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 more pronounced in depressed patients and in those living in a high- expressed emotional en vironment. Support groups: May provide useful information about bipolar disorder and its tr eatment. Patients may bene \201 t from hearing the experiences of others, struggling with similar issues. This may help them to see their problems as not being unique, understand th e need for medication, and access advice and assistance with other practical issues. In the UK, groups such as the Manic Depression Fellowship, MIND, and SANE provide both support an d educational material to patients and their families (see b p. 1010). \200\230At this point in my existence, I cannot imagine leading a normal life without both taking lithium and having had the bene \201 ts of psychother- apy. Lithium prevents my se ductive but disastrous highs, diminishes my depressions, clears out the wool and webbing fr om my disordered think- ing, slows me down, gentles me out, keeps me out of a hospital, ali ve, and makes psychotherapy possible. But, ineffably, psychotherapy heals. It makes some se nse of the confusion, reins in the terrifying thoughts and feelings, returns some control a nd hope and possibility of learning from it all. Pills cannot, do not, ease one back into r eality; they only bring one back headlong, careening, and faster than can be endured at tim es. Psychotherapy is a sanctuary; it is a battleground; it is a place I have been psychotic , neurotic, elated, confused, and despairing beyond belief. But, always, it is where I have believed or have learned to believe \200\223 that I might someday be able to contend with all of this. No pill can help me deal with the problem of not wanting to take pills; likew ise, no amount of psychotherapy alone can prevent my manias and depressions. I need both. I t is an odd thing, owing life to pills, one \200\231s own quirks and tenaci- ties, and this unique, strange, and ultimately profound relationship called psychotherapy. \200\231 Dr Kay Red \201 eld Jamison (1996) An unquiet mind: a memoir of moods and madness, pp. 88 \200\2239. London: Picador 1 Vieta E, Pacchiarotti I, Scott J, et al. (2005) Evidence-based research on the ef \201 c acy of psychologic interventions in bipolar disorders: a critical review. Curr Psychiatry R ep 7: 449 \200\22355. 2 Colom F, Vieta E, Martinez-Aran A, et al. (2003) A randomized trial on the ef \201 cacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiat 60: 402 \200\2237. 3 Lam DH, Wat kins ER, Hayward P, et al. (2003) A randomized controlled study of cognitive therapy for re lapse prevention for bipolar affective disorder: outcome of the \201 rst year. Arch Gen P sychiatry 60:145 \200\22352. 4 Frank E, Kupfer DJ, Thase ME, et al. (2005) Two-year outcome s for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiat 62: 996 \200\2231004. 5 Miklowitz DJ, George EL, Richards JA, et al. (2003) A randomized study of family-focused psy- choeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiat 60: 904 \200\22312. 08_Semple_Chap08.indd 333 12/7/2012 6:52:39 PM CHAPTER 8 Bipolar illness 334 Cyclothymia Previously regarded as a disorder of personality ( \200\230cyclothymic tempera- ment \200\231 \200\224see Box 8.6) mainly because of its early age of onset and rela- tive stability throughout adult life, cyclothymia is now considered to be a mood disorder.1 Clinical features \200 Persistent instability of mood, numerous periods of mild depression and mild elation, not s uf \201 ciently severe or prolonged to ful \201 l the criteria for bipolar affective diso rder or recurrent depressive disorder. The mood swings are usually perceived by the individ ual as being unrelated to life events. The diagnosis is dif \201 cult to establish without a prolonged period of obser- vation or an unusually good account of the individual \200\231s past behavior. In DSM-IV the symptom s must have been present for at least 2yrs, with no period lasting longer than 2mths in whi ch they have been at a normal state. No mixed episodes may have occurred. Epidemiology \200 Prevalence: \200 Age of onset: may present later in life. Commoner in relatives of patients with bipolar affective disorder. 