CHAPTER 8 Bipolar illness 318 \200\230I want to be bipolar \200\231 A worrying trend in outpatient clinics is the \200\230expert \200\231 patient who has self - diagnosed bipolar disorder. One of the unexpected consequences of anti-stigma campaigns i s the identi \201 cation of individuals with celebrities who claim to have a psychiatric d isorder (usually of a \200\230softer \200\231 variety \200\224 like bipolar II, rather tha n bipolar I). Whilst acceptance and more posi- tive attitudes to psychiatric disorders are to be welcomed, it is still the provenance of the psychiatrist to legitimize such presumpti ve diagnoses. Good history taking is of paramount importance. It is essential that dif- fer entials and comorbidity are considered (e.g. personality traits, anxiety, alcohol and subst ance misuse). As far as possible, collateral information may help with possible recall bias and evidence of secondary gain pro- hibit the medicalization of dif \201 cult or impruden t behavior. Clinicians must try and remain objective and not collude with the patient, prof es- sional colleagues, fashionable labeling (e.g. \200\230bipolar spectrum \200\231, see b p. 312), or unsubstantiated claims of Big Pharma. Diagnosis carries not only far-reaching psychosocial consequences but also will often suggest a need for speci \201 c intervention s which are not without risk. The main differentials not to miss include: Thyroid disorders be caused by lithium; may pre sent subclinically as mixed states; and are treatable! Substance abuse: illness/predisposit ion; may be a form of self-medication; should always be treated \201 rst. ADHD: overlappi ng symptoms \200\224restlessness, hyperactivity, distractibility, impulsiveness, poor conce ntration/attention, temper dyscontrol; lifelong, pervasive not episodic; may respond to ant idepressants and mood stabilizers. Borderline PD: intense unstable relationships; acutely s ensitive to abandonment; unrealistically demanding of families and physicians; exhibiting s elf-defeating and self-destructive behaviors; heightened sense of personal rights (repeated vexatious complaints); frequently associated with substance abuse, self-harm (mutilation), and repeated suicidal acts. Other PDs: aggression, histrionics, paranoia, narcissism, hypo chondriasis, manipulative antisocial traits. When these are secondary to bipolar disorder t hey tend to disappear between episodes, and with treatment, and the patient is more likely to be embarrassed and remorseful. Fixed PDs are often demanding, de \201 ant, manipulative , self-defeating, actively undermine efforts to address needs, non- compliant with medicati on, abuse alcohol or substances, and end up in prison. : may resemble depression or mania/hypomania; can can mimic affective states; may unmask pre-existing stormy, unstable lifestyles; overly dramatic; traits often seen in bipolar disorder: dependency, passive 08_Semple_Chap08.indd 318 12/7/2012 6:52:37 PM This page intentionally left blank CHAPTER 8 Bipolar illness 320 Bipolar affective disorder 3: etiology Despite signi \201 cant research efforts the de \201 nitive pathophysiology of bipo- lar disorder remains elusive. There are many similarit ies with gene expres- sion and neuroimaging studies of persons with schizophrenia and major depression, suggesting that mood disorders and schizophrenia may share a biological basis. Genetic Twin, family, and adoption studies point to a signi \201 cant genetic contribu- ti on. First-degree relatives are 7 \227 more likely to develop the condition than the general population (i.e. 10 \200\22315% risk). Children of a parent with bipolar disorder have a 5 0% chance of developing a psychiatric disorder (genetic liability appears shared for schizo phrenia, schizoaffective, and bipolar affective disorder). MZ twins: 33 \200\22390% concord ance; dizygotic (DZ) twins: 23%. Candidate genes Results from 4 genome-wide association studies of large samples of sub- jec ts with bipolar disorder give combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C ( 1C subunit of the L-type voltage- gated calcium channel).1 Other candidates are genes associated with bio- chemical pathways that lithium regulates, e.g. the phosphatidyl inositol pathway (diacylglycerol kinase eta [DGKH] gene); cell death/neuropro- tection mec hanisms (e.g. glycogen synthase kinase 3-beta [GSK3 ]); or circadian periodicity (e.g CLOC K gene) (see Box 8.5). Postmortem studies found decreased levels of expression of oligodend rocyte-myelin-related genes implicating abnormal myelination in the illness. Shared genetics with schizophrenia As well as overlapping family susceptibility, there are emerging reports of shared genes, e.g. G72 on 13q34, which encodes d-amino acid oxidase act ivator (DAOA) and DISC1 (Disrupted in Schizophrenia 1) on 1q42. A