to constantly changing thoughts. Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.. The illness encompasses the extremes of human experience.. or ‘madness’.. a drug of abuse. and dangerously suicidal.CHAPTER 8 Bipolar illness 53 DSM-IV-TR Criteria for Hypomanic Episode A. or foolish business investments) C. attention too easily drawn to unimportant or irrelevant external stimuli) (6) increase in goal-directed activity (either socially.. or irritable mood. sluggish.g. lasting throughout at least 4 days. medication. to patterns of unusually clear. Moods may swing erratically between euphoria and despair or irritability and .. The clinical reality of manic-depressive illness is that it is far more disabling and infinitely more complex than the current psychiatric nomenclature would suggest. The disturbance in mood and the change in functioning are observable by others. behaviors. light therapy) should not count toward a diagnosis of Bipolar II Disorder. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. Behavior can be frenzied. at work or school. D.g. fast and creative associations. electroconvulsive therapy.g. that is clearly different from the usual non depressed mood..

manic Most recent episode. depressed Most recent episode. depressed . hypomanic Most recent episode. unspecified Bipolar disorder not otherwise specified Cyclothymic disorder Bipolar II disorder Most recent episode. the highs associated with mania are generally only pleasant and productive during the earlier. Manic patients.54 ATYPICAL ANTIPSYCHOTICS desperation. hypomanic Most recent episode. Dr Kay Redfield Jamison (1993) Touched With Fire: ManicDepressive Illness and the Artistic Temperament The Free Press. Macmillan. milder stages. for example. are depressed and irritable as often as they are euphoric. The rapid oscillations and combinations of such extremes result in an intricately textured clinical picture. DSM-IV-TR Bipolar Disorders Bipolar I disorder Single manic episode Most recent episode. mixed Most recent episode. New York. pp 47–48.

(e. MZ twins: 33–90% concordance. A genetically predisposed individual experiences an increasing number of minor neurological insults (e. through mechanisms identified in studies of electrophysiological kindling and behavioral sensitization. and glutamine have all been implicated.e. in the frontal cortex and the hippocampus 1). Etiological theories Abnormal ‘programmed cell death’ Animal studies have recently shown that antidepressants. DZ twins: ~23%. and MAP kinases) perhaps explaining their delayed long-term beneficial effects (via under-appreciated neurotrophic effects. 2 Post RM and Weiss SR (1989) Sensitization.g. due to drugs of abuse. J Clin Psychiatry 50. schizoaffective. 1 Manji HK and Duman RS (2001) Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. BDNF. a role has also been suggested for glucocorticoids and other stress-related hormonal responses. and anticonvulsants in mania. Siblings have comparable risks. ‘Kindling’ An older hypothesis2. Neuroimaging studies also indicate of cell loss in these same brain regions. BDNF may contribute to lessening the potential for longer term neuronal consequences. Psychopharmacology Bulletin 35. CREB. This suggests that bipolar affective disorder may be the result of abnormal programmed cell death (apoptosis) in critical neural networks involved in the regulation of emotion. Mood stabilizers and antidepressants may act to stimulate cell survival pathways and increase levels of neurotrophic factors that improve cellular resilience.CHAPTER 8 Bipolar illness 55 Bipolar disorder Etiology Factors identified as important include: Genetic 1st-degree relatives are 7 times more likely to develop the condition than the general population (i. and bipolar affective disorder). 5HT. suggests a role for neuronal injury. 10–15% risk). esp.g. Suppl: 23–30. lithium and valproate indirectly regulate a number of factors involved in cell survival pathways. DA. HPA axis Given the effects of environmental stressors. which in turn may be accelerated by the stress of prolonged episodes of illness. kindling. and of exogenous steroids. Bcl-2. Children of a parent with bipolar disorder have a 50% chance of developing a psychiatric disorder (genetic liability appears shared for schizophrenia. Neurotransmitters NA. . also drawing on animal models. 5–49.

no significant racial differences. 0.psychotic depressive episode before age 25 . allowing for recurrence with or without minor environmental or behavioral stressors (much like epilepsy). which may in turn result in further injury. and suggests that treatment should be as early as possible and long-term. 1st episodes: males tend to be manic. but the length of time between subsequent episodes typically begins to history of bipolar disorder .rapid cycling or >5 depressive episodes .early age of depression onset . This view provides an explanation for later episodes becoming more frequent and more likely to occur independent of life stress. males:females (bipolar II and rapid cycling more common in females.treatment resistant depression . to acute or chronic stress.3–1. Epidemiology Lifetime prevalence 0. which eventually result in mania.) This may be followed by many years (5 or more) without a further episode. mean 21yrs). Nevertheless. Survey data uniformly document that there is usually a 5–10yr interval between age at onset of illness and age at first treatment or first admission to hospital. females depressive). (In bipolar II disorder.antidepressant-induced hypomania . why anticonvulsants may be useful in preventing recurrent episodes. Generally.refractory to >3 antidepressant trials after initial positive response .atypical features . Prodrome When attempting to differentiate from depressive disorders.periodic impulsivity or irritability Course Extremely variable.5% (0.postpartum depression . or other factors). even when there is a history of 5 . age range 15–50+yrs (peaks at 15–19yrs and 20–24yrs. The first episode of Bipolar I disorder is about equally likely to be manic/mixed or depressive in nature. the first recognized episode is almost always a depression.8% bipolar I. the following features (especially in combination) are suggestive of potential bipolar disorder: .5% bipolar II).seasonal pattern . sufficient neuronal damage may persist. for people with a history of recurrent depression the risk of “converting” to a bipolar diagnosis is greatest before age 30. After the 1st episode.56 ATYPICAL ANTIPSYCHOTICS excessive glucocorticoid stimulation.

there is at least a 5% chance of still experiencing a hypomania or mania. ventricular enlargement and sulcal prominence. Often significant comorbidity—esp. and completed suicide in ~10% (males > females usually during a depressive or mixed episode). LFTs. . lost productivity. CT/MRI brain (to exclude tumors. EEG (baseline and to rule out epilepsy). and treatment of acute manic episodes. Investigations As for depression. including CBC. It is known that untreated patients may have more than 10 episodes in a lifetime. infection screen (RPR. drug/alcohol misuse and anxiety disorders. effects on marriage (increased divorce rates) and the family. Less routine tests: urinary copper (to exclude Wilson’s disease [rare]). depressive episodes. electrolytes. other issues. TFTs. full physical and routine blood tests to exclude any treatable cause. both of which significantly increase risk of suicide. there still remains a high degree of unpredictability. in terms of lost work. Morbidity/mortality Morbidity and mortality rates are high. HIV test).CHAPTER 8 Bipolar illness 57 or more depressive episodes. with attempted suicide in 25–50%. prophylaxis. Management See specific sections (pp. Ca2+. 312–25) for management principles. glucose. Although the prognosis is better for treated patients. infarction. and drug screen. hemorrhage. Other baseline tests prior to treatment should include EKG and creatinine clearance. and psychotherapeutic interventions. and that the duration and period of time between episodes stabilizes after the 4th or 5th episode. ANA (SLE). MS)—may show hyperintense subcortical structures (esp temporal lobes).

treatment noncompliance. male sex. few thoughts of suicide. evidence of depression. • Poor prognostic factors: poor employment history. alcohol abuse. Often. few comorbid physical problems.58 ATYPICAL ANTIPSYCHOTICS Prognosis Within the first 2 years of 1st episode. 45% some future episodes. few psychotic symptoms. depressive features between periods of mania and depression. the cycling between depression and mania accelerates with age. good treatment response and compliance. 40% with little effect on risk of recurrence). psychotic features. . 40– 50% of patients experience another manic episode. later age of onset. • Good prognostic factors: manic episodes of short duration. 50– 60% of patients on lithium gain control of their symptoms (7% no recurrence.

XXX) and numerous periods with depressive symptoms that do not meet criteria for a Major Depressive Episode. Note: After the initial 2 years (1 year in children and adolescents) of Cyclothymic Disorder. The symptoms are not due to the direct physiological effects of a substance (e. Schizophreniform Disorder. E. For at least 2 years. D. cyclothymia is now considered to be a mood disorder. occupational. with numerous periods of mild depression and mild elation. or Mixed Episode has been present during the first 2 years of the disturbance.Persistent instability of mood.. The symptoms in Criterion A are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia. Clinical features . Delusional Disorder. DSM-IV-TR Criteria for Cyclothymic Disorder A. there may be superimposed Manic or Mixed Episodes (in which case both Bipolar I Disorder and Cyclothymic Disorder may be diagnosed) or Major Depressive Episodes (in which case both Bipolar II Disorder and Cyclothymic Disorder may be diagnosed). The symptoms cause clinically significant distress or impairment in social. C. the person has not been without the symptoms in Criterion A for more than 2 months at a time. B. During the above 2-year period (1 year in children and adolescents). the presence of numerous periods with hypomanic symptoms (see p. the duration must be at least one year. Manic Episode.g.CHAPTER 8 Bipolar illness 59 Cyclothymic Disorder Previously regarded as a disorder of personality (‘cyclothymic temperament’—see opposite) mainly because of its early age of onset and relative stability throughout adult life. hyperthyroidism). No Major Depressive Episode.g. or Psychotic Disorder Not Otherwise Specified. F. The diagnosis is difficult to establish without a prolonged period of observation or an unusually good account of the individual’s past behavior.. a medication) or a general medical condition (e. not sufficiently severe or prolonged to fulfill the criteria for . or other important areas of functioning. a drug of abuse. Note: In children and adolescents.