3 \200\2236% of general population. usually early adulthood (i.e. teens or 20s), but sometimes Differential diagnosis Bipolar affective disorder, recurrent depressive disorder, drug or a lco- hol misuse, ADHD, conduct disorder, personality disorder (emotionally unstable), medic al conditions (see b p. 307). Course Onset often gradual, making it dif \201 cult to pinpoint when symptoms began. Alter nating ups and downs may \202 uctuate in hours, weeks, or months. Because mood swings are relatively mild and periods of mood elevation may be enjoyable (with increased activity an d productivity, self-con \201 dence, and sociability), cyclothymia frequently fails to com e to medical attention. Person may often present either because of the impact of the depres sive episodes on social and work situations, or because of problems related to comorbid dru g or alcohol misuse. Usually runs a chronic course, persist- ing throughout adult life. In some cases symptoms may cease temporarily or permanently, or develop into more severe mood swings meeting the criteria for bipolar affective disorder or recurrent depressive disorder . Management \200 If pharmacological treatment is contemplated this usually consists of a trial of a mood sta bilizer (e.g. lithium, low dose 600 \200\223900mg/day). 08_Semple_Chap08.indd 334 12/7/2012 6:52:39 PM CYCLOTHYMIA 335 Recently there has been a tendency to use anticonvulsants, such as valproate (500 \200\2237 50mg/day), carbamazepine, or lamotrigine, as these may be better tolerated. As yet there is no clear evidence to suggest any of these approaches is superior. At times of \200\230cri sis \200\231 due to temperamental excesses a short course of a low-dose sedating antipsycho tic (e.g. chlorpromazine 50mg nocte; risperidone 1mg nocte; olanzapine 2.5mg nocte; quetiap ine 25 \200\22350mg nocte) may be helpful. Psychoeducation and insight-orientated psychothe rapy may help the person to understand the condition, and allow them to develop better ways of coping. There is often a reluctance to continue to take medication as this not only tre ats the depressive episodes, but also may be perceived as \200\230blunting \200\231 creati vity, productivity, or intellectual capacity. Box 8.6 Kraepelin \200\231s \200\230cyclothymic temperament \200\231 These are the people who constantly oscillate hither and thither between the two opposite p oles of mood, sometimes \200\230rejoicing to the skies \200\231, sometimes \200\230sad as death \200\231. Today lively, sparkling, beaming, full of the joy of life, the pleasure of enterprise, and the pressure of activity, after some time they meet us depressed, enervate d, ill-humored, in need of rest, and again a few months later they display the old freshnes s and elasticity. Kraepelin E (1896) Manic-depressive insanity and paranoia. (Extract from translation of the 8th edn of Kraepelin \200\231s textbook Psychiatrie) Box 8.7 Schneider 1958 \200\230(Kurt) Schneider (1958, in Psychopathic Personalities) admonished the kin of labil e individuals (who might approximate what we might diagnose today as cyclothymia with borde rline personality features) \200\234on their bad days to keep out of their way as fa r as possible \200\235 (p. 121). Cyclothymes, with some insight into their own temperament, would give the same advice to their loved ones. Cautious trial of anticonvulsants will oft en prove effective in those distressed enough by their behavior as to com- ply with such tr eatment. \200\231 Extract from Akiskal HS (2001) Review article: dysthymia and cyclothymia in psychiatric pra ctice a century after Kraepelin. J Affect Disord 62: 17 \200\22331. 1 When Kahlbaum (1863) introduced the term \200\230cyclothymia \200\231 into modern psychi atry, he described it as the mildest form of manic \200\223depressive disease. Kraepelin (1 896) treated it the same way (see Box 8.6), but Schneider (1958) used the term cyclothymia synonymously with manic \200\223depressive disease. He described and conceptualized the \200\230labile psychopath \200\231 as a personality disorder (see Box 8.7) as distinct from manic \200\223depressive illness. Classi \201 cation systems no longer re \202 ect Schne ider \200\231s view and both DSM-IV-TR and ICD-10 include cyclothymia within the affective (mood) disorders. Debate continues regarding the interface between such subthreshold affect ive conditions, person- ality, and temperament (see also b p. 312 and b p. 318). 