large meta-analysis by th e National Institutes of Health (NIH) on recent genome-wide association studies found evide nce for a shared susceptibil- ity locus around 6p22.1 known to harbor genes involved in imm unity, and turning other genes on and off.2 Neuroimaging A recent meta-analysis of structural and functional brain imaging found decrea sed activation and reduced gray matter in areas associated with emotional regulation, and i ncreased activation in ventral limbic brain regions that mediate and generate emotional res ponses.3 Biochemical factors There is increasing evidence of the importance of glutamate in bipolar disorder and major depression; the cathecholamine hypothesis study sug- gests that an incre ase in epinephrine and norepinephrine causes mania, while a decrease causes depression; dru gs that may cause mania (e.g. cocaine, L-dopa, amfetamines, antidepressants) suggest a role for DA and 5-HT; disruption of Ca2+ regulation may be caused by neurological 08_Semple_Chap08.indd 320 12/7/2012 6:52:37 PM BIPOLAR (AFFECTIVE) DISORDER 3: etiology 321 insults, such as excessive glutaminergic transmission or ischaemia; hormo- nal imbalances a nd disruptions of the hypothalamic \200\223pituitary \200\223adrenal axis involved in homeo stasis and stress response are also important. Environmental factors Stressful life events may lead to episodes. Pregnancy esp. carries a high risk of a mixed affective presentation or frank puerperal psychosis. Box 8.5 Aetiological theories Abnormal programmed cell death Animal studies have recently shown that antidepressants, lit hium, and valproate indirectly regulate a number of factors involved in cell survival pathw ays (e.g. CREB, BDNF, Bcl-2, and MAP kinases), perhaps explain- ing their delayed long-term bene \201 cial effects (via under-appreciated neurotrophic effects, esp. in the frontal c ortex and the hippocampus1). Neuroimaging studies also indicate cell loss in these same bra in regions suggesting that bipolar affective disorder may result from abnormal pro- grammed 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 increa se levels of neurotrophic factors that improve cellular resilience. Kindling An older hypothesis,2 also drawing on animal models, it suggests a role for neuron al injury, through a mechanism involving electrophysiological kindling and behavioral sensi tization. A genetically predisposed individ- ual experiences an increasing number of minor neurological insults (e.g. due to drugs of abuse, excessive glucocorticoid stimulation, acu te or chronic stress, or other factors), which eventually result in mania. After the 1st ep isode, neuronal damage may persist, allowing for recurrence with or without minor environme ntal or behavioral stressors (like epi- lepsy), which may result in further injury. This pr ovides an explanation for later episodes becoming more frequent, why anticonvulsants may be useful in preventing recurrent episodes, and suggests that treatment should be as early as possible and long-term. 1 Manji HK, Duman RS (2001) Impairments of neuroplasticity and cellular resilience in sever e mood disorders: implications for the development of novel therapeutics. Psychopharmacol B ull 35: 5 \200\22349. 2 Post RM, Weiss SR (1989) Sensitization, kindling, and anticonvulsan ts in mania. J Clin Psychiat 50 (Suppl): 23 \200\22330. 1 Ferreira MA, O \200\231Donovan MC, Meng YA, et al. (2008) Collaborative genome-wide assoc iation analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40: 105 6 \200\2238. 2 NIH News (2009) Schizophrenia and bipolar disorder share genetic roots. Lond on: National Institutes of Health. M http://www.nih.gov/news/health/jul2009/nimh-01.htm 3 H ouenou J, Frommberger J, Carde S, et al. (2011) Neuroimaging-based markers of bipolar disor - der: evidence from two meta-analyzes. J Affect Disord 132: 344 \200\22355. 08_Semple_Chap08.indd 321 12/7/2012 6:52:37 PM CHAPTER 8 Bipolar illness 322 Bipolar affective disorder 4: management principles Acute episodes This will depend upon th e nature of the presenting episode (see b p. 306, b p. 310, and b p. 312). Often the episod e may require hos- pital admission (see Hospital admission, b p. 323). Special considera- t ion should also be given to certain speci \201 c issues related to the clinical presentati on, the presence of concurrent medical problems, and particular patient groups, both in ter ms of setting and choice of treatment (see b p. 324). Issues of prophylaxis (see b p. 330) should be considered, and this may sometimes involve not only pharmacological, but also psy cho- therapeutic interventions (see b p. 332). Outpatient follow-up Once the diagnosis has been clearly established, possible physical cau ses excluded, and the presenting episode effectively treated, follow-up has a number of key aims: \200 \200 \200 \200 \200 Establishing and maintaining a therapeutic alliance. Monitoring the patient \200\231s psych iatric status. Providing education regarding bipolar disorder. Enhancing treatment complian ce. Monitoring side-effects of medication and ensuring therapeutic levels of any mood stabi lizer. Identifying and addressing any signi \201 cant comorbid conditions (b p. 324). Prom oting regular patterns of activity and wakefulness. Promoting understanding of and adaption to the psychosocial effects of bipolar disorder. Identifying new episodes early. Reducing the morbidity and sequelae of bipolar disorder. Maintaining a pragmatic view of how interve ntions will help \200\224to reduce frequency and severity of episodes but perhaps not to el iminate them completely \200\224bipolar disorder is a chronic condition. Providing an oppor tunity to discuss any new treatment developments in a balanced and evidence-informed manner . \200 \200 \200 Relapse prevention A key part of psychiatric management is helping patients to identify pre - cipitants or early manifestations of illness, so that treatment can be initi- ated early. This may be done as part of the usual psychiatric follow-up, or form part of a speci \201 c psychotherapeutic intervention (see b p. 332), e.g. insomnia may often be either a preci pitant, or an early indicator, of mania or depression \200\224education about the importanc e of regular sleep habits and occasional use of an hypnotic (see b p. 426) to promote norma l sleep patterns may be useful in preventing the development of a manic episode. Other earl y or subtle signs of mania may be treated with the short-term use of benzodiazepines or ant ipsychotics. A good therapeutic alliance is critical, and the patient, who often has good i nsight, ought to 08_Semple_Chap08.indd 322 12/7/2012 6:52:37 PM BIPOLAR (AFFECTIVE) DISORDER 4: MANAGEMENT PRINCIPLES 323 feel that they can contact their clinician as soon as they are aware of these early warning signs. Use of a Mood Diary or Life Chart can help in this regard (see M http://bipolarnews .org; select \200\230Life Charts \200\231 tab). Hospital admission Frequently acute episodes of bipolar disorder are severe enough to requi re hospital admission (often on a compulsory basis). Issues of safety and the provision of effective treatment will govern decisions about whether a patient can remain in the communi ty. Points to note \200 Patients with symptoms of mania/hypomania or depression often have impaired judgment (somet imes related to psychotic symptoms), which may interfere with their ability to make reasone d decisions about the need for treatment. Risk assessment includes not only behaviors that may cause direct harm (e.g. suicide attempts or homicidal behavior), but also those that ma y be indirectly harmful (e.g. overspending, sexual promiscuity, excessive use of drugs/alco hol, driving whilst unwell). Relapsing/remitting nature of the disorder makes it possible t o work with the patient (when well) and their family/carers to anticipate future acute epis odes \200\224agree a treatment plan. Clinical features and situations where admission may be necessary \200 \200 \200 High risk of suicide or homicide. Illness behavior endangering relationships, reputation, o r assets. Lack of capacity to co-operate with treatment (e.g. directly due to illness, or s to availability of social supports/outpatient resources). Lack (or loss) of psychosocial s upports. Severe psychotic symptoms. Severe depressive symptoms. Severe mixed states or rapi d cycling (days/hours). Catatonic symptoms. Failure of outpatient treatment. Address comorb id conditions (e.g. physical problems, other psychiatric conditions, inpatient detoxi \201 cation). \200 \200 \200 \200 \200 \200 Suitable environment During an acute manic episode, maintain a routine, calm environment (n ot always possible). A balance should be struck between avoiding over- stimulation (e.g. fr om outside events, TV, radio, lively conversation) and provision of space to walk or exerci se to use up excess energy. Where possible, restrict access to alcohol and drugs. Regular o bservations by staff may be overly intrusive, and feel uncomfortable in a busy ward. Patien ts may make requests that may be reasonable, but not practical. Psychiatrist should adopt a pragmatic approach, listen to concerns, and balance risks. This may result in a dif \201 cult decision about whether to detain a patient to a hospital environment, which although f ar from ideal, is the \200\230least worst \200\231 option. 