Overcoming Barriers to Good Outcome:

Frequent Relapse

This is a short algorithm of things to think about when the patient responds to acute treatment but relapses frequently. By "responds" we mean a pattern of response that indicates true drug response rather than a non-specific, probably placebo initial response. Pattern analysis has suggested that early response (recovery in the first two weeks) and non-persistent response (response for a full week followed by an unimproved week) indicates probable placebo response. If this frequently relapsing patient had a placebo pattern of response, that response should be should be considered an unsatisfactory response, and the strategy to optimize pharmacotherapy should be as described in the main algorithm.

If the main problem that accounts for the frequent relapse is non-compliance, see the "Place to Go" entitled "Non-compliance..." Click here to see the first question.

Criteria for when maintenance treatment should be considered are listed below:

1. have had 3 or more episodes of depression² (but note, if there are four or more episodes in a year, this could be rapid cycling bipolar [or, more rarely, unipolar]mood disorder. If so, the maintenance antidepressant could be the cause of the problem. Consider reliance on mood stabilizers, stopping the antidepressant, trying "hypermetabolic" thyroid treatment, and avoid tricyclics, stimulants, and alcohol.)³
2. have had 2 episodes of depression plus any of the following:²
   • the two episodes were severe and occurred within 3 years
   • onset is before age 20
   • there are first degree relatives with a mood disorder
   • there has been recurrence within one year of stopping medication that was given for a previous episode
3. have chronic depression (e.g. - dysthymia) (4)

¹Stewart JW, Quitkin FM, McGrath PJ, et al. Use of pattern analysis to predict differntial relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo. Arch Gen Psychiatry 1998;55:334-343.

²Rush AJ et al. Depression in Primary Care: Volume 2. Treatment of Major depression. U.S. Department of Health and Human Services Agency for Health Care Policy and Research (AHCPR). Rockville, Maryland 1993:109-126.

³Simpson HB, Hurowitz GI, Liebowitz MR. General principles in the pharmacotherapy of antidepressant-induced rapid cycling: a case series. J Clin Psychopharmacol 1997;17(6):460-466

(4)Kocsis JH et al. Long-term follow-up of chronic depression treated with imipramine. J Clin Psychiatry 1991;52:56-59.

uestion: Has the patient received an adequate maintenance treatment regimen (see criteria below) and despite this is relapsing frequently?

• Yes:
• No:

Criteria for Adequate Maintenance Treatment:

1. Patient is being maintained at a medication dose not lower than that which was required for treatment of the acute episode
   • applies to tricyclic and (probably) heterocyclic antidepressants
   • adjunctive medication needed to produce the remission typically needs to be continued¹
   • may apply to SSRI's and other serotonin-active antidepressants such as nefazodone and venlafaxine, but research on this has been minimal...and there is the additional problem that this group of medications seems more prone to lose efficacy...therefore frequent relapse on SSRI's should be managed pharmacologically as "inadequate response" with use of our dosing strategies for SSRI's and algorithm recommendations after failure on an adequate trial of an SSRI.
2. To maximize outcome with maintenance treatment, psychotherapy seems to have some additive effect. Interpersonal Psychotherapy and Cognitive-Behavioral techniques are helpful, but other kinds probably also work.
3. If ECT was required to treat the depression, and drugs have not been effective for maintenance treatment, has maintenance ECT been considered?²

¹Reynolds CF et al. High relapse rate after discontinuation of adjunctive medication for elderly patients with recurrent major depression. Am J Psychiatry 1996;153:1418-1422.

²Fox HA, Salzman C. Resistant depression in the very old - a role for maintenance ECT? Harvard Rev Psychiatry 1995;3:152-155.

uestion: Have medical and drug interaction-related factors been ruled out as contributing to the problem of frequent relapse?

• Yes
• No

Comment: Review diagnosis. Is it DSM-4 criteria-based? Remember that it must be, in order to use this algorithm. Is there a seasonal pattern? Is this a substance-induced mood problem?

Has the patient been placed on another medication which might induce metabolism of the antidepressant and lower its effectiveness? Examples include the anticonvulsants carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin).