g. Because the mood swings are relatively mild and the periods of mood elevation may be enjoyable (with increased activity and productivity. lithium). or months. making it difficult to pinpoint exactly when symptoms began. or because of problems related to comorbid drug or alcohol misuse. and allow them to develop better ways of coping. or develop into more severe mood swings meeting the criteria for bipolar affective disorder or recurrent depressive disorder.If pharmacological treatment is contemplated this usually consists of a trial of a mood stabilizer (e. as these may be better tolerated.The mood swings are usually perceived by the individual as being unrelated to life events. and gabapentin was singularly ineffective as an antimanic. cyclothymia frequently fails to come to medical attention. or lamotrigine. Epidemiology Prevalence 3–6% of general population. selfconfidence. carbamazepine.60 ATYPICAL ANTIPSYCHOTICS bipolar affective disorder or recurrent depressive disorder. but sometimes may present later in life.e. As yet there is no clear evidence to suggest any of these approaches is superior to lithium unless there is a clear history of lithium resistance.Psychoeducation and several focused forms of psychotherapy have been shown to reduce recurrence risk. More traditional forms of insight-orientated psychotherapy also may help the person to understand the condition. either singly or in combination with antipsychotic medication or potent benzodiazepines. Management .Recently there has been a tendency to use anticonvulsants such as valproate. however. . Age of onset: usually early adulthood (i. Usually runs a chronic course. In some cases symptoms may cease temporarily or permanently. Course Onset is often gradual. teens or 20s). weeks. More common in the relatives of patients with bipolar affective disorder. Often the person may present either because of the impact of the depressive episodes on their social and work situations. . and sociability). . Not all anticonvulsants are effective. Concerns about tardive dyskinesia have led to preferential use of the atypical antipsychotics – which all have been shown to be effective antimanic agents – instead of the older compounds. . persisting throughout adult life. The alternating ups and downs may fluctuate in hours.

sometimes ‘sad as death’. in need of rest. and the pressure of activity. Today lively. sometimes ‘rejoicing to the skies’. and again a few months later they display the old freshness and elasticity. sparkling.There is often a reluctance to continue to take medication as this not only treats the depressive episodes. the pleasure of enterprise. or intellectual capacity. Emil Kraepelin (1896) Manic-Depressive Insanity and Paranoia. (Extract from translation of the 8th edition of Kraepelin’s textbook Psychiatrie) .CHAPTER 8 Bipolar illness 61 . ill-humored. beaming. enervated. Kraepelin’s ‘cyclothymic temperament’ These are the people who constantly oscillate hither and thither between the two opposite poles of mood. after some time they meet us depressed. full of the joy of life. but also may be perceived as ‘blunting’ creativity. productivity.

. 125 –34.No spontaneous hypomanic or manic episodes. 332). . . . . .Lack of response to up to 3 antidepressant treatment trials.Postpartum depression.At least one major depressive episode. .Atypical depressive symptoms (DSM-IV criteria). Can J Psychiatry 47. and requiring little sleep (less than 6 hours/night).Psychotic major depressive episodes. optimistic personality style. nondepressed state). .Antidepressant ‘wear-off’ (acute but not prophylactic response). . .Recurrent major depressive episodes (>3).Antidepressant-induced mania or hypomania.g.A family history of bipolar disorder in a first-degree relative. Proposed clinical features ‘Bipolar spectrum disorder’ is characterized by:1 . valproate—see p.Hyperthymic personality2 (at baseline. extroverted and sociable. Ko JY.62 ATYPICAL ANTIPSYCHOTICS ‘Bipolar spectrum disorder’ One view of the affective disorders is that they consist of a continuum (see below). Goodwin FK (2002) ‘Cade’s disease’ and beyond: misdiagnosis. <3 months).Brief major depressive episodes (on average. and a proposed definition for bipolar spectrum disorder. tendency to become easily irritated. . antidepressant use. 1 Ghaemi SN.Early age of onset of major depressive episode (< age 25). Management Patients with features of bipolar spectrum disorder may represent a subset of patients who do not respond well to antidepressants (often precipitating a switch to a hypomanic or manic episode) and for whom an anticonvulsant may be the drug of choice (e. And a history including some of the following: . . 2 Characterised by cheerful.

CHAPTER 8 Bipolar illness 63 The ‘affective continuum’ Dysthymia Unipolar depression Atypical depression Psychotic depression Unipolar spectrum disorder Recurrent depression Bipolar spectrum disorder Bipolar II Bipolar I .

exhibitionism. histrionic.64 ATYPICAL ANTIPSYCHOTICS Bipolar affective disorder (3) Differential diagnosis of bipolar disorders Other psychiatric disorders There are many other psychiatric disorders and conditions which share some of the manic or hypomanic affective and/or neurovegetative features of bipolar disorders: • • • • • • • • • • • • • ADHD Anxiety disorders Conduct disorder Dementias Dissociative disorders (dissociative fugue. dissociative identity disorder) Eating disorders Impulse-control disorders Personality disorders (paranoid. especially if the condition is known to have a direct association with the development of such symptoms (see table XX). borderline. frotteurism. and it can at times be difficult to discern how much to attribute these symptoms (especially neurovegetative) to a primary bipolar disorder or to the medical condition. used recreationally. voyeurism) Substance use disorders General medical conditions Some patients who have manic or hypomanic symptoms can also have one or more general medical conditions. antisocial. . many substances (prescribed for a medical condition. schizotypal. exacerbation. narcissistic) Schizoaffective disorders Schizophrenia and other psychotic disorders Sleep disorders Sexual disorders (paraphilias. A listing of such pharmacological agents is given in table XX. or through environmental exposure) can induce manic or hypomanic symptoms. Pharmacological causes of manic/hypomanic symptoms Finally. A temporal association (onset. remission) between the condition and the manic symptoms can help guide the clinician.

right sided) Brain tumors Huntington’s disease Delirium Nutritional deficiencies/Metabolic deficiencies Folate deficiency B12 deficiency Other Porphyrias . complex partial) Hyperthyroidism Addison’s disease Hypoparathyroidism Carcinoid Menopausal symptoms Hypercalcemia Tertiary syphilis Hepatitic encephalopathy Rheumatoid arthritis Toxoplasmosis HSV encephalopathy Stroke (esp.CHAPTER 8 Bipolar illness 65 General Medical Conditions with Manic/Hypomanic Features Endocrine Acromegaly Cushing’s disease Hyperparathyroidism Hyperglycemia Pheochromocytoma Perimenstrual syndromes Prolactinoma Infectious/Inflamma tory Influenza Mononucleosis HIV/AIDS Encephalitis Systemic lupus erythematosus Neurological Multiple sclerosis Head trauma Wilson’s disease Epilepsy (esp.

66 ATYPICAL ANTIPSYCHOTICS Pharmacological causes of manic or hypomanic symptoms Analgesics and anti-inflammatory agents Tramadol Indomethacin Phenylbutazone Opiates Antibiotic/antiviral agents Isoniazid Chloroquine Dapsone Anticholinesterases Cimetidine Diphenoxylate Mebeverine Antidepressant agents Gastrointestinal agents Cimetidine Metoclopramide Ranitidine Clarithromycin Lysergide Salbutamol Cardiac and antihypertensive agents Captopril Clonidine Digitalis Diltiazem Hydralazine Lidocaine Reserpine Methyldopa Propranolol withdrawal Procainamide Sedatives in withdrawal Barbiturates Benzodiazepines Steroids and hormones Corticosteroids Danazol Prednisone Testosterone Norethisterone Ethanol Oral contraceptives Dexamethasone .

Establishing and maintaining a therapeutic alliance. but also psychotherapeutic interventions (see Psychotherapeutic interventions p.Monitoring side-effects of medication and ensuring therapeutic levels of any mood stabilizer. and particular patient groups. and this may sometimes involve not only pharmacological. Special consideration should also be given to certain specific issues related to the clinical presentation. . follow-up has a number of key aims: . .CHAPTER 8 Bipolar illness 67 Stimulants and appetite suppressants Amphetamine Cocaine Diethylpropion Fenfluramine Caffeine Methylphenidate Neurological agents Amantadine Baclofen Carbamazepine Levodopa Respiratory agents Aminophylline Bromocriptine Phenytoin Ephedrine Pseudoephedrin e Cyproheptadine Methysergide Other miscellaneous agents Cyclosporine Cyclizine Disulfiram Interferon Management principles Acute episodes Management of acute episodes depends upon the nature of the presentation (See Treatment of acute manic episodes ppXXX.Enhancing treatment compliance. the presence of concurrent medical problems. and Treatment of depressive illness pp. XXX).Providing education regarding bipolar disorder. possible physical causes excluded.XXX). XXX. XXX) should be considered. Often the manic episodes are of a nature and degree that hospital admission will be necessary (for criteria and considerations see Hospital admission p. XXX). . and the presenting episode effectively treated.Monitoring the patient’s psychiatric status. Hypomania/hypomanic episode p. . Outpatient follow-up Once the diagnosis has been clearly established. both in terms of setting and choice of treatment (see Other issues affecting management decisions pp. . XXX). Issues of maintenance (see Maintenance p.