08_Semple_Chap08.indd 335 12/7/2012 6:52:39 PM CHAPTER 8 Bipolar illness 336 Lithium Despite problems with tolerability, lithium1 still remains the gold standard in the treatment of bipolar affective disorder. The effectiveness of long- term treatment with li thium is supported by at least 9 controlled, double- blind studies,2 far exceeding the avai lable support for other alternatives to lithium treatment, although the last decade has see n an emerging literature supporting the use of anticonvulsant, antipsychotic, or sedative a gents. Mode of action Uncertain numerous effects on biological systems (particularly at high con- centrations). Lithium can substitute for Na2+, K+, Ca2+, Mg2+ and may have effects on cell membrane electrophysiology. Within cells, lithium inter- acts with systems involving other cations, including the release of neuro- transmitters and 2nd messenger systems, (e.g. aden ylate cyclase, inositol 1,4,5,-triphosphate, arachidonate, protein kinase C, G proteins and cal- cium), effectively blocking the actions of transmitters and hormones. Also reduction in receptor up-regulation, perhaps explaining lithium \200\231s value as an adjunctive trea tment. Interactions \200 Increased plasma concentration (risk of toxicity even at therapeutic serum levels): ACE inh ibitors/angiotensin-II receptor antagonists, analgesics (esp. NSAIDs), antidepressants (esp . SSRIs), anti-epileptics, antihypertensives (e.g. methyldopa), antipsychotics (esp. halope ridol), calcium-channel blockers, diuretics, metronidazole. Decreased plasma concentration (risk of decreased ef \201 cacy): theophylline. Other interactions: of hypothyroidism), an tidiabetics (may sometimes impair glucose tolerance), antipsychotics (increased risk of EPS Es), muscle relaxants (enhanced effect), parasympathomimetics (antagonizes neostigmine and pyridostigmine). antacids, anti-arrhythmics (e.g. amiodarone: increased risk Guidelines on lithium therapy (Box 8.8)3 \200 Prior to commencing lithium therapy: TFTs, renal function (eGFR), baseline weight and heigh t (BMI), if clinically indicated \200\224ECG, pregnancy test. Starting dose: depending on s erum monitoring to max 2g (usual dose 800mg \200\2231.2g) \200\224 actual dose depends upon preparation used (molar availability varies even when amounts (mg) are the same (see Table 8.3). Monitoring: each change of dose. Take blood samples 12hr post-dose. Once a therapeut ic serum level lithium level/eGFR every 3mths, TFTs every 6mths, monitor weight (BMI), and check for side-effects (see b p. 338). physical examination, FBC, U&Es, usually 400 \200\223600mg given at night, increased weekly check lithium level 7 days after starting and 7 days after 4 has been established: continue to check 08_Semple_Chap08.indd 336 12/7/2012 6:52:39 PM LITHIUM 337 reduce gradually over 1 \200\2233mths, particularly if patient has Stopping: history of man ic relapse (even if started on other anti-manic agent). Box 8.8 Safer lithium therapy The UK National Patient Safety Agency (NPSA) issued a Patient Safety Alert (NPSA/2009/PSA00 5) on safer lithium therapy. This was in response to reports of harm caused to patients, in cluding fatalities, by lithium therapy and was developed in collaboration with the Prescrib ing Observatory for Mental Health (POMH-UK) of the RCPsych, the National Drugstore Associat ion (NPA), other organizations, clinicians, and patients. It was designed to help NHS organ izations, including com- munity pharmacies, in England and Wales (and latterly Scotland) to take steps to minimize the risks associated with lithium therapy. The follow- ing recommen dations were made: \200 \200 Patients should be monitored in accordance with NICE guidelines. There are reliable systems to ensure blood test results are communicated between laboratories and prescribers. Throug hout their treatment patients receive appropriate ongoing verbal and written information an d complete a record book.* Prescribers and pharmacists check that blood tests are monitored regularly and that it is safe to prescribe and/or dispense lithium. Systems are in place t o identify and deal with medicines that might adversely interact with lithium therapy. The NPSA patient information booklet, lithium alert card and record book for blood tests ca n be downloaded from the RCPsych website: M http://www.rcpsych.ac.uk/quality/ quality,accre ditationaudit/prescribingobservatorypomh/saferlithiumtherapy.aspx Table 8.3 Lithium preparations (UK) Preparation Active component Available strengths Camcolit (tablets) Lithium carbonate 250/400mg (scored) Li-liquid (oral solution) Lithium citrate 509mg/5mL Liskonum (tablets) Lithium carbonate 450mg (scored) Priadel (tablets) Lithium carbonate 200/400mg (scored) Priadel (liquid) Lithium citrate 520mg/5mL 1 The use of lithium salts in the treatment of \200\230psychotic excitement \200\231 is us ually credited to John Cade in 1949 (Med J Aust 2: 349 \200\22352). However, this was a \200\230rediscovery \200\231 of the use of lithium to treat \200\230insanity \200\231 \201 rst described by Hammond WA, in 1871 (in A treatise on diseases of the nervous system. New York: Appleton, pp. 325 \200\22384). 