Cleon Cornes

Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression

Recent evidence points to the prophylactic efficacy of maintaining recurrent unipolar patients on the same dose of antidepressant medication that was used to treat the acute episode (Frank et al., 1990; Kupfer et al., 1992). Therefore, the question of whether such patients should be tapered to a lower maintenance dose after successful resolution of an acute episode is clearly important. In this report we describe a small randomized clinical trial in which patients were assigned to either full-dose or half-dose maintenance treatment for a period of 3 years. Survival analysis suggests that superior prophylaxis can be achieved with a full-dose as compared to a half-dose maintenance treatment strategy (p < 0.07). Mean survival time for the full-dose subjects was 135.17 (SE 19.75) weeks as compared to 74.94 (SE 19.78) weeks (median of 43.1 weeks) for the half-dose subjects. We conclude that for patients who have suffered several recurrences, full-dose maintenance treatment is the more effective prophylactic strategy.

Akathisia, pseudoakathisia and tardive dyskinesia: Clinical examples

Abstract Akathisia is a side effect of neuroleptic drugs characterized by a subjective sense of inner restlessness leading to an inability to sit still and a compulsion to move. 1 There has been a great deal of recent literature encouraging clinicians to consider the diagnosis of akathisia. The major emphasis of these reports has been to distinguish akathisia from the anxiety and hyperactivity frequently seen in psychotic patients and thereby to prevent worsening of this extrapyramidal symptom by the addition of increasing doses of neuroleptics. 1–5 In other words, the thrust of the literature has been education to avoid underdiagnosing akathisia. We believe that there may also be a need to avoid overdiagnosing akathisia. Specifically, it is often difficult to distinguish akathisia and tardive dyskinesia. The involuntary, late onset, treatment unresponsive lower extremity involvement of tardive dyskinesia is not always clinically distinct from the subjectively distressful akathisia which is theoretically of early onset, is treatment responsive and has voluntary movements as a secondary phenomenon. A review of the literature on akathisia and tardive dyskinesia suggests several possible important relationships between these disorders. First, there may be a positive association between the occurrence of akathisia and tardive dyskinesia. Second, some akathisia may actually be tardive dyskinesia or some form fruste of tardive dyskinesia which we have called pseudoakathisia. Finally, there may be a progression from true akathisia through pseudoakathisia and finally to clear cut tardive dyskinesia.

Distinguishing akathisia and tardive dyskinesia: a review of the literature.

Akathisia and tardive dyskinesia, both side effects of neuroleptic drugs, should be easily distinguishable. Akathisia is fundamentally a subjective disorder characterized by a desire to be in constant motion resulting in an inability to sit still and a compulsion to move. Tardive dyskinesia is an involuntary movement disorder characterized by repetitive purposeless movements which typically involve the buccolingual masticatory areas but which can include choreoathetoid limb movement. Clinicians, however, are not always able to distinguish akathisia and tardive dyskinesia. The authors review the literature on akathisia and tardive dyskinesia in an attempt to understand the basis for this diagnostic confusion. They suggest six areas of inquiry which may help in distinguishing the two disorders: (1) the nature of the subjective distress, (2) the voluntary or involuntary nature of the movements, (3) the time of onset of the disorder, (4) the location of signs and symptoms, (5) the presence of other extrapyramidal symptoms, and (6) the response to pharmacologic interventions. In addition to diagnostic confusion, the literature review suggests an association between akathisia and tardive dyskinesia. Because this association is poorly understood, three possibilities are suggested: (1) The occurrence of akathisia may predispose to subsequent tardive dyskinesia; (2) Akathisia may evolve into tardive dyskinesia; and/ or (3) There may be a third group of disorders, distinct from akathisia and tardive dyskinesia, which the authors call tardive akathisia. Each of these possibilities are discussed.

The value of maintenance interpersonal psychotherapy (IPT) in older adults with different IPT foci.

OBJECTIVE/METHODS The authors examined recurrence rates of major depression in elderly subjects with different foci of interpersonal psychotherapy (IPT), who were treated for up to 3 years with either monthly maintenance IPT and pill placebo or with monthly clinical management and pill placebo. RESULTS Among subjects with an IPT focus on role conflict, a greater proportion of those treated with maintenance-IPT survived for 3 years without recurrence than those treated with placebo/clinical management. Median time to recurrence was 68.9 weeks in IPT-treated patients versus 16.3 weeks for patients in clinical management. Subjects with an IPT focus on abnormal grief or role transition demonstrated no effect differential for maintenance IPT and pill-placebo on recurrence prevention over supportive clinical management and pill-placebo. CONCLUSION If replicated in a larger sample, these findings have important implications for ongoing case-management decisions.

Open-trial maintenance pharmacotherapy in late-life depression: Survival analysis

We report preliminary findings from an ongoing, open trial of maintenance nortriptyline pharmacotherapy in 27 elderly depressed patients (median trial length: 18 months). While patients were on maintenance nortriptyline (mean dose: 50 mg/day) with steady-state plasma levels in the range of 50-150 ng/ml, 58% of Q-6 monthly ratings on the Hamilton Rating Scale for Depression have been 10 or lower, Folstein Mini-Mental State ratings have remained above 27, and a minimal level of side effects with no increase over time has been observed. Four of 27 patients (14.8%) have suffered recurrences and have required rehospitalization at 6, 9, 10, and 13 months. Survival analysis showed an 85% survival rate (without recurrence) at 12 months and 81.5% at 18 months. Mean survival time without recurrence is 21.3 months to date. Although our pilot experience with maintenance nortriptyline in late-life depression appears more favorable than outcomes reported in earlier naturalistic studies (where no attempt was made to keep patients in systematic maintenance therapy), the need for controlled studies of maintenance therapies in late-life depression is nonetheless underscored by the current data and other naturalistic data from the United Kingdom.