Identifying new episodes early. . .g. 314). or an early indicator. 324). who often has good insight. A good therapeutic alliance is critical. and the patient. 398) to promote normal sleep patterns may be useful in preventing the development of a manic episode). so that treatment can be initiated early. . of mania or depression—education about the importance of regular sleep habits and occasional use of an hypnotic (see p.68 ATYPICAL ANTIPSYCHOTICS .Promoting understanding of and adaptation to the psychosocial effects of bipolar disorder. Other early or subtle signs of mania may be treated with the short-term use of benzodiazepines or antipsychotics. Relapse prevention A key part of psychiatric management—helping patients to identify precipitants or early manifestations of illness.Identifying and addressing any significant comorbid conditions (p.Promoting regular patterns of activity and wakefulness. ought to feel that they can contact their clinician as soon as they are aware of these ‘early warning signs’. (e. .Reducing the morbidity and sequelae of bipolar disorder. This may be done as part of the ‘usual’ psychiatric follow-up. insomnia may often be either a precipitant. . or form part of a specific psychotherapeutic intervention (see Psychotherapeutic interventions p.

admit to hospital (or if in hospital. Management Address issues of misuse. Concurrent medical problems .). if severe consider admission to hospital. etc. SSRI treatment or substance abuse).g.Risk of violence Assess nature of risk (see pp. consider ECT. Other factors may contribute (e. multiple sclerosis. . hypothyroidism. clarify psychiatric diagnosis. consider need for secure setting. . note association with rapid cycling mood. conduct disorder. paranoid delusions.Risk of suicide Assess nature of risk (see p.Psychotic symptoms It is not uncommon for patients to experience delusions and/or hallucinations during episodes of mania and a significant minority of depressive episodes also are psychotic. For issues of substance misuse or other psychiatric morbidity these should be addressed directly (see specific sections). 45). Valproate and lamotrigine have been found to be more effective than other mood stabilizers.Catatonic symptoms During a manic episode (‘manic stupor’). . Occurs in 10-20% of patients with Bipolar Disorder.CHAPTER 8 Bipolar illness 69 Other issues affecting management decisions Specific clinical features Certain clinical features will strongly influence the choice of treatment. . Substance misuse may lead to relapse both directly and indirectly (by reducing compliance). . if diagnosis clear treat with ECT and/or benzodiazepine. . Management Admit to hospital. Note increased risk with rapid mood cycling. Admit to hospital. If significant risk. Worse long term prognosis. Equally. ADHD. if detoxification considered.Substance-related disorders. . admit to hospital as risk of suicide may be increased. Initial rule out of medical conditions should be completed (e. Women>>Men. agitation. 646– 7). anxiety disorder. exclude medical problem.Rapid Cycling Defined as 4 or more discreet mood episodes per year. and dysphoria.g. Comorbidity is high. Management Mood stabilizer with/without an antipsychotic. often confusing the clinical picture. alcohol consumption may increase when on lithium.Other comorbidities Personality disorders. or unacceptable uncertainty. consider ECT. increase level of observation).

HIV-infected patients may be more sensitive to CNS side-effects of mood stabilizers. benzodiazepines) should be considered separately. Teratogenic risks of lithium probably have been exaggerated. inflammatory bowel disease) may exacerbate mood symptoms. antipsychotics.70 ATYPICAL ANTIPSYCHOTICS The presence of other medical problems may affect the management either by exacerbating the course or severity of the disorder or by complicating pharmacological treatment (i.Endocrine disorders e. Older patients may be more sensitive to the side-effects of lithium (particularly neurological) and may require lower therapeutic levels (i. . support.g. The long-term effects of these treatments on development have not been fully studied. below 0. but therapeutic levels are the same as for adults. there is often evidence of previous depressive episodes in their 40s and 50s. issues of tolerability and drug interactions). Lithium may be excreted more quickly. Education.g. . depressed. ECT is rarely used.Use of steroids for inflammatory conditions (e. but may be effective. Risks associated with other adjunctive agents (e.) . allowing more rapid dose adjustments. . . XXX). CNS disorders). Special patient groups . clinical experience indicates that lithium and other antimanic therapies are effective. Youth may be at particular risk for weight gain.Cardiovascular/renal/hepatic disorders May restrict the choice of drug therapy or increase the need for closer monitoring (see pp.Infectious diseases e.g. XXX). Consider ECT as first-line for treatment of significant manic.g. .e.e. Atypical antipsychotics and lamotrigine . hypo/hyperthyoidism.Children and adolescents (see p. antidepressants. particularly when treated with atypical antipsychotics. and other specific psychosocial interventions should be considered (usually involving family.Pregnancy and lactation (see pp.The elderly (see p. XXX) Although not extensively studied in these age groups. teachers. Full physical examination is necessary to exclude medical causes (esp. etc. asthma. XXX) When a first manic episode occurs in a patient after age 60. Atypical antipsychotics have received a “black box” warning that cautions about the risk of increased mortality (~2%) in controlled studies of elders with dementia.7mmol/L). or psychotically depressed episodes.

CHAPTER 8 Bipolar illness 71 may have the safest profiles. but further research is needed. .

. reputation.Catatonic symptoms. inpatient detoxification). .The relapsing/remitting nature of the disorder makes it possible to work with the patient (when well) and their family to anticipate future acute episodes and agree a treatment plan should they occur. . Points to note .Severe depressive symptoms. or secondary to availability of social supports/outpatient resources). . suicide attempts or homicidal behavior).A need to address comorbid conditions (e.Illness-related behavior that endangers relationships. which may interfere with their ability to make reasoned decisions about the need for treatment. Clinical features and situations where admission may be necessary . .Severe psychotic symptoms. .g. overspending.72 ATYPICAL ANTIPSYCHOTICS Hospital admission Frequently acute manic episodes require hospital admission (often on a compulsory basis because of loss of insight and inability to make informed choices about the need for treatment).Patients with symptoms of mania/hypomania or depression often have impaired judgment (sometimes related to psychotic symptoms). physical problems.Failure of outpatient treatment. other psychiatric conditions.Severe mixed states or rapid cycling (days/hours). . or assets. directly due to illness. excessive use of drugs/alcohol.g. . . .Lack (or loss) of psychosocial supports.g.High risk of suicide or homicide.Risk assessment includes not only behaviors that may cause direct harm (e. .Lack of capacity to cooperate with treatment (e. sexual promiscuity. but also those that may be indirectly harmful (e.g. Issues of safety and the provision of effective treatment will govern the decisions about whether a patient can remain in the community. driving while unwell). .

it is often best to tell unpleasant truths (i. yet uncompromising in negotiations. and balancing risks. radio. a routine. A balance should be struck between avoidance of overstimulation (e. and make requests of staff that may well be ‘reasonable’ but not practical. The psychiatrist needs to adopt a pragmatic approach. listening to concerns. is the ‘least worst’ option. calm environment is desirable (but not always possible). As manic individuals can be uncannily aware of less-than honest responses. TV. from outside events. Patients may find regular observations by staff overly intrusive. “You must stay here in the hospital for at least 5 days”) in a calm manner and not to engage in long debates aimed at reaching consensus. .. Sometimes this may result in a difficult decision about whether to detain a patient to a hospital environment.e. access to alcohol and drugs should be restricted.CHAPTER 8 Bipolar illness 73 Suitable environment? During an acute manic episode. which although far from ideal. lively conversations) and provision of sufficient space to walk or exercise in order to use up excess energy.g. feel uncomfortable in a busy ward. Where possible.

e. The fact that lorazepam is well absorbed after intra1 Gelenberg AJ and Hopkins HS (1996) Antipsychotics in bipolar disorder. and pretreatment blood sugar and lipid profiles are recommended to facilitate monitoring if longer term therapy with atypical antipsychotics is subsequently indicated. to sedate the acutely agitated manic patient whilst waiting for the effects of other primary mood-stabilizing agents. for severe mania or psychotic symptoms. lack of psychotic symptoms or suicidal behavior. and up to 80% among more treatment-responsive subsets (i. Due to this delayed effect. or in conjunction with. in place of. 328–31) Lithium remains the first-line treatment for acute mania. As noted previously. Journal of ClinicalPsychiatry 57(Suppl.). 896). compliance with medication. Benzodiazepines Another approach to reduce the need for antipsychotics is the adjunctive use of benzodiazepines.) Note: At least 2 weeks of treatment is necessary to reach maximal effectiveness for manic patients. .or second episode patients without a history of cycling and minimal depressive features. an antipsychotic. esp. the high frequency of EPS and risk of TD has driven the field’s preference for atypical antipsychotics over older agents such as haloperidol or chlorpromazine. waist size.. with associated acute behavioral disturbance. either alone or in combination with lithium. nonpsychotic first. Predictors of good response Previous response to lithium. with a response rate of at least 50% across all patients. antipsychotics are useful in the rapid control of severely agitated or psychotic patients with bipolar disorder1. addition of an antipsychotic or a benzodiazepine is usually required (see below). and are effective. euphoria (not dysphoria). the antimanic efficacy of clozapine should not be overlooked. Documentation of weight.74 ATYPICAL ANTIPSYCHOTICS Treatment of acute manic episodes First-line treatment Lithium (see pp. Antipsychotics As in acute behavioral disturbance (see p. Clonazepam and lorazepam are the most widely studied compounds. FHx of mood disorder. Atypical antipsychotics – unlike the older drugs – also have been shown to reduce the risk of relapse following successful acute phase therapy. When the more commonly used atypical antipsychotics are ineffective. 49–52.