2 Burgess S, Geddes J, Hawton K, et al. (2001) Li thium for maintenance treatment of mood disor- ders. Cochrane Database System Rev 3: Art. n o.: CD003013. 3 NICE (2006) Guideline on bipolar disorder, CG38, including guidance on init iating, monitoring, stopping, and other risks associated with lithium therapy. 4 NICE sugge sts lithium levels between 0.6 \200\2230.8 mmol/L when prescribed for the \201 rst time. Those who have relapsed on lithium, or who still have subthreshold symptoms with functional impairment while on lithium, may warrant a trial of at least 6mths with levels between 0.8 \200\2231.0 mmol/L. 08_Semple_Chap08.indd 337 12/7/2012 6:52:39 PM CHAPTER 8 Bipolar illness 338 Lithium: adverse effects As lithium is a highly toxic ion, safe and effective therapy requi res monitor- ing of serum levels. Up to 75% of patients treated with lithium will experi- e nce some side-effects.1 Dose-related side-effects Polyuria/polydipsia (reduced ability to concentrate urine due to antidiuretic hormone [ADH] antagonism), weight gain (effects on carbohydrate metabolism and /or oedema), cognitive problems (e.g., dulling, impaired memory, poor concentration, confus ion, mental slowness), tremor, seda- tion or lethargy, impaired co-ordination, GI distress (e.g., nausea, vomiting, dyspepsia, diarrhea), hair loss, benign leukocytosis, acne, and oe dema. Management Usually dealed with by lowering the dose of lithium, or altering the dose schedu le or formulation. If side-effects persist, additional medications may be necessary, e.g. B -blockers (tremor), thiazide or loop diuretics ( polyuria, polydipsia or oedema), topical a ntibiotics or retinoic acid (acne). GI prob- lems can be managed by administering lithium w ith meals or switching lithium preparations, such as lithium citrate. Cardiac conduction problems Usually benign ECG changes (e.g. T-wave changes, widening of QR S). Rarely, exacerbation of existing arrhythmias or new arrhythmias due to conduction de \201 cits at the sinoatrial (SA) or atrioventricular (AV) nodes (contraindicated in heart f ailure, sick sinus syndrome). Long-term effects Renal function 10 \200\22320% of patients on long-term therapy demonstrate morphologi- cal kidney changes (interstitial \201 brosis, tubular atrophy, and sometimes glomerular scler osis). >1% may develop irreversible renal failure (rising serum creatinine) after 10yrs or more of treatment. If urea and creatinine levels become elevated, assess the rate of deteri oration (see b p. 476); the decision whether to continue lithium depends on clinical ef \201 cacy and degree of renal impairment; seek advice from a renal specialist and a clini- cian with expertise in the management of bipolar disorder. Subclinical/clinical hypothyroidism 5 \200\22335%, more frequent in women, tends to appear after 6 \200\22318mths of treat- ment, and may be associated with rapid cycling bipolar dis order. Although lithium-induced hypothyroidism is generally reversible on discontinuation, it does not constitute an absolute contraindication for continuing lithium treatment as the associated hypothyroidism is readily treated with lev- othyroxine.2 It is worth noting tha t, in addition to the classic signs and symptoms of hypothyroidism, patients with bipolar d isorder are also at 08_Semple_Chap08.indd 338 12/7/2012 6:52:39 PM LITHIUM: ADVERSE EFFECTS 339 risk of developing depression and/or rapid cycling as a consequence of suboptimal thyroid f unctioning. Should these symptoms occur and subop- timal thyroid functioning be con \201 r med, thyroid supplementation with or without lithium discontinuation is the treatment of ch oice. Teratogenicity (see b p. 968) The much-quoted 400-fold increased risk of Ebstein \200 \231s anomaly (a congeni- tal malformation of the tricuspid valve) due to 1st trimester lit hium expo- sure now appears to be substantially less than \201 rst reported \200\224at mo st an eight-fold relative risk.3 Other reported 2nd and 3rd trimester problems include poly hydramnios, premature