08_Semple_Chap08.indd 323 12/7/2012 6:52:38 PM CHAPTER 8 Bipolar illness 324 Other issues affecting management decisions Speci \201 c clinical features Certain clinica l features will strongly in \202 uence the choice of treatment. For issues of substance mi suse or other psychiatric morbidity these should be addressed directly (see speci \201 c s ections). \200 not uncommon for patients to experience Psychotic symptoms: delusions and/or hallucinations during episodes of mania or depression. Management \200\224mood stabilizer with/without an antipsychotic; consider ECT; if severe consider admission to hospital. Catatonic symptoms: Management \200\224admit to hospital; e xclude medical problem; clarify psychiatric diagnosis; if clear treat with ECT and/or benzo diazepine. assess nature of risk (see b p. 51), note association Risk of suicide: with rapi d cycling mood. If signi \201 cant risk, or unacceptable uncertainty, admit to hospital (o r if in hospital, increase level of observation), consider ECT. Risk of violence: risk with rapid mood cycling, paranoid delusions, agitation, and dysphoria. Admit to hospital, consi der need for secure setting. Substance-related disorders: clinical picture. Substance misus e may lead to relapse both directly and indirectly (by reducing compliance). Equally, alcoh ol consumption may increase when on lithium. Management \200\224address issues of misuse; i f detoxi \201 cation considered, admit to hospital as risk of suicide may be increased. Ot her comorbidities: during a manic episode (manic stupor). assess nature of risk (see b p. 692). Note increased comorbidity is high, often confusing the personality, anxiety or conduct disorder, ADHD. Concurrent medical problems The presence of other medical problems may affect the managemen t either by exacerbating the course or severity of the disorder or by com- plicating drug t reatment (i.e. issues of tolerability and drug interactions). \200 may restrict the choic e of drug Cardiovascular/renal/hepatic disorders: therapy or increase the need for closer monitoring (see b pp. 972 \200\2237). Endocrine disorders: Infectious diseases: CNS side-effects of mo od stabilizers. Use of steroids: \200 e.g. hypo/hyperthyoidism. e.g. HIV-infected patients may be more sensitive to e.g. for treatment of asthma/IBS. Special patient groups \200 Children and adolescents be effective, but long-term effects on development have not been fully studied. Lithium may be excreted more quickly, allowing more rapid dose adjustments, but therapeutic levels are the same as for adults. Risks assoc iated with other adjunctive agents (e.g. antipsychotics, antidepressants, benzodiazepines) should be considered separately. ECT is rarely used, but may be effective. Education, suppo rt, and other (see b p. 657). Lithium has been shown to 08_Semple_Chap08.indd 324 12/7/2012 6:52:38 PM OTHER ISSUES AFFECTING MANAGEMENT DECISIONS 325 speci \201 c psychosocial interventions should be considered (usually involving family, te achers, etc.). (see b p. 521). When a \201 rst manic episode occurs in a The elderly pati ent after age 60, there is usually evidence of previous depressive episodes in their 40s an d 50s. Full physical examination is necessary to exclude medical causes (esp. CNS disorders ). Older patients may be more sensitive to the side-effects of lithium (particularly neurol ogical) and may require lower therapeutic levels (i.e. below 0.7mmol/L). (see b pp. 968 \200\22371). Consider ECT as \201 rst Pregnancy and lactation line for treatment of signi \201 cant manic, depressed, or psychotically depressed episodes. Published guidelines There are now a number of guidelines that can help inform practice inc lud- ing the slightly ageing APA guideline (2002),1 the Scottish SIGN guideline (2005),2 th e UK NICE guideline (2006),3 and the BAP guideline (2009).4 Many UK hospitals are also deve loping Integrated Care Pathways (IntCPs), which will include treatment guidelines based on these, as well as re \202 ect- ing local custom and practice. 1 American Psychiatric Association (2002) Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiat 159(Suppl 4): 1 \200\22350. M http://www.psychiatryonl ine.com/pracGuide/ pracGuideTopic_8.aspx 2 Scottish Intercollegiate Guideline Network (2005 ) Bipolar affective disorder: a national clinical guideline. SIGN 82. M http://www.sign.ac. uk/pdf/sign82.pdf 3 NICE (2006) Bipolar disorder. Transcranial magnetic stimulation for sev ere depression. Clinical Guideline CG38. M http://www.nice.org.uk/nicemedia/live/11327/3839 1/38391.pdf 4 Goodwin GM, Consensus Group of the British Association for Psychopharmacology (2009) Evidence-based guidelines for treating bipolar disorder: revised second edition \200\224recommendations from the British Association for Psychopharmacology. J Psychopharma col 23: 346 \200\22388. M http:// www.bap.org.uk/pdfs/Bipolar_guidelines.pdf 08_Semple_Chap08.indd 325 12/7/2012 6:52:38 PM CHAPTER 8 Bipolar illness 326 Treatment of acute manic episodes For severe behavioral disorder Follow local protocols for