A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression

The authors assessed the severity of nortriptylines side‐effects in older patients with recurrent major depression during placebo‐controlled, double‐blind maintenance therapy. Data were from 37 patients completing 2–3 years of maintenance therapy; 29 were on nortriptyline and eight were on placebo. The authors detected a time‐by‐treatment interaction for dry mouth (greater in nortriptyline‐treated patients), but no increased association of nortriptyline with constipation, weight change or orthostatic symptoms. Heart rate was consistently higher in nortriptyline‐maintained patients as compared with placebo. The total ‘side‐effect’ score on the Asberg Rating Scale, as well as complaints of physical tiredness, daytime sleepiness and nocturnal sleep disturbance, were related primarily to residual depression rather than treatment with nortriptyline. Copyright

Which elderly depressed patients remain well on maintenance interpersonal psychotherapy alone?: report from the Pittsburgh study of maintenance therapies in late-life depression.

The aim of this study was to identify elderly depressed patients who can remain well on maintenance Interpersonal Psychotherapy (IPT) alone, after discontinuation of antidepressant medication. Using Cox proportional hazards models, increased severity of depression at pretreatment was associated with increased recurrence rates, to an extent greater in patients maintained on monthly IPT than in those maintained on nortriptyline. The long‐term response to maintenance IPT was correctly identified in 20/25 cases by a pretreatment Hamilton score of≥ 20. Fourteen of sixteen patients with pretreatment scores of≥ 20 experienced recurrence of major depression on maintenance IPT, while 6/9 patients with pretreatment scores of less than 20 did not. (Fisher exact P=.01). The same pattern of recurrence in relation to severity was not evident in maintenance placebo, nortriptyline, or combination treatment. In addition, Hamilton scores during continuation treatment were lower (≤ 7) among those who remained well on maintenance IPT than among those who had recurrences. Elderly patients whose depressions are milder at baseline and who show excellent symptomatic remission during acute and continuation therapy may be good candidates for monthly maintenance IPT after initial successful treatment with antidepressant medication and psychotherapy. Depression and Anxiety 10:55–60, 1999.

Foci of Interpersonal Psychotherapy (IPT) in Depressed Elders: Clinical and Outcome Correlates in a Combined IPT/Nortriptyline Protocol

The primary problem areas or foci of interpersonal psychotherapy (IPT) in elders with recurrent major depression, the clinical correlates of single and multiple IPT foci, and their relationship to acute clinical response are described. 127 consecutive elderly patients (mean age 67.9, sd = 6.0) participating in the open (i.e., nonblind, nonrandomized) acute and continuation phases of a controlled maintenance therapies protocol were treated with combined IPT and nortriptyline. Multivariate analysis of variance was used to contrast the clinical and demographic profiles associated with different IPT foci. Kaplan-Meier survival analysis, stratifying on primary IPT focus, and by single versus multiple foci, was used to assess rapidity of response to treatment. We found no association between IPT focus (interpersonal dispute, role transition, or grief) and probability of recovery, or time to clinical response, under conditions of open combined treatment, nor between multiple versus single IPT foci, despite impor...

Nortriptyline Side Effects During Double-Blind, Randomized, Placebo-Controlled Maintenance Therapy in Older Depressed Patients

The authors assessed the severity of nortriptyline side effects in older patients with major depression during 12 months of double-blind therapy. Data were from 40 patients completing 1 year of maintenance therapy: 26 were on nortriptyline and 14 were on placebo. The authors detected significant time-by-treatment interactions for various side effects (all greater in treated patients), but not for overall side effects score. Clinically, these differences were judged to be minor and correctable. On the other hand, total side effect scores, physical tiredness, and subjective sleep disturbance covaried significantly with Hamilton Depression scores regardless of treatment assignment. Somatic worry, tiredness, and sleep complaints appeared to reflect residual depression rather than treatment assignment.

Tardive dyskinesia and informed consent: myths and realities

Tardive dyskinesia is a potentially irreversible neurologic syndrome secondary to long-term neuroleptic drug use. It is characterized by slow. rhythmical. automatic stereotyped movements particularly in the buccolingual masticatory area. extremities. and trunk muscles in patients who have received neuroleptic drugs for at least three months. Unlike other neurologic side effects to neuroleptic drugs, tardive dyskinesia is resistant to treatment with anticholinergic drugs. There is no generally effective treatment of tardive dyskinesia. I The prevalence of tardive dyskinesia varies widely in different studies but most likely is in the range of 10 to 20 percent of patients on maintenance neuroleptics. Of the total to to 20 percent of patients with tardive dyskinesia, less than to percent of them have severe abnormal movements with a fourth to a third of patients with the disorder showing moderately severe movements. While early studies suggested as many as 60 percent of cases of tardive dyskinesia were irreversible, more recent studies are more optimistic that frequent reversibility may be possible with early detection and discontinuation or reduction of neuroleptic medication. Confounding the detection and management of tardive dyskinesia is the fact that the very cause of the syndrome, neuroleptic drugs, also serves to mask it. Thus tardive dyskinesia is frequently not detected until the drugs are stopped or the dosage reduced. It is not clear what the relationship is between so-called withdrawal emergent dyskinesias and tardive dyskinesia that appears on a steady dose of neuroleptic. I However, it is clear that tardive dyskinesia is today a major public health issue in psychiatry.2 We are talking about a sometimes irreversible. sometimes severe, sometimes grotesque neurologic disorder induced by longterm exposure to what is currently the best and. to many minds, the only effective treatment for schizophrenia. It is no small wonder then that tardive dyskinesia has aroused a great deal of concern in the psychiatric community. Some have attempted to deny its existence, its irreversibility or its etiologic connection to neuroleptic