delivery, thyroid abnormalities, neph- rogenic diabetes insipidus, an d \202 oppy baby syndrome. The estimated risk of major congenital anomalies for lithium-e xposed babies is 4 \200\22312% com- pared with 2 \200\2234% in untreated control groups. Management A balance needs to be struck between the risks of teratogenicity and the risks o f relapse following discontinuation:3 \200 Mild, stable forms of bipolar disorder: stoppe d pre-pregnancy. Moderate risk of relapse: during the \201 rst trimester (4 \200\22312wks after last menstrual period). Severe forms of bipolar disorder, who are at high risk of re lapse: should be maintained during pregnancy (with informed consent, appropriate counseling , prenatal diagnosis, and detailed ultrasound and echocardiography at 16 \200\22318wks gest ation). lithium may be tapered down and lithium should be tapered and discontinued lithium Toxicity The usual upper therapeutic limit for 12-hr post-dose serum lithium level is 1.2mm ol/L. With levels >1.5mmol/L most patients will experience some symptoms of toxicity; >2.0m mol/L de \201 nite, often life-threatening, toxic effects occur. There is often a narrow t herapeutic window where the bene \201 cial effects outweigh the toxic effects (esp. in old er patients). Early signs and symptoms Marked tremor, anorexia, nausea/vomiting, diarrhea (sometimes bloo dy), with dehydration and lethargy. As lithium levels rise Severe neurological complications \200\224restlessness, muscle fasci culation/myoclonic jerks, choreoathetoid movements, marked hypertonicity. This may progress to ataxia, dysarthria, increased lethargy, drowsiness, and confusion/delirium. Hypotension and cardiac arrhythmias precede circulatory collapse, with emerging seizures, stupor, and eventual coma (high risk of permanent neurological impairment or death). 08_Semple_Chap08.indd 339 12/7/2012 6:52:40 PM CHAPTER 8 Bipolar illness 340 Management \200 Education of patients (methods of avoiding toxicity, e.g. maintaining hydration and salt in take, and being alert to early signs and symptoms). Careful adjustment of dosage may be all that is required. In severe toxicity (e.g. following OD), rapid steps to reduce serum lith ium level are urgently necessary. This may involve forced diuresis with intravenous isotoni c saline, or in cases where toxicity is severe or accompanied by signi \201 cant renal fai lure, haemodialysis. Review need for prophylaxis (see \200 b p. 330). 1 Goodwin FK, Jamison KR (1990) Manic-depressive illness. Oxford: Oxford University Press. 2 Bocchetta A, Bernardi F, Pedditzi M, et al. (1991) Thyroid abnormalities during lithium t reatment. Acta Psychiatr Scand 83: 193 \200\2238. 3 Cohen LS, Friedman JM, Jefferson JW, et al. (1994) A reevaluation of risk of in utero exposure to lithium. J Am Med Ass 271: 146 \200\22350. 08_Semple_Chap08.indd 340 12/7/2012 6:52:40 PM This page intentionally left blank CHAPTER 8 Bipolar illness 342 Valproate/valproic acid In the UK, despite the widespread use of sodium valproate as a mood sta- bilizer, the only licensed preparation for bipolar affective disorder contains valpro ic acid as semisodium valproate (Depakote ). There are no pub- lished placebo-control tria ls of the ef \201 cacy of sodium valproate in bipolar affective disorder \200\224despite d ata being published on tolerability (suggesting GI side-effects are less with Depakote ). Psychiatric indications \200 \200 b p. 326. Acute mania (up to 56% effective); see Acute depressive episode (in bipolar affective disor der) in combination with an antidepressant. Data limited; see b p. 328. Prophylaxis of bipo lar affective disorder \200\224possibly more effective in rapid cycling; see b p. 330. Mode of action Uncertain. Modulates voltage-sensitive Na channels, acts on second- messenge r systems, and increases bioavailability of GABA (or mimics action at post-synaptic recepto r sites) in the central nervous system. Pharmacokinetics Sodium valproate is available in tablet, liquid, solution, syrup, enteric- coated, and MR forms. Semisodium valproate (Depakote ) comes as enteric-coated tablets co ntaining valproic acid and sodium valproate. They are both rapidly absorbed when taken oral ly (peak serum level for sodium valproate 2hr; semisodium valproate 3 \200\2238hr) with a plasma half-life of 6 \200\22316hr (see Box 8.9 and Table 8.4). Interactions \200 Raised serum levels with phenobarbital, phenytoin, and antidepressants (TCAs, \202 uoxeti ne). Decreased