CHAPTER 8 Bipolar illness 75 muscular injection (unlike other benzodiazepines) has made it particularly useful for some very agitated patients. Current practice reserves ECT for clinical situations where pharmacological treatments may not be possible. 3 Mukherjee S. such as pregnancy or severe cardiac disease. or when the patient’s illness is refractory to drug treatments. AJP 151. Sackeim HA. Schnur DB (1994) Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. ECT has been shown to be the most rapidly effective treatment option for patients with severe mania3. 169–76 .

may be effective. mixed episodes. stable or decreasing frequency of manic episodes. absence of psychotic symptoms. but has failed to garner sufficient evidence of efficacy in larger scale controlled trials. Valproate is about as effective as lithium in head to head studies of acute phase therapy and certainly should be considered the treatment of choice for patients who are intolerant of or not responsive to lithium. secondary mania (e.g. Valproate is generally well tolerated. ‘mixed’ episode. ‘rapid cycling’—where some consider it ‘first-line’. Carbamazepine (see p. or less severe forms of bipolar spectrum disorders.XXX) became the most commonly used mood stabilizer by psychiatrists in the United States in the late 1990s. although its longer term efficacy still is not convincingly established. but the level of empirical support is not sufficient to justify a formal FDA indication. either alone or in combination with lithium or antipsychotics. which has shown some promise in both depressed and manic bipolar patients. 334) or its derivative. 4 It may be better tolerated in patients with comorbid drug or alcohol problems or obesity. Biol Psychiatry 48. 539–57.g. rapid cycling. Other There is no current evidence to recommend use of gabapentin in bipolar disorder (mania or hypomania). 4 McElroy SL and Keck PE Jr. oxcarbazepine. Controlled studies suggest acute antidepressant effects as well. brain injury).76 ATYPICAL ANTIPSYCHOTICS Use of anticonvulsants Valproate (see p. (2000) Pharmacologic agents for the treatment of acute bipolarmania. episode part of schizoaffective disorder. Predictors of good response Previous response to carbamazepine. Predictors of good response May be more effective in particular patients e. Topiramate is best known for its effects in promoting weight loss. The jury is still out on Topiramate. dysphoric mania. dysphoria. drug-induced. . neurological disorder. poor compliance (due to wide therapeutic window). Lamotrigine is approved for preventive therapy of bipolar I disorder (prevention greater for depressive than manic relapses). keeping in mind the caveat that it essentially doubles plasma levels to lamotrigine. although some caution is needed in treatment of patients with alcoholism and liver disease. Valproate also is well-suited for combined treatment regimes.

2006. Minkwitz M. B. the latter was approved for therapy of both Bipolar I and Bipolar II depressions in late 2005). Cutler AJ. Am J Psychiatry. J. placebocontrolled trial of quetiapine in the treatment of bipolar I or II depression. 2005.E. lamotrigine and several of the atypical antipsychotics are currently being used as monotherapies for patients with bipolar depression.. both olanzapine and quetiapine have shown definite efficacy in placebo controlled studies (the former drug was not given an FDA indication because of the superior performance of the fluoxetine-olanzapine combination. MacFadden W. perhaps partly because of the risk of precipitating a manic episode or inducing/accelerating rapid cycling. In general. . it may be worth considering focused psychological interventions instead of pharmacotherapy (as in unipolar depression. Weisler RH. 8(6):478-488.. for the Bolder II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: A confirmatory double-blind. M. 1 Although the antidepressants that are used to treat major depressive episodes are widely thought to be effective in the treatment of bipolar depression. In fact. W. placebo-controlled study (the Bolder II study). only one antidepressant – fluoxetine – is specifically approved for treatment of bipolar depression and that indication is limited to the use of fluoxetine in combination with olanzapine. double-blind.CHAPTER 8 Bipolar illness 77 Treatment of depressive episodes The pharmacological treatment of depressive episodes in bipolar disorder represents a particular challenge. antidepressants are recommended for use only in combination with mood stabilizers to less the risk of treatment-emergent affective switches (TEAS). Weisler. p. Wilson E.H. Paulsson. A randomized. Clin. there is surprisingly little prospective research and some of the studies have yielded contradictory findings.R. 3 Thase.162:1351-1360... Mullen J. Khan. W. Ketter TA. 26(6):600-609.E. Psychiatry Rep. 2006 2 Calabrese JR. Calabrese. MacFadden.. R. 259). Curr. Psychopharm.23 1 Thase. Keck PE. Although the antidepressant effects of lamotrigine have been inconsistent in larger scale controlled studies. Pharmacotherapy of bipolar depression: an update. J. When symptoms are milder... Mccoy R. Naturalistic studies suggest that response rates tend to be lower (than observed in major depressive disorder). Chang. M. A. Alternatively.

Kitchen CMR. then consider addition of an antidepressant or an additional mood stabilizer. (2001) Double-blind. or where urgent treatment necessary. Vieta E.If patient currently ‘drug-free’ consider initiation of either a mood stabilizer (e. Grunze H. check serum levels. Nolen WA. Kupka RW. lamotrigine. Evans DL. . greater safety in overdose. Altshuler LL. S57–66. McElroy S. Mintz J. or carbamazapine) to the treatment regimens of patients with bipolar disorder. 4 In general. optimize (ensure compliance). valproate. Shelton MD (2003) Latest maintenance data on lamotrigine in bipolar disorder. XXX).e.If depressive symptoms persist. Keck PE. choice will depend on issues of previous response.g. Eur Neuropsychopharmacol. hypothyroidism). 3 Nemeroff CB. even at “normal” serum levels (see p. side-effects (both desired and undesired).If patient already on prophylaxis. Recent evidence suggests monotherapy with lamotrigine may have utility in the treatment of refractory bipolar depression4.78 ATYPICAL ANTIPSYCHOTICS Initial management . AJP 158. Be alert for evidence of lithium toxicity. . exclude/treat associated problems (e. Denicoff KD.g..If severely depressed. Choice of antidepressant Although evidence is scarce. 4 Calabrese JR. 13 Suppl 2. Suppes T. Additional mood stabilizer Although only a handful of controlled clinical trials comparing standard treatments for depression in patients with bipolar disorder are lacking. and tolerability issues (see p. et al. and – in all likelihood – less tendency to cause TEAS than the TCAs3. . 4 Post RM. consider ECT (see below). Br J Psychiatry. it is a widely accepted practice to add a 2nd mood stabilizer (i. lithium or valproate). bupropion and sertraline. clinicians should not forget the therapeutic potential of the MAOIs for patients with more difficult-to-treat episodes of bipolar depression. Leverich GS. 2006. Mood switch in bipolar depression: comparison of adjunctive venlafaxine. When newer antidepressants are ineffective and ECT is not a therapeutic option. suicidal. most clinicians favor either the SSRIs or bupropion because of superior tolerability. placebocontrolled comparison of imipramine and paroxetine in the treatment of bipolar depression. Gyulai L. Recent data suggest that venlafaxine – perhaps because of its noradrenergic effects – may be more likely to cause TEAS than the other newer antidepressants.B. XXX). 906–12. . Frye MA.189:124-131. N.

ECT has been reported to cause memory impairment.Perhaps the best-established treatment for more refractory cases of bipolar depression.CHAPTER 8 Bipolar illness 79 ECT . For treatment —resistant depressive episodes. acute confusion. As relapse almost invariables follows successful treatment within 6-9 months. ECT also should not be overlooked (esp in severe cases). and other neurological problems in patients on lithium. it is important to ensure that preventive therapy is initiated. 5 Bauer M. (2002) Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. XXX). . . Neuropsychopharmacology 27. Alternative strategies/treatment resistance Other suggested strategies include: the use of adjunctive triiodothyronine (T3)—even if there is no evidence of (sub)clinical hypothyroidism5. Berghofer A. Bschor T. . hence lithium should be withdrawn prior to treatment. principles of management are as for unipolar depression (see p. 620–8. et al.Anticonvulsants oppose the desired convulsant effects of ECT and should also be withdrawn prior to treatment.

