Mohammed T. Abou-Saleh

440 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYefficacy in the elderly, with 60–80% of patients responding totreatment. The authors concluded that the efficacy data are notrobust when an SSRI is compared with placebo; the only availablereport from a randomized placebo-controlled trial of fluoxetine inoutpatients 15 found a lower drug–placebo difference than thatfound for many studies with TCAs. Moreover, comparison offluoxetine with nortriptyline in inpatients with severe depressionand heart disease showed that nortriptyline may be more effectivein this population 16 . A meta-analysis of the comparative efficacyand safety of SSRIs and TCAs in elderly patients 17 showed nodifferences in safety and dropout rates.The side-effects profile of SSRIs includes nausea, diarrhoea,insomnia, headaches, agitation, anxiety and sexual dysfunction.The SSRIs also seem to worsen parkinsonism. As with otherantidepressants 18 there have been case reports of hyponatraemia,hypomania and seizures 7 . An important aspect of their use is theirdrug–drug interactions, and their inhibitory effects on hepaticcytochrome p450 isoenzymes, the route through which manydrugs commonly prescribed for elderly people are metabolized 19 .Paroxetine, norfluoxetine and sertraline have clinically importantinhibitory effects (in vivo) on cytochrome P2D6, resulting inincreased plasma concentrations of co-administered TCAs, suchas desipramine, and antipsychotics, such as haloperidol 20 . Sertraline,however, had a modest effect on plasma nortriptyline levelsin depressed elderly patients 21 . Fluoxetine increases plasma levelsof co-administered carbamazepine; alprazolam and fluvoxamineincrease plasma concentration of co-administered TCAs andantipsychotics by inhibiting cytochrome P1A2 9 . An extensive listof drugs metabolized by various p450 isoenzyme types is providedin the reviews by Catterson et al. 5 and Rivard 7 .CONTINUATION AND PROPHYLACTICTREATMENTEarly studies indicated a poor outcome of late-life depression 25 ,with high relapse, recurrence and chronicity. This view was basedon naturalistic observation without monitoring of compliance,adequate dosage and duration of treatment, including prophylactictreatment, and was therefore challenged 26 . Controlled studiesof maintenance antidepressant medication, however, showedbetter outcome for late-life depression 27 . The Pittsburgh groupreported a 3 year follow-up study of maintenance treatment withnortriptyline or placebo with or without interpersonal psychotherapy(IPT) 28 and showed that 80% of patients assigned tonortriptyline, with or without IPT, remained in remission. ThePittsburgh group also identified the elderly patients who remainedwell after placebo-controlled discontinuation of antidepressantmedication for a period of 1 year. Recovery of good subjectivesleep quality by early continuation treatment was useful inidentifying which remitted elderly depressed patients remainedwell with monthly IPT after discontinuation of antidepressantmedication 29 . Moreover, effective maintenance treatment withnortriptyline was associated with enhancement in the rate of deltawaveproduction in the first non-rapid eye movement sleep and ofrapid movement activity throughout the night 30 .A recent study of the effect of treatment on the 2 year course oflate-life depression 31 showed a 74% survival rate without relapse.This good outcome was obtained by the use of full-dose antidepressantmedication, frequent follow-up and rigorous treatmentof relapse.The US National Institute of Mental Health consensusstatement update 3 concluded that recent evidence supports therecommendation for at least 6 months of treatment beyondrecovery for those with first onset in late life, and for at least 12months for those with a recurrent illness 32 . Moreover, prophylactictreatment should be of the same type and of same dosage asthat which was successful in the initial acute phase. The consensusstatement also concluded that treatment response and long-termoutcome for all the patients is generally similar to that observed inyounger adults, but the temporal course may be somewhat slowerin the elderly and risk of relapse somewhat greater 3 . The use oflithium in continuation and prophylactic treatment of depressionin the elderly has also been recommended 27,33,34 , with the use oflower doses/plasma levels 34 . Lithium may be a more favourableprophylactic treatment than antidepressants in recurrent depressionwith melancholia and in depression with psychotic features(delusional depression), which are particularly common amongthe elderly, with a tendency to respond less well to antidepressants26,34 . The other advantage of lithium therapy is the evidentdecreased mortality, whether from suicide or other causes 35 .Arecent 1 year prospective, placebo-controlled study of maintenancelithium in conjunction with cognitive–behavioural psychotherapyin elderly depressed patients 36 showed that, although cognitive–behavioural psychotherapy reduced depression severity duringfollow-up, lithium therapy was no better than placebo. Thisappears to be related to poor compliance, a finding that highlightsthe serious difficulties in undertaking prophylactic studies inelderly depressed patients.TREATMENT OF BIPOLAR DISORDERElderly patients with late presentation or late-onset maniarespond well to standard antimanic treatment with neuroleptics,lithium and anticonvulsants 37 . Neuroleptic treatment is bestavoided in the elderly because of its known extrapyramidal sideeffects, except for floridly psychotic, agitated and behaviourallydisturbed patients who need rapid control of symptoms. Lithiumremains the treatment of choice, followed by valproic acid 37 . Theevidence for the efficacy of lithium in late-life mania is based onretrospective and uncontrolled studies; there have been nocontrolled studies, and there have been no controlled studies ofthe efficacy of anticonvulsants in late-life mania. It has beensuggested that valproate is a safer alternative treatment to lithiumthan carbamazepine, whether used as single or adjunct treatment,in elderly manic patients 37 . There are no guidelines regarding theoptimal plasma concentration of valproate in relation toefficacy 37 .A recent evidence-based review of the treatment of mania,mixed state and rapid cycling in younger populations 38 concludedthat lithium and divalproex sodium are effective in mania,whereas divalproex sodium and carbamazepine are more effectivein mixed states. Divalproex sodium is the drug of choice for rapidcycling disorder. With bipolar depression, lithium is recommendedas a first-line treatment and the addition of a secondmood stabilizer or the TCA would be an appropriate next step 39 .The guidelines for the continuation and prophylactic treatmentof bipolar illness in late life are similar to those advocated foryounger patients, except for the notion of high recurrence ratesnecessitating prophylactic treatment, even after a first-onset manicepisode. Lithium remains the medication of choice for prophylaxis34 . An open naturalistic study of lower doses/plasma-lithiumlevels of lithium 34 showed efficacy in the elderly comparable tothat in younger patients at plasma lithium levels as low as0.4 mmol/l, with fewer side effects and renal and thyroid adverseeffects.TREATMENT-RESISTANT DEPRESSIONTreatment-resistant depression occurs in one-third of elderlydepressed patients 40 and can only be ascertained after adequaterecognition, compliance with treatment and effective treatment 41 .