# 12 - Other treatments # Other treatments 574 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 After prescribing ■ ■Assess and measure symptoms on a regular basis to establish effectiveness. ■ ■Monitor weight, height and waist to hip circumference at each visit and repeat all fasting bloods at 3 months (then every 6 months). Offer advice on healthy lifestyle and exercise. ■ ■The duration of most medication trials is ­3–­5 ­weeks –­ this is the period over which most improvement is anticipated to occur. This should guide decisions about how long to try a single drug in a patient. A complete absence of response at 2 weeks should prompt consideration of a switch to another SGA (or a dose increase where labelling allows). ■ ■If there is no response, check adherence, measure blood levels where possible and consider increasing the dose. Consider concurrent use of an SGA and MS. ■ ■Judicious extrapolation of the evidence from adults9 is required because of the very limited evidence base in youths with bipolar disorder. This includes treatment duration and prophylaxis.6,7,10 Maintenance treatment should follow adult guidelines. Consider the use of lithium early in the course of treatment, either by switching to lithium monotherapy prophylaxis or as an adjunct to a successful acute medication. Lithium has therapeutic advantages over other options in adults but should only be used where adherence is assured. Specific issues ■ ■Bipolar depression is a common clinical challenge and its treatment has been studied much less in youths than in adults (Tables 5.4 and 5.6). Antidepressants should be used rarely and with care for the minimum duration possible and only in the ­presence of an antimanic agent.6 There is limited evidence for the benefit of antidepressants in bipolar depression in adults.11 Because of the dearth of trials in youth, we are compelled to extrapolate from adult studies,6 which suggest use of the ­olanzapine/fluoxetine combination as the most effective treatment, along with lurasidone, which is supported by evidence from several trials in children aged ­10–­17 years.­12–­14 The metabolic effects of olanzapine arguably make it a second-­line choice after lurasidone. ■ ■The exact relationship between ADHD and bipolar depression is still debated. Some evidence suggests that stimulants in children with ADHD and manic symptoms may be well tolerated15 and that they may be safe and effective to use after mood stabilisation.15 Caution and experience with prescribing these drugs are required. ■ ■The DSM-­5 category of disruptive mood dysregulation disorder (DMDD) includes severely irritable children (who were commonly misdiagnosed as having bipolar depression in the USA). There is no established treatment for DMDD. Lithium is ­ineffective16 but SSRIs and psychological treatment options, such as parenting ­interventions, may be considered.17 Other treatments ■ ■Adjunct treatments including psychoeducation, CBT and especially family-­focused interventions can enhance treatment and reduce depression relapse rates in bipolar disorder.18 Prescribing in children and adolescents CHAPTER 5 ■ ■There is emerging evidence that a combination of omega-­3 fatty acids with inositol is effective in mania and hypomania in children aged ­5–­12 years.19 Confirmatory trials are needed. ■ ■Cariprazine may be effective in young people but evidence is limited.20 ■ ■The use of high-­frequency rTMS in adolescents with treatment-­resistant unipolar depression is only supported by open-­label studies21 and no RCT has been done in youth with either unipolar or bipolar depression. Therefore, its use is still  ­considered experimental. One randomised sham-­controlled study found rTMS ineffective in treating acute mania in youth (as an add-­on to standard pharmacotherapy).22 ■ ■One small trial supported the adjunctive use of melatonin (6mg/day) in adults with mania.23 Evidence is not yet sufficient to recommend its use in children. Table 5.3  Pharmacological treatments of mania in children and adolescents. Medication Comment Lithium Lithium is cleared relatively quickly in children so twice daily dosing will be required, especially when using liquid or non-­modified-release preparations.24 One double-­blind placebo-­controlled randomised trial25 showed significant reductions in substance use and clinical ratings after 