Leadbetter R. These include patients with ‘mixed mania’ (i. carbamazepine may be more effective in the treatment of bipolar spectrum than classical bipolar disorder. Calabrese JR. depressive symptoms during manic episodes) and patients with ‘rapid cycling’ mania. Carbamazepine Appears to be effective in the long-term treatment of bipolar disorder. . Some subtypes of what has become known as the ‘bipolar spectrum’ may not respond as well to lithium. J Clin Psychiatry. First-line treatment Lithium (see p. Kimbrell TA. Grunze H.80 ATYPICAL ANTIPSYCHOTICS Maintenance treatment of bipolar disorder Primary aim Prevention of recurrent episodes (either mania or depression. Bowden CL. 2 Dunn RT. Also strongly recommended for patients with Bipolar II Disorder. mania following discontinuation of other psychotropic medications. to a lesser extent.e. with an overall response rate of 63%2. Although it does not have worldwide approval as yet. (1998) The efficacy and use of anticonvulsants in mood disorders. 215– 35. American Psychiatric Association.65:432-441. 2004. Clinical Neuropharmacology 21. Greene P. (APA Guidelines 20041).5 1 American Psychiatric Association: Practice Guidelines for the Treatment of Psychiatric Disorders. White R. Kasper S. A pooled analysis of 2 placebo-controlled 18month trials of lamotrigine and lithium maintenance in bipolar I disorder. 5 Goodwin GM.) Indications Following effective remission of a manic episode. XX) To date lithium remains the first-line choice for maintenance treatment in patients with a ‘classical’ course of illness. et al. Emerging evidence would seem to suggest a role for anticonvulsants in these patients. Second-line treatments Valproate Has demonstrated efficacy in rapid cycling bipolar disorder and the added confidence of being the most widely prescribed therapy for bipolar depression. although unequivocal evidence of successful prophylaxis has not yet emerged. Lamotrigine Efficacy established in a pair of controlled studies for prevention of depressive and. Frye MS. 2004.


Bipolar illness 81

Other anticonvulsants There have been promising reports on the efficacy of oxcarbazepine. At this time there remains no convincing evidence for efficacy with topiramate, gabapentin, gabitril, or pregabalin in the treatment of Bipolar Disorder. Atypical Antipsychotics Over the past several years several of the atypical antipsychotics have been approved for longer term use after successful acute phase therapy.

Alternative/augmentative agents
Alternatives treatment strategies, or potential augmentative agents, include a number of other compounds which may have some clinical utility, but for which the evidence remains weak. These include: calcium channel antagonists such as verapamil, nifedipine, and nimodipine; thyroid hormones.

Risks of discontinuation
With long-term treatment it is essential that patients are well informed about the risks and implications of stopping medication. Substantial evidence exists that abrupt discontinuation of lithium is associated with an increased risk of relapse. The risk, particularly of mania, may be minimized by gradually reducing the lithium dose. Although comparable studies are not available for the anticonvulsants, a similarly cautious approach would seem advisable.

Suicide prevention
Since patients with bipolar disorder represent a group at high risk of suicide, it is reasonable to ask whether the above treatment strategies reduce the occurrence of suicidal acts. Retrospective and prospective studies do suggest that long-term lithium therapy reduces the risk of suicide, and may even reduce the known associated risk of cardiovascular disease. At present there is still little data available on the anti-suicidal effects of the anticonvulsants in bipolar disorder. Prospective studies looking at the issue of outcome in bipolar disorder suggest that lithium may be significantly superior to carbamazepine in this regard.



Psychotherapeutic interventions
Most patients will struggle with some of the following issues:
- Emotional consequences of significant periods of illness and receiving the diagnosis of a chronic psychiatric disorder. - Developmental deviations and delays caused by past episodes. - Problems associated with stigmatization. - Problems related to self-esteem. - Fear of recurrence and the consequent inhibition of normal psychosocial functioning. - Interpersonal difficulties. - Issues related to marriage, family, childbearing, and parenting. - Academic and occupational problems. - Other legal, social, and emotional problems that arise from illness-related behaviors. For some patients, a specific psychotherapeutic intervention (in addition to usual psychiatric management and social support) will be needed to address these issues. Approaches include: psychodynamic, interpersonal, and cognitive behavioral therapies. In addition, couple therapy, family therapy, and group therapy may be indicated for some patients. The selection of appropriate interventions is influenced by the local availability of such treatments, as well as the patient’s needs and preferences.

Key elements of selected interventions
CBT Time-limited, with specific aims: educate the patient about bipolar disorder and its treatment, teach cognitive behavioral skills for coping with psychosocial stressors and associated problems, facilitate compliance with treatment, and monitor the occurrence and severity of symptoms. Interpersonal and social rhythm therapy To reduce lability of mood by maintaining a regular pattern of daily activities (e.g. sleeping, eating, physical activity, and emotional stimulation). Recent evidence suggests these


Bipolar illness 83

psychotherapeutic interventions provide improved longterm outcomes. 6 Family therapies Usually brief, include psychoeducation (of patient and family members) with specific aims: accepting the reality of the illness, identifying precipitating stresses and likely future stresses inside and outside the family, elucidating family interactions that produce stress on the patient, planning strategies for managing and/or minimizing future stresses, and bringing about the patient’s family’s acceptance of the need for continued treatment. Support groups These may provide useful information about bipolar disorder and its treatment. Patients may benefit from hearing the experiences of others, struggling with similar issues. This may help them to see their problems as not being unique, understand the need for medication, and access advice and assistance with other practical issues. In the US, groups such as NAMI (, Depression and Bipolar Support Alliance (, and the Child and Adolescent Bipolar Foundation ( provide both support and educational material to patients and their families.


Frank E. Kupfer DJ. Thase ME. Mallinger AG. Swartz HA. Fagiolini AM. Grochocinski V. Houck P. Scott J. Thompson W. Monk T. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Archives of General Psychiatry. 62(9):996-1004, 2005 Sep.

4. et al. However. G proteins and calcium).5. lithium 1 still remains the ‘gold standard’ in the treatment of bipolar affective disorder against which other treatments are measured.g.g. The effectiveness of long-term treatment with lithium is supported by at least 9 controlled. Ca2+. inositol 1. 325–84). First approved by the FDA in 1970 for treatment in ‘manic depresssion. protein kinase C.-triphosphate. calcium-channel blockers. Hawton K. adenylate cyclase. although the last decade has seen an emerging body of research supporting the use of anticonvulsant. K+. Hammond in 1871 (‘The treatment of insanity’ in A Treatise on Diseases of the Nervous System . Drug Interactions Increased plasma concentration (risk of toxicity even at therapeutic serum levels) ACE inhibitors/angiotensin II antagonists.A. New York: Appleton. 3 Burgess S. 349– 352). this was a ‘rediscovery’ of the application of lithium to the treatment of ‘insanity’ first described by W. Elimination: 90-98% of drug is excreted unchanged in the urine. lithium interacts with systems involving other cations. Geddes J. arachidonate.84 ATYPICAL ANTIPSYCHOTICS Lithium Despite problems with tolerability. Pharmacokinetics Half-life: 18-24 hours (can increase to >36hrs in elderly or in renal impairment). or sedative agents. antipsychotic. The Cochrane Library. Within cells. The use of a specific agent for a specific disorder heralded the start of the modern era of psychopharmacology. . This evidence far exceeds the available support for other possible alternatives to lithium treatment. NSAIDs and Cox-2 inhibitors). double-blind studies2. Mg2+ and may have effects on cell membrane electrophysiology. antihypertensives (e. Not protein bound. antidepressants (esp. effectively blocking the actions of transmitters and hormones. haloperidol). (2002) Lithium for maintenance treatment of mood disorders. SSRIs). antipsychotics (esp. Mode of action Uncertain—numerous effects on biological systems (particularly at high concentrations). antiepileptics. methyldopa). Bioavailability not affected by food. including the release of neurotransmitters and 2nd messenger systems.3. diuretics 1 The use of lithium salts in the treatment of ‘psychotic excitement’ is usually credited to John Cade in 1949 ( Medical Journal of Australia 2. (e. 1 Oxford: Update Software.’ 2 Price LH and Heninger GR (1994) Lithium in the treatment of mood disorders NEJM 331. perhaps explaining lithium’s value as an adjunctive treatment. Lithium can substitute for Na+. 591–8. There is also a reduction in receptor up-regulation. analgesics (esp.

4 mmol/L.8-1. Lithium levels Check lithium level approximately 5 days after starting the medication and 5 days after each dosage adjustment. electrolytes. . Blood samples should be trough levels 12 hours following the last dose. however. Maintenance Monitoring Once a therapeutic serum level (0. amiodarone: increased risk of hypothyroidism). antibiotics (esp. Starting dose Usually start 300mg bid.6-1. and thyroid function must be followed. and EKG (for patients >50yo). Target lithium levels for the elderly and for patients with special medical considerations are generally lower. antidiabetics (may sometimes impair glucose tolerance).CHAPTER 8 Bipolar illness 85 (esp.4 mmol/L). metronidazole. bicarbonate. pregnancy test (in women of child-bearing age). sibutramine (risk of serotonin syndrome) Initiating and monitoring lithium therapy Prior to commencing lithium therapy renal function (BUN/Cr. renal function.2mmol/L) has been established.6–1. thiazides). MAOI (malignant hyperthermia). Also consider CBC with differential. tetracyclines) Decreased plasma concentration (risk of decreased efficacy) Antacids. clinical response. urinalysis and 24-hour creatinine clearance (CrCl). antipsychotics (increased risk of EPS). and side effects. parasympathomimetics (antagonizes neostigmine and pyridostigmine).g. Actual dose also depends on preparation used (as molar availability varies even when milligram amounts are the same)— see opposite. In acute stabilization. sodium-containing products Other interactions Anti-arrhythmics (e. theophylline. Titrate dosage upwards (e.). usual effective dose is approximately 1800mg/d in divided doses (target lithium level ~ 0. In maintenance phase. methyldopa. Of note. usual dosing range is 9001200mg/d (target lithium level ~ 0. neuromuscular-blocking agents (prolong blockade). iodine salts (increase risk of hypothyroidism). chlorpromazine. a higher rate of relapse has been shown in healthy adults maintained at levels of <0. ongoing lithium levels.g. caffeine. increase weekly in increments of 300mg/d) as indicated by plasma lithium level. the optimal therapeutic lithium level may vary from patient to patient. thyroid function (TSH).2 mmol/L).