management (see b p. 325). Pharmacological interventions should be regarded as separate fr om speci \201 c management of acute mania, although there is a degree of overlap. Evidence supports use of haloperidol and clonazepam, clinical practice the use of chlorpromazine an d lorazepam or diazepam. For severe/life-threatening manic episode (or previous good response/advance statement of p reference) ECT should be strongly considered as 1st line treatment and has been shown to be one of the best treatment options in acute mania.1 Current practice reserves ECT for clini cal situations where pharmacological treat- ments may not be possible, such as pregnancy or severe cardiac disease, or when the patient \200\231s illness is refractory to drug treatm ents. If currently on antidepressant medication Give consideration to reducing, stopping, or swap ping to an alternative medication if manic episode related to commencement or recent dose c hange (or possible compliance issues). Not currently on any treatment The role of antipsychotic treatment Most guidelines recommend use of one of the licensed se cond generation antipsychotics (SGAs) \201 rst line in view of ease of use, rapidity of a ction, and tolerability (see Table 8.2). There is a role for older antipsychot- ics too \200\224a very recent meta-analysis found risperidone, olanzapine, and haloperidol among th e best of the available options for the treatment of manic episodes.2 Lithium or valproic a cid would then be second line unless there is clear evidence of previous bene \201 t. Table 8.2 Licensed antipsychotics (UK). Starting doses and therapeutic ranges (see BNF for further details) Drug Starting dose Therapeutic range Olanzapine 15mg/day 5 \200\22320mg/day Quetiapine 50mg bd 400 \200\223800mg/day Risperidone 2mg/day 1 \200\2236mg/day Aripiprazole 15mg/day 15 \200\22330mg/day Asenapine 10mg bd 10 \200\22320mg/day If already on valproic acid or lithium \200 Ensure compliance and therapeutic dose. \200 Consider adding antipsychotic treatment. 08_Semple_Chap08.indd 326 12/7/2012 6:52:38 PM TREATMENT OF ACUTE MANIC EPISODES 327 If already on antipsychotic medication \200 Ensure compliance and therapeutic dose. \200 Consider adding lithium or valproate. Treatment notes \200 (see b p. 336): remains a \201 rst-line option for acute mania, Lithium with a response r ate of around 80%. Note: Up to 2wks of treatment may be necessary to reach maximal effectiv eness for manic patients. Due to this delayed effect, esp. for severe mania or psychotic sy mptoms, with associated acute behavioral disturbance, addition of an antipsychotic or a ben zodiazepine usually required (see Benzodiazepines). \200 Predictors of good response: with medication, >3 previous episodes, FHx of mood disorder, e uphoria (not dysphoria), lack of psychotic symptoms or suicidal behavior. previous response to lithium, compliance (see b p. 342): also effective in the treatment of acute Valproate mania. Well tolerated and has very few drug interactions, making it more suitable for combined treatment regimes. May also work faster than lithium, but not suitable for wo men of child-bearing age. \200 Predictors of good response: may be more effective in particular patients e.g. \200\230rap id cycling \200\231 \200\224where some consider it \201 rst line, dysphoric mania, mixed episodes, stable or decreasing frequency of manic episodes, or less severe forms of bipolar spectrum disorders. Benzodiazepines: doses just to achieve suf \201 cient sedation. Clonazepam and lorazepam a re most widely studied, alone or in combination with lithium, (see b p. 346): or its deriva tive, oxcarbazepine, Carbamazepine may be effective, either alone or in combination with li thium or antipsychotics.3 May be better tolerated in patients with comorbid drug or alcohol problems, obesity, or women of child-bearing age. previous response to carbamazepine, \200 may reduce the need for using high antipsychotic Predictors of good response: poor compliance (due to wide therapeutic window), absence of p sychotic symptoms, secondary mania (e.g. drug-induced, neurological disorder, brain injury) , dysphoria, \200\230mixed \200\231 episode, rapid cycling, episode part of schizoaffectiv e disorder. Other anticonvulsants: there is no current evidence to recommend use of any other anticonvu lsant. The strongest evidence is for lamotrigine (see b p. 331 and b p. 348), but in depres sive episodes, not mania or hypomania. Topiramate has shown some promise in both depressed and manic bipolar patients, with the added bene \201 t of promoting weight loss. Overall, however, the evidence is still very limited. 1 Mukherjee S, Sackeim HA and Schnur DB (1994) Electroconvulsive therapy of acute manic epi - sodes: a review of 50 years \200\231 experience. Am J Psychol 151: 169 \200\22376. 