6 weeks in adolescents with bipolar disorder and comorbid substance misuse. In a double-­blind placebo-­ controlled discontinuation trial (N = 40) over 2 weeks, no significant difference in relapse rates were found between lithium and placebo.26 A later double-­blind placebo-­controlled study (N = 81), over 8 weeks, demonstrated a significantly larger change in YMRS score in lithium-­treated youths. There was a significant increase in thyrotropin with lithium, but no difference in weight gain.27 Lithium and divalproex did not differ in an 18-­month maintenance trial in youths (N = 60) who initially stabilised on combination pharmacotherapy of lithium and divalproex.28 However, given the compelling evidence for lithium maintenance and prophylaxis in adults, we recommend that clinicians consider its use in adolescents in preference to valproate. Valproate should be avoided in adolescents in any case. A meta-­analysis29 found lithium to be ‘clearly inferior’ to risperidone in mania. Lithium may also be inferior to quetiapine in the treatment of mania in children and adolescents.30 One small 6-­month study found higher relapse rates in those who discontinued lithium compared with those who continued.31 Another naturalistic 8-­month study showed lithium to be effective and well tolerated.32 Valproate In an RCT (N = 150)33 divalproex ER (titrated to clinical response or ­80–­125mg/L) did not lead to significant differences in mean YMRS compared with placebo at 4 weeks. (Also see risperidone and quetiapine sections below.) Valproate should be avoided in all peri-­ and post-­pubertal children and adolescents. Oxcarbazepine A double-­blind placebo-­controlled study (N = 116) did not show significant differences between placebo and oxcarbazepine (mean dose 1515mg/day) in reducing mania rating at 7 weeks.34 (Continued ) 576 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Medication Comment Olanzapine A double-blind placebo-­controlled study (N = 161)35 showed olanzapine (­5–­20mg/day) to be significantly more effective than placebo over a period of 3 weeks. There was greater weight gain in the treatment group (weight gain was 3.7kg for olanzapine vs 0.3kg for placebo) and associated significantly increased fasting glucose, total cholesterol, AST, ALT and uric acid. The addition of topiramate reduces weight gain by more than a half.36 Risperidone A double-­blind placebo-­controlled study (N = 169) showed risperidone (at doses 0.­5–­2.5 or ­3–­6mg) to be more effective than placebo in YMRS mean score reduction in a 3-­week follow-up.37 The lower dose led to the same benefits at a lower risk of adverse effects. Sleepiness and fatigue were common. Mean weight increase in treatment groups was 0.7kg vs 1.7kg for the low-­dose arm and 1.4kg for the high-­dose arm. In the Treatment of Early Age Mania (TEAM) study, higher response rates (and metabolic side effects) occurred with risperidone (mean dose 2.57mg) than with lithium (mean level 1.09mmol/L) and divalproex sodium (mean level 113.6mg/L).38 A randomised follow-up of this study showed again the superiority of risperidone as an alternative treatment for non-­responders to lithium and divalproex sodium, and as an add-­on treatment to partial responders to the two drugs.39 These results need to be interpreted with caution as the definition of mania was broader than that used in some countries. The same caveat applies when considering another double-­blind placebo-­controlled trial showing significantly better results for risperidone (mean dose 0.5mg) than for valproic acid (mean level 81mg/L) in ­3–­7-­year-­old children supposedly diagnosed with mania.40 Quetiapine A double-­blind placebo-­controlled study (N = 277)41 showed quetiapine (at doses of 400 or 600mg/day) to be significantly better than placebo in reducing mean YMRS scores at 3 weeks. The most common side effects included somnolence and sedation. Weight gain was 1.7kg in the quetiapine group and 0.4kg for placebo. Quetiapine is effective as an adjunct to valproate compared with valproate alone (N = 30, 6 weeks)42 and was as effective as valproate in a double-­blind trial (N = 50, 4 weeks).43 Aripiprazole A double-­blind placebo-­controlled study44,45 showed aripiprazole (at doses 10 or 30mg/day) to be significantly better than placebo at both 4 weeks (N = 296)44 and 30 weeks (N = 210).45 