What to do if a dose is missed . highlighting the relevant issues discussed in the pages following on adverse effects. may be switched to qhs if tolerated . Lithium preparations Preparation Eskalith Eskalith CR Lithobid lithium carbonate lithium citrate Formulation Capsule Tablet (controlled release) Tablet (slow release) Capsule Syrup alcohol) (contains Available dosages 300mg 450mg (scored) 300mg 150/300/600m g 300mg/5mL Other Dosing Considerations .Effects of dehydration and dietary considerations .Common side effects and signs of toxicity . and thyroid function once or twice. Information for the patient Starting lithium should be fully discussed with the patient. kidney.86 ATYPICAL ANTIPSYCHOTICS During the first 6 months: check renal function and lithium level every 2-3 months.Immediate-release formulations are usually initiated in divided doses (bid-tid). thyroid function.Controlled-release formulations may be given once daily at bedtime or divided bid . and lithium level every 6-12 months or whenever clinically indicated.Potential long-term complications and thus the need for regular monitoring of blood levels. After the first 6 months: check renal function.How and when to take their dose . Emphasis should be on a number of issues: .Appropriate contraceptive measures and dialogue about pregnancy risks .A reminder of these issues is usually given in the form of a pamphlet or information handout. however. and thyroid functioning .What medications/illnesses may change blood levels .

thiazide diuretic or amiloride (nephrogenic diabetes insipidus). dyspepsia. nausea. vomiting. or valproic acid for the treatment of acute mania . weight gain (effects on carbohydrate metabolism and/or edema). GI distress) by lowering peak levels .. sedation/lethargy. non-specific T wave changes. poor concentration. confusion. Patients with tremor at therapeutic lithium levels should avoid caffeine. tremor. Therefore. If side-effects persist.1 Dose-related side-effects Polyuria/polydypsia (reduced ability to concentrate urine due to antidiuretic hormone [ADH] antagonism).g. and edema. hypercalcemia. GI problems can be managed by administering lithium with meals or switching formulations (sustained release or lithium citrate).Sustained release formulations may reduce side effects (esp.May be most useful in patients with euphoric mania (versus those with mixed state or rapid cycling) . cognitive problems (e.CHAPTER 8 Bipolar illness 87 . Up to 75% of patients treated with lithium will experience some sideeffects. impaired coordination. gastrointestinal distress (e. widening of QRS).g. . mental slowness).Low-dose lithium may be an effective augmenting agent in the treatment of depression Lithium has a narrow therapeutic window and has the potential of being highly toxic at supratherapeutic drug levels. benign leucocytosis. Rarely.g.Rapid discontinuation of lithium increases relapse . give the same total daily dose when possible .When switching a patient from immediate-release capsules to controlled-release formulation. acne. impaired memory. often given in conjunction with benzodiazapines. Oxford University Press. or altering the dose schedule or formulation. dulling. Cardiac conduction problems Usually benign EKG changes (e. topical antibiotics or retinoic acid (acne). exacerbation of existing arrhythmias or induction of new arrhythmias 1 Lithium—adverse effects Goodwin FK and Jamison KR (1990) Manic-Depressive Illness. safe and effective therapy requires regular monitoring of serum levels. antipsychotics. hair loss. additional medications may be necessary: propranolol (tremor).Due to the delayed onset of action. Management Usually managed by lowering the dose. diarrhea).

and severe cardiovascular disease.5mmol/l most patients will experience some symptoms of toxicity. toxic effects occur. nausea/vomiting. Subclinical/clinical hypothyroidism 5–35% of patients on lithium develop hypothyroidism. 2nd ed. in addition to the classic signs and symptoms of hypothyroidism.5-2.88 ATYPICAL ANTIPSYCHOTICS due to conduction deficits at the SA or AV nodes. diarrhea (sometimes hematemesis) with associated dehydration and lethargy. muscle fasciculation/myoclonic jerks. Acta Psychiatr Scand. rarely clinically significant. 1991 83. however. sick sinus syndrome. Even though lithium-induced hypothyroidism is generally reversible upon discontinuation. . It is worth noting that. American Psychiatric Press. Thyroid dysfunction tends to appear 6-18 months after initiation of lithium. choreoathetoid movements. Washington. Bernardi F. often life-threatening.0mmol/L) Severe neurological complications—restlessness. 3 Bocchetta A. and 2 Jefferson JW (ed. anorexia. Lithium is contraindicated in heart failure. tubular atrophy. et al. This may progress to ataxia.) (1987) Lithium Encyclopedia for Clinical Practice . With levels >1. 3 Toxicity The usual upper therapeutic limit for 12-hour post-dose serum lithium level is 1. drowsiness. There are case reports in which patients have developed irreversible renal failure after 10 years or more of treatment. increased lethargy. More frequent in women and patients >50 years old. 193–8. Pedditzi M. >2. patients with bipolar disorder are also at risk of developing depression and/or rapid cycling as a consequence of suboptimal thyroid functioning. it does not constitute an absolute contraindication for continuing lithium treatment as the associated hypothyroidism is readily treated with thyroxine2.0mmol/l definite. (1991) Thyroid abnormalities during lithium treatment.0mmol/L) tremulousness. Early signs and symptoms (approx 1.2mmol/l. marked hypertonicity. dysarthria. Long-term effects Renal function ~10–20% of patients on long-term therapy demonstrate morphological kidney changes (interstitial fibrosis. There is often a narrow therapeutic window where the beneficial effects outweigh the toxic effects. As lithium levels rise (>2. and sometimes glomerular sclerosis.).

(1994)5 suggested guidelines: .Severe forms of bipolar disorder. premature delivery. nephrogenic diabetes insipidus. XX on pregnancy) The much-quoted 400-fold increased risk of Ebstein’s anomaly (a congenital malformation of the tricuspid valve) due to first trimester lithium exposure4.Prevention by patient psychoeducation. (1994) A reevaluation of risk of in utero exposure to lithium. Management .5mmol/L. As levels climb above 2.Mild. The estimated risk of major congenital anomalies for lithiumexposed babies is 4–12% compared with 2–4% in control groups. Teratogenicity (see p. avoiding certain medications (as outlined above) and being watchful for early signs and symptoms of toxicity. . Hypotension and cardiac arrhythmias generally precede circulatory collapse. and floppy baby syndrome. Even so. there is serious risk of seizures. Friedman JM. . now appears to be substantially less than first reported—at most an 8-fold relative risk5. MTP Press. . coma. stable forms of bipolar disorder—lithium may be tapered down and stopped pre-pregnancy. following overdose).g.g. 146–50. Management A careful balance needs to be struck between the risks of teratogenicity and the risks of relapse following discontinuation. 5 Cohen LS.Moderate risk of relapse—lithium should be tapered and discontinued during the first trimester (4–12 weeks after last menstrual period).) Handbook of Lithium Therapy. . There is no antidote. .In moderate to severe toxicity (e. Cohen et al. e. Jefferson JW. rapid steps to reduce serum lithium level are urgently necessary. permanent neurological impairment or even death. 421–29. who are at high risk of relapse—lithium should be maintained during 4 Weinstein MR (1980) In: Johnson FN (ed. lithium today is considered a first-line treatment of bipolar disorder during pregnancy.CHAPTER 8 Bipolar illness 89 confusion/delirium. thyroid abnormalities. however.Careful adjustment of lithium dosage may be all that is required in mild toxicity. Other reported second and third trimester problems include polyhydramnios. This may involve forced diuresis with intravenous isotonic saline and electrolyte repletion. JAMA 271. hemodialysis is the treatment of choice in cases where toxicity is severe or accompanied by significant renal failure. maintaining hydration and salt intake. et al.

