# Combining Drug Therapy and Psychotherapy for Depression



## David Baxter PhD (Oct 27, 2006)

Combining Drug Therapy and Psychotherapy for Depression
By David Mintz, MD 
_Psychiatric Times_, October 2006, Vol. XXIII, No. 11

It was just over a generation ago that the routine combination of psychotherapy and drug therapy seemed impossible. Especially in America, psychiatry was polarized by ideologic and political struggles between psychoanalysis and biologic psychiatry. American psychoanalysts tended to regard psychopharmacology as an inferior treatment that covered over problems rather than addressing them. They assumed that symptoms suppressed by drugs would eventually be replaced by others equally disabling. In turn, proponents of biologic psychiatry often viewed psychoanalysis as a form of quackery that was, at best, a costly waste of time, and, at worst, heightened distress that the psychopharmacologist was trying to ameliorate.

*Benefits of combined treatment* 
In the 1970s, a number of influential studies cut through ideologic assumptions and began to reshape the way we viewed the practice of combining therapy and medications. Klerman and coworkers1 tested the assumption that psychotherapy and psychopharmacology were essentially in conflict, each undermining the work of the other. There was no evidence that psychopharmacologic treatment led to therapy discontinuation or to symptom substitution or that psychotherapy exacerbated patients' distress. Then, Luborsky and colleagues,2 in a meta-analysis comparing the effectiveness of different psychodynamic psychotherapies, made an interesting discovery. All therapies were equally effective, with one notable exception: combined treatment with psychotherapy and medication was found to be notably superior to either treatment alone.

Since then, numerous studies have shown combined treatment for depression to have many benefits over single-modality treatment (Table 1). This applies not only to psychodynamic therapy, but also to interpersonal therapy (IPT), a manualized descendent of psychodynamic psychotherapy.3 The evidence was less clear for cognitive-behavioral therapies (CBT), with several early studies showing only nonsignificant trends toward a benefit of combined treatment.4 It appears, however, that this may reflect limitations in study design typical of that period.5 Other studies showed a benefit to combining CBT and pharmacotherapy.6-8

Does this mean that all patients presenting with depression should be offered treatment with a combination of psychotherapy and medications? In an ideal world with unlimited resources, this might be the case. However, there is the cost/benefit ratio to consider. Though combined treatment is more effective than single-modality treatment, the effect sizes are generally modest.9 Differences that are statistically significant may not be clinically significant. Given the added strain of providing combined treatment on limited mental health services, it would be far better selectively to provide combined treatment to those patients most likely to show a significant benefit.

*Types of patients likely to respond to combined treatment* 
Although the evidence base is still rather small, there is some guidance about which patients with depression would most likely have a substantial benefit from combined treatment. Patients with more severe depression,10 endogenous depression,11 chronic depression,12-14 and dysfunctional cognitions15 all show more robust and clinically significant responses to combined treatment (Table 2).

Inadequate response to single-modality treatment is another reason to consider combined treatment. Patients whose depression has not responded well to antidepressant therapy alone show an increased rate of response when that treatment is paired with psychotherapy.16 Similarly, nonresponders to psychotherapy receive added benefit when antidepressants are added.17 It is worth noting that these categories of patients are the ones that typically are receiving treatment from psychiatrists. With the majority of antidepressants prescribed by nonpsychiatrists, psychiatrists typically see patients with more severe, chronic, and treatment-resistant conditions and those patients whose treatments are complicated by dysfunctional attitudes and maladaptive personality styles. Consequently, most patients receiving referral for specialized psychiatric treatment would be appropriately treated with combined treatment with psychotherapy and medications.