There was a higher incidence of extrapyramidal side effects in the treatment groups (especially the higher dose). Weight gain was significantly more common in the treatment groups compared with placebo (3.0kg for placebo; 6.5kg for the low-­dose arm and 6.6kg for the high-­dose arm) at week 30. Ziprasidone A double-­blind placebo-­controlled trial (N = 237)46 showed ziprasidone (at flexible doses ­40–­160mg) to be more effective than placebo in reducing mean YMRS scores at 4 weeks. Sedation and somnolence were the most common side effects, while it demonstrated a neutral metabolic profile and no QTc prolongation. A second RCT of 171 participants showed broadly similar outcomes.47 Asenapine A 3-­week double-­blind placebo-­controlled study (N = 350) demonstrated statistical superiority of asenapine over placebo for each of the doses used (2.5, 5 or 10mg BD), with significant difference as early as day 4. However, many side effects were reported, including weight gain of more than 7% of baseline in ­8–­12% of the asenapine group vs 1.1% in the placebo group, metabolic changes (increase in insulin, lipids, glucose), as well as somnolence, sedation, oral hypoaesthesia and paraesthesia.48 ALT, alanine transaminase; AST, aspartate aminotransferase; ER, extended release; MS, mood stabilisers; YMRS, Young Mania Rating Scale. Table 5.3  (Continued) Prescribing in children and adolescents CHAPTER 5 Table 5.4  Pharmacological treatments of bipolar depression in children and adolescents. Medication Comment Olanzapine/ fluoxetine combination A large study (N = 255) of the olanzapine/fluoxetine combination (either 6/25 or 12/50mg daily) for 8 weeks49 showed an advantage for the combination. Most frequent side effects were weight gain (4.4kg for olanzapine/fluoxetine and 0.5kg for placebo), somnolence and hyperlipidaemia. The olanzapine/fluoxetine combination is recommended by UK NICE guidelines,6 along with quetiapine, as first-­line treatment for bipolar depression in children and adolescents, as in adults. Although the olanzapine/fluoxetine combination is not currently available as a single preparation in the UK or European Union, its effects can be achieved by combining olanzapine and fluoxetine (e.g. 5/20 or 10/40mg). Lurasidone Lurasidone has been shown to be effective in bipolar depression in ­adults­­50–52 and it does not seem to cause weight gain and other metabolic disturbances. It is also safe and effective in treating schizophrenia in adolescents.53 Lurasidone was effective in bipolar depression in children (­10–­17 years) both acutely12 and in a 2-­year follow-­up study.14 Dose ranged from 18.5mg (20mg) to 74mg (80mg). Lurasidone may be the preferred antipsychotic in children on account of its good tolerability.54 In fact, a 2022 network meta-­analysis14 considered lurasidone to be the optimal treatment for bipolar depression in youths. Quetiapine A small study in 32 adolescents,55 followed by a larger RCT (N = 193),56 failed to show effectiveness. The second study had a very high placebo response, which is not usually seen in adult quetiapine studies57 and which may reflect issues in diagnosing mood disorders in multisite studies.58 A 2022 meta-­analysis suggested quetiapine was ineffective in bipolar depression in young people.14 Lamotrigine Lamotrigine has only modest, if any, effects in adult bipolar depression59 and it has not been studied in RCTs for the treatment of acute bipolar depression in children and adolescents and is, therefore, not recommended as a first-­line drug. Moreover, a placebo-­controlled randomised withdrawal study of adjunctive lamotrigine for bipolar disorder in youth, lasting over 36 weeks, failed to show any benefit in preventing time to occurrence of a bipolar event.60 Table 5.6  Recommended first-­line treatments for bipolar depression.* Lurasidone 18.5mg (20mg) to 74mg (80mg) daily Olanzapine/fluoxetine 6/25mg to 12/50mg daily *Continue acutely effective dosing regimen as prophylaxis and consider need for lithium if not already prescribed. Table 5.5  Recommended first-­line treatments for acute mania.* Aripiprazole 10mg daily Risperidone 0.­5–­2.5mg daily Olanzapine ­5–­20mg daily Quetiapine Up to 400mg daily Asenapine 2.­5–­10mg twice daily *Continue acutely effective dosing regimen as prophylaxis and consider need for lithium if not already prescribed.