serum levels with carbamazepine. Toxicity may be precipitated by other highl y protein-bound drugs (e.g. aspirin), which can displace valproate from its protein-binding sites. \200 Side-effects and toxicity \200 Dose-related side-effects: vomiting, diarrhea), raised LFT s, tremor, and sedation \200\224if persistent, may require dose reduction, change in prepar ation, or treatment of speci \201 c symptoms (e.g. B-blocker for tremor; H2-blocker for dy spepsia). Unpredictable side-effects: thrombocytopenia (reversible upon drug reduction/disc ontinuation), hair loss (usually transient), increased appetite, and weight gain. Rare, idi osyncratic side-effects: agranulocytosis, polycystic ovaries/hyperandrogenism. Toxicity/ove rdose: wide therapeutic window; hence, unintentional overdose is uncommon. Signs of overdos e include somnolence, heart block, eventually coma, and even death (haemodialysis may be ne eded). GI upset (anorexia, nausea, dyspepsia, mild, asymptomatic leukopenia and irreversible hepatic failure, pancreatitis, 08_Semple_Chap08.indd 342 12/7/2012 6:52:40 PM VALPROATE/VALPROIC ACID 343 Box 8.9 Treatment guidelines for sodium valproate \200 Full medical history (particularly liver disease, hematological problems, and bleeding diso rders)/full physical examination; check FBC, LFTs, baseline ECG, weight/height (BMI). Sodiu m valproate: tds), increase every few days or every week by 200 \200\223400mg/day according to response and side-effects, up to a maximum of 2500mg/ day, or until serum levels are 50 \200\223125mmol/L (see Table 8.4). Usual maintenance dose 1 \200\2232g/day. Valproic acid as semisodium valproate: start with 250mg tds (or up to 20mg/kg for acute manic episode) an d increase every few days or every week by 250 \200\223500mg/day to a maximum of 2000mg/day , or until serum levels are 50 \200\223125mmol/L (see Table 8.4). Usual maintenance dose 10 00 \200\2232000mg/day. Once the patient is stable, simplify regime. If GI upset is a proble m with sodium valproate, consider changing to enteric-coated, slow-release (Epilim Chrono ), or Depakote . If poor compliance is an issue, consider use of slow-release tablets. Onc e established, check FBC, LFTs, serum valproate level, and BMI every 6 months. start with a low, divided dose (e.g. 200mg bd or \200 \200 Points to note \200 There is no well-established correlation between serum concentrations and mood-stabilizing effects. Best advice is to use similar doses and serum levels that are considered therapeut ic for epilepsy. Closer clinical monitoring for side-effects may be necessary for patients who cannot reliably report early signs. 08_Semple_Chap08.indd 343 12/7/2012 6:52:40 PM CHAPTER 8 Bipolar illness 344 Table 8.4 Valproate/valproic acid preparations (UK) Preparation Active agent Available strengths Depakote Valproic acid T 250/500mg Convulex Valproic acid C 150/300/500mg Sodium valproate (generic)/ Orlept Sodium valproate T 100/200/500mg L 200mg/5mL Epilim Sodium valproate T 100/200/500mg L 200mg/5mL Epilim Chrono (MR) Sodium valproate 200/300/500mg Epilim Chronosphere (MR granules) Sodium valproate 50/100/250/500 750/1000mg sachets Episenta (MR) Sodium valproate C 150/300mg Granules 500mg/1g Epilim intravenous Sodium valproate IV 400mg powder with 4mL water ampoule Episenta Sodium valproate IV 100mg/mL 3mL ampoule Key T: tablet; C: capsule; L: liquid 08_Semple_Chap08.indd 344 12/7/2012 6:52:40 PM This page intentionally left blank CHAPTER 8 Bipolar illness 346 Carbamazepine Psychiatric indications \200 Acute mania (less effective than lithium/equivalent ef \201 cacy to antipsychotics) \200 \224alone or in combination with lithium \200\224see b p. 326. Acute depressive episode (in bipolar affective disorder) \200\224alone or in combination with lithium \200\224see b p. 328. Prophylaxis of bipolar affective disorder \200\224data limited \200\224see b p. 330. Mode of action Uncertain. Modulates sodium and calcium ion channels, receptor-media- tion o f GABA and glutamine, and various intracellular signaling pathways. Pharmacokinetics Carbamazepine is available in a variety of forms (solutions, suspensions, syrups, and chewable or slow-release formulations), all with similar bioavailability. Peak plasma concentrations between 4 \200\2238hrs (usually), may be as late as 26hrs. Plasma hal f-life 18 \200\22355hrs. With long-term use, carbamazepine induces its own metabolism, decr easing the half-life to 5 \200\22326hrs (Box 8.10 and Table 