2 Cipr iani A, Barbui C, Salanti G, et al. (2011) Comparative ef \201 cacy and acceptability of a ntimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 378: 1306 \200 \22315. 3 McElroy SL and Keck PE Jr (2000) Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiat 48: 539 \200\22357. 08_Semple_Chap08.indd 327 12/7/2012 6:52:38 PM CHAPTER 8 Bipolar illness 328 Treatment of depressive episodes Bipolar depression occurs more frequently, lasts longer, i s more disruptive and is associated with greater risk of suicide than mania. Yet until rece ntly research has focused more on treatment of mania and prophylaxis. The pharmacological t reatment of depressive episodes in bipolar disorder rep- resents a particular challenge.1. Although almost all of the antidepressants used in the treatment of unipolar depression are effective in the treatment of bipolar depression, the response rates are lower and there i s the risk of precipitating a manic episode or inducing/accelerating rapid cycling.2 When s ymptoms are mild to moderate, consider combining pharmacological and psychological interven tions (as for unipolar depression, b p. 252). If patient is already on prophylaxis \200 \200 \200 Optimize (ensure compliance), check serum levels. Exclude/treat associated problems (e.g. h ypothyroidism). Review need for other medications that may lower mood. Consider other condi tions that may mimic or cause depression ( b p. 248). Consider adding SSRI (in conjunction with prophylaxis). If not on antipsychotic then consider addition of quetiapine instead of SSRI (see Treatment notes b p. 328). \200 If evidence of recent mood instability (manic/hypomanic episodes and depression) \200 \200 1st line: 2nd line: increase or (re)commence antimanic agent. consider using lamotrigine. If no response to SSRI \200 Consider alternative antidepressant, e.g. mirtazapine, venlafaxine; or augmentation strateg ies (see Treatment notes b p. 328). Consider addition of quetiapine or olanzapine if not cu rrently on an antipsychotic (see Treatment notes b p. 328). For severe/life-threatening depressive episode (or previous good response/advance statement of preference) \200 ECT should be strongly considered as 1st line treatment. \200 Alth ough well established for treatment of unipolar depressive disorder, ECT in bipolar disorde r has not been fully researched, but should not be overlooked (esp. severe cases). Take car e if the patient is on prophylaxis (see b p. 287). Following remission of depressive symptoms \200 \200 Taper antidepressants after 8wks of maintenance treatment. Continue mood stabilizer to prev ent relapse. Treatment notes \200 Choice of antidepressant: although evidence is scarce, recent studies have suggested that t he SSRIs may be better tolerated, work more quickly, and have a lower associated risk of in ducing mania or rapid cycling compared to tricyclic antidepressants.3 In general, choice wi ll depend on issues of previous response, side-effects (both desired 08_Semple_Chap08.indd 328 12/7/2012 6:52:38 PM TREATMENT OF DEPRESSIVE EPISODES 329 and undesired), and tolerability issues (see b p. 266). As second-line treatment, an antide pressant may be better tolerated than a second mood stabilizer. The role of antipsychotics: quetiapine is licensed to treat depression in bipolar disorder (50mg nocte day 1, 100mg da y 2, 200mg day 3, 300mg day 4; adjust according to response, usual dose 300mg nocte; max. 6 00mg daily). Ef \201 cacy has been demonstrated in 2 robust RCTs (BOLDER 1 & 2) and the EM BOLDEN I & II replication trials.4 Olanzapine, as an olanzapine \200\223 \202 uoxetine com bination (OFC), is licensed for bipolar depression in the USA as Symbyax (6/25, 6/50 or 1 2/50mg/day). Not licensed for bipolar depression in the UK, but licensed for mania and prop ylaxis. Recommended as 2nd line after SSRIs in NICE (CG38, 2006) guidelines (see b p. 325). Preliminary data suggest aripiprazole (15mg/day) may also be used. Other anticonvulsants: recent meta-analysis supports monotherapy with lamotrigine (licensed in USA, but not in UK; see b p. 348), particularly for treatment-refractory bipolar depression.5 Gabapentin appea rs much less effective. Controlled clinical trials comparing standard treatments for depres sion in patients with bipolar disorder are lacking. It is a widely accepted practice to add a second mood stabilizer to the treatment regimens of patients with bipolar disorder (e.g. carbamazepine or valproate). Be alert for evidence of lithium toxicity, even at \200\230n ormal \200\231 serum levels (see b p. 339). other suggested strategies Alternative strategi es/treatment resistance: include: the use of adjunctive tri-iodothyronine (T3) \200\224even if there is no evidence of clinical hypothyroidism;6 and the novel use of inositol.7 Evide nce for omega-3 fatty acids is equivocal at best. For treatment- resistant depressive episo des, principles of management are as for unipolar depression (see b p. 260). 