Has the patient been put on some other medication which could induce depression? Examples include neuroleptics, anabolic steroids, propranolol (Inderal), and glucocorticoids (may induce manic reactions).¹

¹Rush AJ et al. Depression in Primary Care: Volume 1. Detection and Diagnosis. U.S. Department of HHS, AHCPR. Rockville, Maryland 1993:67-71.

Recommendations:

Optimize maintenance treatment regimen as suggested in the criteria noted above. Consider some of the following factors which may contribute to relapse even when there is an adequate maintenance program:

• 1. Have new medical conditions arisen which could reduce the effectiveness of the medication? Examples include hypothyroidism and low folic acid levels.¹
  2. Has the patient been put on some other medication which could induce depression? Examples include neuroleptics, anabolic steroids, propranolol (Inderal), and glucocorticoids (may induce manic reactions).²
  3. Has the patient been placed on another medication which might induce metabolism of the antidepressant and lower its effectiveness? Examples include the anticonvulsants carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin).
  4. Is this a psychotic depression which is being treated with medications for non-psychotic depression? If there was a past history of psychotic depression, and the present episode is non-psychotic, there is evidence that such depressions could be psychotic depressions in an earlier phase and could require an antipsychotic as part of the regimen.³
  5. Be sure that there is no ongoing active alcohol abuse or dependence. This is associated with incomplete recovery in antidepressant-treated patients.

¹Fava M et al. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-428.

²Rush AJ et al. Depression in Primary Care: Volume 1. Detection and Diagnosis. U.S. Department of HHS, AHCPR. Rockville, Maryland 1993:67-71.

³Parker G et al. Distinguishing psychotic and non-psychotic melancholia. J Affect Disord 1991;22:135-148.

*Worthington J, Fava M, Agustin C, et al. Consumption of alcohol, nicotine, and caffeine among depressed outpatients: relationship with response to treatment. Psychosomatics 1996;37:518-522.

uestion: Is there a high level of ongoing or recurrent psychosocial stress?

• No
• Yes

Comment: Relapse and residual symptomatology are common when stressors persist. Psychotherapy will usually be necessary to provide more effective coping strategies. Supportive, empathic listening and availability can be invaluable. However, some patients who are highly vulnerable to stress develop excessive attachment to the therapist. Any attempt to reduce the contact with the therapist may precipitate relapse. Or, the patient may become attached to an institution (despite a succession of different therapists there) and may have difficulty if frequent visits (or admissions) do not occur. Answer "yes" above if this is the case.

Recommendation:

This patient is relapsing even though there has been reasonable maintenance pharmacotherapy and psychotherapy. Possible contributing medical factors have been addressed. Despite the apparent good acute response to pharmacotherapy, we may be dealing with a placebo or suboptimal response. Return to the beginning of this "Frequent relapse..." section (eg - by pressing "back" on your right mouse button several times if necessary), and then start a new consultation. Consider the present treatment unsatisfactory, work through the algorithm, and review the next set of options for this diagnostic situation.

Recommendation:

Click here to see some suggestions for medical/drug-related factors which may need to be ruled out as possible contributors to the frequent relapse that is occurring.

Recommendation:

Psychotherapy is considered to be helpful in preventing relapse: probably any type will be helpful in blunting the impact of stress on the course of the depressive illness. Cognitive therapy has a particularly good track record.¹ A highly critical spouse is one of the strongest predictors of relapse, so this problem deserves active attention.² Persistent low self-esteem or negative self-appraisal should be addressed. Comorbid personality disorder predicts frequent relapse and may require specific treatment: return to the pharmacotherapy algorithm and locate the section on treatment resistant depression on the flowchart, and consider the recommendations. As indicated earlier, substance/alcohol abuse/dependence precipitate relapse, and this would be another point to reconsider those diagnoses and, if present, treat appropriately.

¹Fava GA et al. Cognitive behavioral treatment of residual symptoms of primary major depressive disorder. Am J Psychiatry 1994;151:1295-1299.

²Hooley J, Teasdale J. Predictors of relapse in unipolar depression: expressed emotion, marital distress, and perceived criticism. J Abn Psychology 1989;98:229-235.