2004. Al. During pregnancy. prenatal diagnosis and detailed ultrasound and echocardiography at 16–18 weeks gestation).90 ATYPICAL ANTIPSYCHOTICS pregnancy (with informed consent. 161:608-620. Am J Psychiatry. weekly in the last month. lithium levels should be monitored every 2-4 weeks. 7 . and every few days before and after delivery. appropriate counseling. Management of bipolar disorder during pregnancy and the postpartum period. 7 1 Yonkers et.

pancreatitis. agranulocytosis. chlorpromazine.Toxicity may be precipitated by other highly protein-bound drugs (e. elevated LFTs. it is also indicated in various seizure disorders and migraine headaches. Side-effects and toxicity Dose-related side-effects GI upset (anorexia. Interactions . dizziness. it remains a first-line agent in the treatment of bipolar disorder. nausea. Unpredictable side-effects Mild leukopenia and thrombocytopenia (reversible upon drug reduction/discontinuation). vomiting. and teratogenicity. cholestyramine. fluoxetine). asthenia. Furthermore. and increases bioavailability of GABA (or mimics action at postsynaptic receptor sites) in the central nervous system. phenytoin. saturation-dependent kinetics. primidone. TCAs. H2-blocker for dyspepsia. . Extensively metabolized by the liver. Modulates voltage- sensitive sodium channels. polycystic ovarian syndrome/hyperandrogenism. ataxia. Rare. tremor. Highly protein bound (80-90%) and has non-linear. may require dose reduction.Decreased serum levels with carbamazepine. diarrhea). Pharmacokinetics Rapidly absorbed when taken orally (peak serum level 1-5hr) with a plasma half-life of 6–16hrs. . idiosyncratic side-effects Irreversible hepatic failure.Raised serum levels with felbamate. clarithromycin. acts on second-messenger systems. or treatment of specific symptoms (e. beta-blocker for tremor.g. headache. change in preparation.CHAPTER 8 Bipolar illness 91 Valproate/valproic acid Valproic acid was the first FDA-approved antiepileptic drug (AED) for the treatment of acute mania. hair loss (usually transient. which can displace valproate from its protein-binding sites. Time to steady-state 2-3 days. Mode of action Uncertain. and sedation—if persistent. topiramate. rifampin. there is data to suggest that it may be more effective than other mood stabilizing agents in mixed episodes and rapid cycling. To this day. consider treatment of MVI with Zinc/Selenium). dyspepsia. antidepressants (esp. aspirin). increased appetite. and weight gain. Teratogenicity see page XX .g. Beyond mood stabilization.

Valproate/Valproic Acid preparations Preparation Depakote Active agent Divalproex sodium Available dosages C 125/250/500m g . LFTs.LFTs: baseline. clinicians will generally target 50-120mcg/mL . fasting glucose.Although there is no well-established correlation between serum concentrations and mood-stabilizing effects. coma. Depakote ER) should be administered once daily using a dose 8-20% higher than the total daily dose of the immediaterelease formulation . Hemodialysis may be needed as toxicity can proceed to heartblock. . and fasting lipids annually. May load 30mg/kg/d in the inpatient setting. Consider testosterone in women with symptoms of hyperandrogenism or menstrual irregularities.Acute Mania: Load 15-20mg/kg/day (or approximately 750-1000mg) divided in bid dosing (or qhs with extended-release). Consider ammonia level if mental status changes. . and even death.Non-Acute: Initiate 250-500mg/day divided in bid dosing (or qhs with extended-release). then titrate upwards . at two months. and pregnancy test (in women of child-bearing age).Other: Follow weight. 5 days after change in dose.CBC: baseline. Consider amylase in patient with GI discomfort. consider changing to enteric-coated or slow-release formulation Monitoring .g. Also consider baseline EKG and coags (if history of bleeding). and then 2-3x/year . Treatment guidelines .VPA level: Measure 5 days after start of medication. or whenever addition/discontinuation of other interacting drugs . and then 2-3x/year . Check platelet counts and coags prior to planned surgeries or as clinically indicated.Before starting: CBC with platelets.Extended release formulations (e.If GI upset is a problem.92 ATYPICAL ANTIPSYCHOTICS Toxicity/overdose Wide therapeutic window. hence unintentional overdose is uncommon. at two months.

CHAPTER 8 Depakote Sprinkles Depakote ER Depakene Depakene Elixir Depacon Bipolar illness 93 C 125mg T 250/500mg C 250mg L 250mg/5mL IV 100mg/mL Divalproex sodium Divalproex sodium Valproic acid Valproic acid Sodium Valproate .

Pharmacokinetics Peak plasma concentrations usually 4–12hrs (depending on formulation). and various intracellular signaling pathways. receptor-mediation of GABA and glutamine. rarely after longer periods).Carbamazepine decreases the plasma levels of many drugs metabolised by the liver e. Modulates sodium and calcium ion channels. decreasing the half-life 5– 26hrs. hormonal contraceptives. cytochrome P450 3A4 is the major isoform. 76% protein-bound. may be as late as 26 hrs. other anticonvulsants.94 ATYPICAL ANTIPSYCHOTICS Carbamazepine Although psychiatrists have been using carbamazepine as a second or third line mood stabilizer for years. With long-term use. hepatic failure. .g. Mode of Action Uncertain. sometimes developing many months after starting treatment. protease inhibitors. Interactions .g. . Stevens-Johnson syndrome). calcium channel blockers (diltiazem and verapamil. erythromycin. nefazodone. only recently did Equetro™ earn FDA approval for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder. probably more common in the elderly. Metabolized by the liver. Idiosyncratic side-effects Agranulocytosis. Plasma halflife 18–55hrs. BDZs (except clonazepam).Carbamazepine serum concentrations can be increased by certain drugs e. SSRIs. increase in free cortisol levels (rarely clinically significant). and pancreatitis (these side effects usually occur within the first 3–6 months of treatment. exfoliative dermatitis (e. thyroid hormones. azole antifungals Side-effects and toxicity Unpredictable side-effects Antidiuretic effects leading to hyponatremia (6–31%). aplastic anemia. Routine blood .g. but not nifedipine or nimodipine). TCAs. decrease in total and free thyroxine levels. Carbamazepine is also approved for use in various seizure disorders and trigeminal neuralgia. antipsychotics. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200-800 mg. carbamazepine induces its own metabolism.Contraindicated in use with MAOI.

Consider EKG. and diplopia. Maximum daily dose is 2000mg/day. or even coma.LFTs: baseline. 5 days after change in dose. Monitoring . cardiac conduction problems. Other rare side-effects Systemic hypersensitivity reactions.e. cardiac problems (tachycardia. and other anticholinergic symptoms. cerebellar/extrapyramidal signs. however doses higher than 1600mg/day are generally not recommended.) Treatment guidelines for carbamazepine . Symptoms of overdose: nystagmus. then every 2 weeks for two months. ataxia. then increase 200mg/day at weekly interval.Initiate with a low divided dose of 200mg bid. and proteinuria). baseline Na.CBC with platelets: baseline. hematuria.Carbamazepine level: Measure 5 days after start of medication. extremely rare renal problems (failure. gastric lavage.CHAPTER 8 Bipolar illness 95 monitoring does not reliably predict blood dyscrasias. then every 2 weeks for two months. respiratory depression. clinicians will generally target a trough level of 4-15 g/mL. Usual total daily dosage range is 800-1200mg. Acute intoxication may present as marked irritability. arrhythmias/conduction disturbances). then every 3 months . . May be fatal in overdose (if >6g ingested). oliguria. convulsions. . stupor. Significant overdose requires emergency medical management (i.TFTs: baseline.BMP: baseline. liver/kidney/thyroid functions. sedation. GI upset. or exfoliative dermatitis—patient education about early symptoms and signs essential. Teratogenic effects see p xxx Toxicity/overdose Early signs: dizziness. Divide dosing bid (extended release formulation) or TID-QID (Immediate release formulation). or whenever addition/discontinuation of other interacting drugs . impairment of consciousness. symptomatic treatment. then every 6 months .Although there is no well-established correlation between serum concentrations and mood-stabilizing effects.Prior to starting: CBC. hypotension. ophthalmoplegia. close monitoring. pregnancy test. hepatic failure. then every 3-6 months . then every 6 months . psychiatric symptoms. and possible hemodialysis.

etc.Other: Consider obtaining baseline and regular iron levels. Baseline and periodic eye exams recommended. cardiac history. >45 years of age. Carbamazepine preparations Preparation Tegretol Tegretol Elixir Tegretol XL Carbatrol Equetro carbamazepin e carbamazepin e Formulation Tablet (also in chewable form) Suspension Extended Release Tablet Extended Release Capsule Extended Release Capsule Tablet (also in chewable form) Suspension Available dosages 100/200mg 100mg/5mL 100/200/400mg ER 100/200/300mg ER 100/200/300mg ER 100/200mg 100mg/5mL .).96 ATYPICAL ANTIPSYCHOTICS .g. Obtain EKG as clinically indicated (e.

but early evidence suggests that it has similar mechanism to carbamazepine. diplopia. and abnormal gait. and differs only in that it contains a keto-group substitution in the 10-11 position. clarithromycin. speech/language difficulties. Idiosyncratic side-effects Association with Cognitive adverse events including psychomotor slowing. abdominal pain. Interactions . it is not as well studied. and oral contraceptives. tremor. coordination abnormalities (i. Pharmacokinetics Time to peak serum level 3-13 hours. difficulty concentrating. protease inhibitors.CHAPTER 8 Bipolar illness 97 Oxcarbazepine Oxcarbazepine has the identical chemical structure of carbamazepine. vomiting. Serious side-effects Clinically significant hyponatremia (sodium <125 mEq/L) has been observed in 2. In vitro studies suggest that the active metabolite blocks voltage-sensitive sodium channels. Approximately 40% protein bound. ataxia and gait disturbances). Steady state plasma concentrations are reached within 2-3 days when given bid. . abnormal vision. The half-life is 2-9 hours. this newer antiepileptic drug has been used increasingly as an alternative agent in the treatment of Bipolar disorder. Mode of Action Unknown. dyspepsia.Contraindicated in use with MAOI Side-effects and toxicity Most Common side-effects dizziness. These were typically mild-moderate in severity. nasea.Oxcarbazepine may reduce serum levels of calcium channel blockers. somnolence/fatigue.5% of patients in controlled trials (generally during the first 3 months of treatment). Unfortunately. fatigue.e. somnolence. Because it tends to be better tolerated and does not appear to confer the same adverse risk profile. Of those patients who are allergic . ataxia. Oxcarbazepine is rapidly metabolized in the liver to its active metabolite (10-monohydroxyoxcarbazepine) which is primarily responsible for the medication’s pharmacological effect.