8.5). Interactions \200 Carbamazepine decreases the plasma levels of many drugs metabolized by the liver, e.g. anti psychotics, BDZs (except clonazepam), TCAs, other anticonvulsants, hormonal contraceptives, thyroid hormones. Carbamazepine serum concentrations can be increased by certain drugs, e. g. erythromycin, calcium channel blockers (diltiazem and verapamil, but not nifedipine or n imodipine), SSRIs. Side-effects and toxicity \200 antidiuretic effects leading to hyponatraemia Unpredictabl e side-effects: (6 \200\22331%), probably more common in the elderly, sometimes developing many months after starting treatment; decrease in total and free thyroxine levels/increase in free cortisol levels (rarely clinically signi \201 cant). Idiosyncratic side-effects: f ailure, exfoliative dermatitis (e.g. Stevens \200\223Johnson syndrome), and pancreatitis (t hese side-effects usually occur within the \201 rst 3 \200\2236mths of treatment, rarely after longer periods). Note: routine blood monitoring does not reliably predict blood dyscr asias, hepatic failure, or exfoliative dermatitis \200\224patient education about early sym ptoms and signs is essential. Other rare side-effects: conduction problems, psychiatric sym ptoms (including occasional cases of mania and psychosis), and, extremely rarely, renal pro blems (failure, oliguria, haematuria, and proteinuria). Toxicity/overdose: Acute intoxicati on may present as marked irritability, stupor, or even coma. May be fatal in overdose (if > 6g ingested). Symptoms of overdose \200\224nystagmus, ophthalmoplegia, cerebellar/extra-pyr amidal agranulocytosis, aplastic anemia, hepatic systemic hypersensitivity reactions, cardiac early signs \200\224dizziness, ataxia, sedation, and diplopia. 08_Semple_Chap08.indd 346 12/7/2012 6:52:40 PM CARBAMAZEPINE 347 signs, impairment of consciousness, convulsions, respiratory depression, cardiac problems ( tachycardia, hypotension, arrhythmias/ conduction disturbances), GI upset, and other antich olinergic symptoms. Signi \201 cant overdose requires emergency medical management (i.e. c lose monitoring, symptomatic treatment, gastric lavage, and possible haemodialysis). Box 8.10 Treatment guidelines for carbamazepine \200 Full medical history (particularly liver disease, hematological problems, and bleeding diso rders); physical examination; check FBC, LFTs, U&Es, baseline ECG and weight/height (BMI). Start with a low, divided dose (e.g. 200 \200\223600mg/day in 2 \200\2234 divided doses), i ncrease every few days or every week by 200mg/day according to response and side-effects, u p to 800 \200\2231200mg/day, with slower increases thereafter as indicated, to a maximum of 2000mg/ day, or until serum levels are 4 \200\22315g/mL (trough level \200\224taken immedi ately prior to morning dose, and 5 days after dose change). See Table 8.5. Maintenance dose s are usually around 1000mg/day (range 200 \200\223 1600mg/day). Doses higher than 1600mg/d ay are not recommended. Check FBC, LFTs, and serum carbamazepine level every 2wks during \201 rst 2mths of treatment, then reduce monitoring to every 3mths, then every 6mths once w ell established (and monitor BMI). Once the patient is stable, simplify regimen and conside r use of slow-release preparation, to enhance compliance. Points to note Closer clinical monitoring for side-effects may be necessary for patients wh o cannot reliably report early signs. If carbamazepine is combined with lithium, there may be increased risk of developing acute confusional state. Closer monitoring is advisable and minimization of the use or dose of other medications (e.g. antipsychotics, anticholinergic s, BDZs) that may contribute to confusion. Table 8.5 Carbamazepine preparations Preparation Formulation Available strengths Tegretol Tablet (also Chewtabs ) 100/200/400mg Liquid 100mg/5mL Suppositories 125/250mg Tegretol Prolonged Release MR tablet 200/400mg Carbagen SR MR capsule 200/400mg Carbamazepine (generic) Tablet 100/200/400mg 08_Semple_Chap08.indd 347 12/7/2012 6:52:41 PM CHAPTER 8 Bipolar illness 348 Lamotrigine Psychiatric indications \200 Maintenance treatment of bipolar disorder to delay relapse (depression, mania, hypomania, m ixed episodes) \200\223 see b p. 330. May be more effective than other mood stabilizers in preventing depressive episodes in bipolar disorder. Mode of action Unknown. Inhibits voltage-gated Na channels and glutamate release. Also has weak inhibitory effect on 5-HT3 receptors.