1 Hirschfeld RM (2004) Bipolar depression: the real challenge. Eur Neuropsychopharmacol 14 (Suppl 2): S83 \200\2238. 2 Compton MT, Nemeroff CB (2000) The treatment of bipolar depress ion. J Clin Psychiat 61 (Suppl): 57 \200\22367. 3 Nemeroff CB, Evans DL, Gyulai L, et al. ( 2001) Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treat ment of bipolar depression. Am J Psychol 158: 906 \200\22312. 4 For a review of the studies see: Bogart GT, Chavez B (2009) Safety and ef \201 cacy of quetiapine in bipolar depressi on. Ann Pharmacother 43: 1848 \200\22356. 5 Geddes JR, Calabrese JR, Goodwin GM (2009) Lamo trigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from \201 ve randomized trials. Br J Psychiat 194: 4 \200\2239 . 6 Bauer M, Berghofer A, Bschor T, et al. (2002) Supraphysiological doses of L-thyroxine i n the maintenance treatment of prophylaxis-resistant affective disorders. Neuropsychopharma col 27: 620 \200\2238. 7 Chengappa KN, Levine J, Gershon S, et al. (2000) Inositol as an ad d-on treatment for bipolar depression. Bipolar Disord 2: 47 \200\22355. 08_Semple_Chap08.indd 329 12/7/2012 6:52:39 PM CHAPTER 8 Bipolar illness 330 Prophylaxis Primary aim Prevention of recurrent episodes (mania, hypomania, or depression). Suicide prevention Patients with bipolar disorder represent a group at high risk of suicide . Retrospective and prospective studies do suggest that long-term lithium therapy reduces t he risk of suicide. There is still little data available on the anti-suicidal effects of ot her prophylactic treatments. Indications Following effective remission of acute symptoms of mania or bipolar depression; also recommended in bipolar II disorder. Procedure following remission of acute symptoms of mania or depression \200 Ensure therapeutic dose of mood stabilizer/optimal balance of risk \200\223bene \201 t for any antipsychotic medication. Withdraw gradually any additional antipsychotic or benzodiaz epine used to manage acute symptoms. When euthymia achieved following depressive episode, c onsider tapering antidepressant after 8wks. Continue monitoring of side-effects, blood leve ls and physical checks as per protocols for individual agents (see b pp. 336 \200\22349). Guiding principles \200 \200 Manage with lowest dose necessary of any maintenance medication. Aim for single agent if po ssible; most will require mood stabilizer + low-dose antipsychotic or mood stabilizer + ant idepressant. Off-license use of valproate or antipsychotic may be justi \201 ed in the mai ntenance phase if there is good evidence of bene \201 t in acute phase management (i.e. co ntinuation is not unreasonable, perhaps at a lower dose, and few medications are licensed). \200\230Wait and see \200\231 policy for possible bipolar II disorder where use of mood s tabilizer may prevent more serious later episodes should be discussed with the patient in l ight of detailed clinical interview (esp. high genetic risk), since treatments themselves a re not without risks (evidence supports possible use of quetiapine or lamotrigine in this r egard but these are off-license indications). Licensed treatments \200 (b p. 336): to date, remains the \201 rst-line choice for Lithium maintenance treatment i n patients1 especially with a \200\230classical \200\231 course of illness. Some subtypes of what has become known as the \200\230bipolar spectrum \200\231 may not respond as well to lithium. These include patients with mixed mania (i.e. depressive symptoms during manic episodes) and patients with rapid cycling mania. Emerging evidence would seem to suggest a role for anticonvulsants in these patients. 08_Semple_Chap08.indd 330 12/7/2012 6:52:39 PM PROPHYLAXIS 331 (see b p. 342): appears to be effective in the Carbamazepine long-term treatment of bipolar disorder, with an overall response rate of 63% . Although it does not have worldwide approval as yet, carbamazepine may be more effective in the treatment of bipolar spectrum than classical bipolar disorder. Aripiprazole manageme nt of acute mania (15 \200\22330mg/day). Quetiapine: only licensed for continuation therapy when effective for management of acute mania or bipolar depression (300 \200\223800mg/day) . : only licensed for continuation therapy when effective for Unlicensed treatments \200 Valproate/valproic acid in rapid cycling bipolar disorder and the added con \201 dence of being the most widely prescribed therapy for bipolar depressio n, although unequivocal evidence of successful prophylaxis has not yet emerged. Indeed, the recent BALANCE study showed that both combination therapy (lithium plus valproate) and lit hium monotherapy are more likely to prevent relapse