mixed episodes). hypomania. mania. Monitoring . placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. nausea.Prior to starting: pregnancy test (in women of childbearing age) and serum electrolytes with sodium level. Teratogenic effects see p xxx Treatment guidelines for oxcarbazepine . . Of note. obtundation). however. malaise. most patients who develop hyponatremia are initially asymptomatic. then increase 300-600mg/day at weekly intervals. at one month. . and then every 3 months (or as clinically indicated for signs/symptoms of hyponatremia. headache. The effectiveness in the acute treatment of mood episodes has not been established. doubleblind. i. lethargy. Other rare side-effects Serious dermatological reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported. Usual total daily dosage is 1200mg/day divided bid.Initiate with a low divided dose of 300mg bid. Doses >2400mg/d are generally not advised. There is some evidence that lamotrigine may be more effective than other mood stabilizers in preventing depressive episodes in Bipolar Disorder.e.Electrolytes: baseline. Evidence is supported by two multicenter.98 ATYPICAL ANTIPSYCHOTICS to carbamazepine. 35-30% will have a reaction to oxcarbazepine. Oxcarbazepine preparations Preparation Trileptal Trileptal Elixir Formulation Tablet (scored) Liquid Available dosages 150/300/600m g 300mg/5mL Lamotrigine Indicated for the maintenance treatment of bipolar disorder to delay the time to occurrence of mood episodes (depression.

rifampin. Pharmacokinetics Rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%).CHAPTER 8 Bipolar illness 99 Mode of Action Unknown. and a rash associated with a variable number of the following systemic manifestations (i. of no more than half the dose used in patients not receiving valproate. more than doubles the elimination half-life of lamotrigine). and rash. sleepiness. if administered to a patient receiving valproate. Risk of Rash Approximately 10-14% of patients receiving lamotrigine will develop a rash. fever. ritonavir. nausea. even in the presence of drugs that increase the apparent clearance of lamotrigine. some individuals may develop a serious skin reaction that requires hospitalization. Interactions . Inhibits voltage-gated sodium channels and glutamate release. and certain estrogen-containing oral contraceptives. Peak plasma concentrations occur anywhere from 1-5 hours following. hematologic. methsuximide. Drug is 55% protein bound. and time to steady state is 5-8 days. oxcarbazepine (30%). Among these rashes include StevensJohnson syndrome. The bioavailability is not affected by food drug administration. Although the majority of rashes are benign. . lymphadenopathy. Rarely. the majority of these deaths occurred in association with other serious medical events.Certain medications have been shown to increase clearance of lamotrigine: Carbamazepine (40%). headache. toxic epidermal necrolysis.Valproate decreases the clearance of lamotrigine (i. blurred or double vision. facial swelling. making it difficult to identify the initial cause. Half-life 24 hours. Accordingly. insomnia. vomiting. Also has weak inhibitory effect as 5-HT3 receptors. angioedema. lack of coordination.e.e. and hepatologic abnormalities). primidone. deaths have . lamotrigine must be given at a reduced dosage. phenytoin (50%). however. Side-effects and toxicity Most Common side-effects dizziness. phenobarbital (40%). Rare side-effects Rare incidence of multiorgan failure and various degrees of hepatic failure. Some cases has been fatal or irreversible.

As monotherapy: Start 25mg/day for weeks 1 and 2.With carbamazepine (and/or phenytoin. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling/defiguring. Increase to 400mg for week 7 and onwards. These serious skin reactions are most likely to occur within the first 2-8 weeks of treatment. blood dyscrasias (neutropenia. Accordingly. unless the rash is clearly not drug related. lamotrigine should ordinarily be discontinued at first sign of rash. It has been suggested that the risk of rash increases with coadministration with valproate. It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL. primidone. Target dose: 100mg. Increase to 50mg/day for week 5. or exceeding the recommended dose escalation. it is not possible to predict reliably which rashes will prove to be serious or life threatening. . Increase to 200mg/day for week 5. Target dose: 200mg. Target dose: 400mg/day (usually given in bid divided dose). exceeding the recommended initial dose. thrombocytopenia. pancytopenia. Other rare side-effects Serious hypersensitivity reactions. phenobarbital. aplastic anemia and pure red cell aplasia). Increase to 25mg/day for weeks 3 and 4. Although most rashes resolve even with continuation of treatment. it is recommended . Increase to 100mg/day for week 5. .With Valproate: Start 25mg every other day for weeks 1 and 2. withdrawal seizures Teratogenic effects see p xxx Treatment guidelines for lamotrigine . rifampin) and NOT taking Valproate: Start 50mg/day for weeks 1 and 2. anemia. Increase to 300mg for week 6. leukopenia. Increase to 100mg/day for week 6 and onwards. .If a patient has discontinued lamotrigine for a period of more than 5 half-lives. Increase to 200mg for week 6 and onwards. Increase to 50mg/day for week 3 and 4. unless the potential benefits clearly outweigh the risks. Increase to 100mg/day for week 3 and 4.Prior to starting: pregnancy test (in women of childbearing age). rarely.10 ATYPICAL ANTIPSYCHOTICS been reported. and. .

XXX for pregnancy) Unfortunately.Drug levels: The value of monitoring plasma concentrations has not been established. 2/5/25mg (CH) 2/25mg Teratogenicity of Antiepileptics (see p. or swelling of lips or tongue) may herald a serious medical event and that the patient should be seen by a physician immediately to determine if lamotrigine should be discontinued.Prior to initiation of treatment.3%) or lamotrigine (2. monitoring of the plasma levels of concomitant drugs may be indicated. painful sores in the mouth or around the eyes. there is an estimated 1-2% estimated risk for neural tube defect among infants born to mothers 8 Morrow J. The European and International Registry of Antiepileptic Drugs in Pregnancy surveillance system suggests that the risk for major congenital malformations is higher with valproic acid (6. (See Side Effects) Lamotrigine preparations Preparatio n Lamictal Lamotrigine Formulation Tablet (chewable available) Tablet (chewable available) Available dosages 25/100/150/200mg. 8 Most notably.45(Suppl3):206. Getting it right for children born to mothers with epilepsy: morphology. clinically controlled studies comparing the relative risks of each antiepileptic drug (AED) during pregnancy. lymphadenopathy. however. there are no large-scale. particularly during dosage adjustments.1%) when compared to carbamazepine (2. Because of the possible pharmacokinetic interactions. antiepileptic therapeutic serum levels are 810mcg/mL Monitoring .CHAPTER 8 Bipolar illness 10 that initial dosing recommendations and guidelines be followed .g. the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.9%). Epilepsia. fever. 2004. . .. hives.Although there is no well-established correlation between serum concentrations and mood-stabilizing effects.

Atypical Antipsychotics All atypical antipsychotics are FDA approved for use in the treatment of schizophrenia. Certain AEDs (phenobarbital. quetiapine (Seroquel®). phenytoin. . however. Refer to the Schizophrenia Chapter for detailed pharmacologic parameters and side effect profiles of these medications. aripiprazole (Abilify®). even if they do not intend to become pregnant. which poses a risk of neonatal hemorrhage. some now carry FDA approved indications for acute mania. olanzapine (Zyprexa®). jitteriness.e. risperidone (Risperdal®). hepatic toxicity. and growth and development difficulties. most experts recommend administering Vitamin K 20mg daily to pregnant patients taking these medications (and 1mg IM to the newborn). limb malformations. hypoglycemia. There is less solid evidence that carbamazepine also may carry a 0. ziprasidone (Geodon®). The Center for Disease Control strongly recommends at least 0. Though lamotrigine and oxcarbazepine have been used in Europe for at least a decade.2% in the general population). and paliperidone (Invega®). and bipolar maintenance.14-0. primidone. This highlights the importance of discussing potential teratogenic effects with all women of childbearing age and monitoring contraceptive status.4 mg of folic acid daily to be given to all women of childbearing age. bipolar depression. Frequently patients are not even aware they are pregnant at the time of fetal neural tube closure (i. craniofacial abnormalities. hypotonia.5% elevated risk of spina bifida. Therefore. Atypical antipsychotic medications include: clozapine (Clozaril®). Other AED-related complications include neonatal irritability. as this has shown to reduce the risk of spina bifida. 17-30 days post-conception). bipolar mania. there is little information available on their safety in pregnancy. and carbamazepine) are competitive inhibitors of prothrombin precursors.10 ATYPICAL ANTIPSYCHOTICS receiving valproate during the first trimester of pregnancy (as compared with 0. feeding difficulties.

CHAPTER 8 Bipolar illness 10 .

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