My experience of 15 years in a tertiary referral mood disorders unit has validated many recent studies suggesting that resistance to antidepressant treatment is more common than previously judged or conceded. About four years ago, I commenced testing augmentation of antidepressant drugs with atypical antipsychotics in treatment-resistant subjects and observed dramatically rapid improvement in a percentage of my patients. I have since learned that other psychiatrists have come to a similar conclusion by a similar testing process. This should not be viewed as necessarily challenging the zeitgeist of evidence-based treatment guidelines and consensus statements as the gold standard, but should encourage discussion as to how formalized efficacy data and clinically observed effectiveness data may best complement each other.
I observed two distinct improvement patterns in those patients who responded to the augmenting strategy. The first group of patients described a rapid improvement in mood, often in response to a low-dose atypical (e.g., olanzapine [Zyprexa] 2.5 mg to 5 mg) and generally in close association with restoration of sleep and a reduction in any anxiety symptoms. Improvement in these patients was usually evident in one to three days. Once improvement had occurred and patients were euthymic, the atypical could generally be ceased after another day or two, allowing the antidepressant and/or mood-stabilizing medication as the only necessary maintenance strategy -- at least, until any future episode.
In a second group of subjects, there was a slow and generally incomplete remission. There was a specific augmenting effect, since the patient would usually report a worsening of mood if the atypical was ceased. When the atypical was recommenced, the patient would again generally report partial benefit. In such patients, a higher dose of the atypical was generally required.
I was unable to find any treatment or practice guidelines advocating the use of antipsychotic or neuroleptic drugs for the management of depression, although one review suggested that the older antipsychotic drugs had antidepressant properties. Robertson and Trimble (1982) had evaluated more than 30 double-blind trials of typical antipsychotics, which were generally compared with a tricyclic or irreversible monoamine oxidase inhibitor antidepressant drug. Thus, their review did not consider typical neuroleptics as augmenting agents only as singleton antidepressants in head-to-head comparisons with antidepressant drugs. Their review data indicated that the antipsychotics were just as effective as the antidepressants, appeared comparatively free of side effects and tended to have an earlier onset of action. It is of interest that this antidepressant potential of antipsychotic drugs has been ignored in formal treatment guidelines, perhaps reflecting concerns about side effects of the older antipsychotic drugs, particularly tardive dyskinesia.
My colleague and I elected to write up a case series of two dozen non-psychotically depressed patients treated with an atypical antipsychotic (Parker and Malhi, 2001). However, journal assessors were critical of case series data and judged that only a randomized, controlled treatment study was acceptable. Our paper, in which we described clinical features and considered the possible psychopharmacological rationale for atypicals, was eventually published.
In a case series report, Ostroff and Nelson (1999) described eight non-psychotic responders to a selective serotonin reuptake inhibitor remitting within one week of risperidone (Risperdal) augmentation. In 2001, Shelton et al. reported a controlled study whereby a small number of subjects with recurrent, non-psychotic, treatment-resistant depression were randomly assigned to receive olanzapine alone, fluoxetine (Prozac) alone, or the two drugs in combination. The combination produced significantly greater improvement than either monotherapy strategy over the next eight weeks, with the combination therapy being associated with a very rapid improvement in mood state. This report is the only published randomised, controlled trial examining the impact of augmenting with an atypical antipsychotic and hopefully will encourage studies of other atypical drugs as augmenting agents.
Atypical augmentation is now being built into treatment recommendations and guidelines. While Trivedi and Kleiber (2001) included the theoretical combined use of an antidepressant and an antipsychotic, Fava (2001) noted the positive reports of the combination of an antidepressant and an atypical in reviewing strategies for managing treatment-resistant depression.
Fava M (2001), Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 62(suppl 18):4-11.
Ostroff RB, Nelson JC (1999), Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60(4):256-259.
Parker G (2002), Olanzapine augmentation in the treatment of melancholia: the trajectory of improvement in rapid responders. Int Clinical Psychopharmacol 17(2):87-89.
Parker G, Malhi G (2001), Are atypical antipsychotic drugs also atypical antidepressants? Aust N Z J Psychiatry 35(5):631-638.
Robertson MM, Trimble MR (1982), Major tranquillisers used as antidepressants. A review. J Affect Disord 4(3):173-193.
Shelton RC, Tollefson GD, Tohen M et al. (2001), A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158(1):131-134.
Trivedi MH, Kleiber BA (2001), Using treatment algorithms for the effective management of treatment-resistant depression. J Clin Psychiatry 62(suppl 18):25-29.