than valproate monotherapy.2 Lamotrigin e studies for prevention of depression and, to a lesser extent, mania following discontinua tion of other psychotropic medications.3 Other anticonvulsants: ef \201 cacy of oxcarbazep ine, topiramate, gabapentin, and tiagabine, but the evidence is relatively weak. Other anti psychotics: alone or in combination with lithium or valproate. Risperidone may also have an adjunctive or maintenance role. Older antipsychotics, including depots (usually low dose), are almost certainly effective but evidence is (unfortunately) lacking. Alternative/augmen tative agents: may have some clinical utility include: Ca2+ channel antagonists such as ver apamil, nifedipine, and nimodipine; thyroid hormones; tamoxifen; omega-3 fatty acids; and e ven vitamin/mineral supplements. (see b p. 346): has demonstrated ef \201 cacy (see b p. 348): ef \201 cacy established in a pair of controlled there have been promising reports on the olanzapine also appears to be effective either a number of other compounds that Risks of discontinuation Substantial evidence exists that abrupt discontinuation of lithium is associ- ated with an increased risk of relapse. The risk, particularly of mania, may be minimized by gradually reducing the lithium dose. Although compara- ble studies are not av ailable for the anticonvulsants or SGAs, a similarly cautious approach would seem advisable . 1 Kessing LV, Hellmund G, Geddes JR, et al. (2011) Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort stud y. Br J Psychiat 199: 57 \200\22363. 2 BALANCE investigators and collaborators (2010) Lithi um plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open- label trial. Lancet 375: 385 \200\22395. 3 Goodwin GM, Bowden CL, Calabrese JR, et al. (2004) A pooled analysis of 2 placebo-controlled 18-mo nth trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiat 65 : 432 \200\22341. 08_Semple_Chap08.indd 331 12/7/2012 6:52:39 PM CHAPTER 8 Bipolar illness 332 Psychotherapeutic interventions Most patients will struggle with some of the following issu es: \200 Emotional consequences of signi \201 cant periods of illness and receiving the diagnosis o f a chronic psychiatric disorder. Developmental deviations and delays caused by past episod es. Problems associated with stigmatization. Problems related to self-esteem. Fear of recur rence and the consequent inhibition of normal psychosocial functioning. Interpersonal dif \201 culties. Issues related to marriage, family, child-bearing, and parenting. Academic an d occupational problems. Other legal, social, and emotional problems that arise from illnes s- related behaviors. \200 \200 \200 \200 \200 \200 For some patients, a speci \201 c psychotherapeutic intervention (in addition to usual psy chiatric management and social support) will be needed to address these issues. Approaches include: psychodynamic, interpersonal, behavioral, and cognitive therapies. In addition, co uple, family, and group therapy may be indicated for some patients. The selection of approp riate interventions is in \202 uenced by the local availability of such treatments, as wel l as the patient \200\231s needs and preferences. Key elements of selected interventions1 \200 2 key component to most therapies, psychoeducation Psychoeducation: goes further than simply delivering information, and does appear to reduce recurrence and relapse. Patients are given a theoretical and practical approach to underst and their illness and the medication they are prescribed. Through understanding, patients c an attain improved adherence to medication, recognize symptoms that might lead to decompens ation, and recover occupational and social function. CBT: 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 . 4 to reduce lability of Interpersonal and social rhythm therapy (IPT/SRT): mood by mainta ining a regular pattern of daily activities, e.g. sleeping, eating, physical activity, and emotional stimulation. Evidence suggests IPT/SRT should be initiated immediately following an acute episode when individuals are most likely to make the lifestyle changes required to achieve social rhythm stability. Family-focused therapy (FFT): (of patient and family memb ers) with speci \201 c aims: accepting the reality of the illness, identifying precipitati ng stresses and likely future stresses inside and outside the family, elucidating family in teractions that produce stress on the patient, planning strategies for managing and/or mini mizing future stresses, and bringing about the patient \200\231s family \200\231s acceptanc e of the need for continued treatment. Bene \201 ts 3 time-limited, with speci \201 c aims: educate the patient about bipolar 5 usually brief, includes psychoeducation 08_Semple_Chap08.indd 332 12/7/2012 6:52:39 PM PSYCHOTHERAPEUTIC INTERVENTIONS 333