Combined treatment produces not only faster8 and greater short-term benefits, but greater long-term benefits as well. Patients receiving combined treatment with CBT have a lower relapse rate than do patients receiving medications alone.18,19 Patients who received IPT and drugs had better long-term social adjustment than patients on drugs alone.1 For patients older than 60 years, the combination of IPT and medication has been shown to reduce the rate of depressive relapse.20 In addition, compared with pharmacotherapy alone, combined medication and group therapy seems to reduce relapse after discontinuation of treatment.13

*What makes combined treatment better?* 
We still do not know much about what accounts for the superiority of combined treatment.Some benefit may accrue simply from additive effects.Each treatment is effective in its own right; thus, adding the effectiveness of each provides a cumulative effect. Additive effects may result from the fact that therapy and medications converge on the problem of depression from two different angles, perhaps even literally. Functional neuroimaging of the differential effects of psychotherapy and antidepressant medications suggests that, while both treatments show considerable overlap in effects on cerebral metabolism, medication effects develop "bottom up," emanating from the brain stem upward, while psychotherapy effects emerge in a "top down" fashion, spreading downward from the frontal cortex.21 The two modalities may exert an additive effect by addressing different symptom domains. Therapy, for example, might address the hopelessness related to depression, while medications more directly address neurovegetative aspects of depression.22

There may also be interactive effects that contribute to the increased efficacy of combined treatment. Pharmacotherapy may, for example, make some patients more available for therapy by easing treatment-interfering problems such as psychosis, disabling anxiety, or the amotivational syndrome of depression. Recent evidence suggests that there may also be some more directly biologic interactive effects. One of the neurobiologic effects of antidepressant use appears to be an increase in neural turnover, with increased sprouting and trimming of dendritic synapses.23 This intriguing research suggests that antidepressants may make for more plastic neural networks, which may, in turn, allow for more rapid learning, as in psychotherapy.

Psychotherapy may also enhance the effectiveness of medication. One way in which this may occur is through improved compliance. Several studies have demonstrated that patients receiving psychotherapy concurrently with medications have a lower rate of pharmacologic treatment discontinuation.23-26 Concurrent treatment may also improve the therapeutic alliance27 and enhance patient satisfaction with treatment.25,28 The therapeutic alliance, in turn, has a profound effect on antidepressant efficacy.29 Additionally, the psychosomatically preoccupied patient prone to negative medication reactions may benefit from attention to psychological origins of somatic reactions.27,30

*Combining and integrating treatments* 
How does one go about combining treatments? Some of the more robust findings in favor of combined treatment have been associated with structured and highly integrated forms of care, such as IPT or the cognitive behavioral analysis system of psychotherapy (CBASP). It seems likely that treatment integration is related to outcome. A treatment in which the psychopharmacologist and psychotherapist are openly skeptical of each other's work and are working at cross-purposes is not likely to be successful.

When there is a split treatment arrangement, with one person providing psychotherapy and another providing psychopharmacology, good communication between treaters and the sharing of overall treatment goals may enhance treatment. Treatments in which the pharmacologic work is seen to support the therapy and the therapy supports the drug treatment may be the most integrated, as with the model of psychodynamic psychopharmacology developed by Mintz and Belnap,27 which is tailored for work with treatment-resistant patients. In this model, pharmacologic treatment is aimed primarily at supporting the capacity of the patient to usefully engage in psychotherapy. The therapist then feels a direct connection to the medications and sees problems with medication (e.g., noncompliance, fear of dependency, a tendency to develop side effects) as targets for therapeutic exploration. The psychotherapy then explicitly supports the patient's healthy use of medication. The same kind of integrative approach could be undertaken with CBT and medication.

It is not clear at this point whether a single-provider model enhances treatment integration and outcome. To date, there are no published studies that address this issue. In the absence of evidence that single-provider treatments are superior, the economics of health care have tended to promote the delivery of split treatments under the assumption that it would be less costly to have psychotherapy provided by a lower-paid, nonmedical therapist than by the prescribing psychiatrist.

In contrast to this assumption, two studies using different methodologies, have examined the question of which treatment (single-provider or split) was more costly.31,32 Both studies found single-provider combined treatment to be less costly than split treatments with a psychiatrist/pharmacologist and a nonmedical therapist. While it is not yet clear whether single-provider treatment is more clinically effective than split treatment, the evidence suggests that it is more cost-effective.

While combined treatment has been shown to be generally more effective than single-modality treatments and substantially more effective for certain kinds of patients, there is still much work that needs to be done to establish whether there are other subpopulations of patients with depression who would benefit from combined treatment. There is also still much to learn about the specific factors (e.g., treatment integration) that contribute to the greater treatment effectiveness of combined treatment.

_Dr Mintz is director of residency training and continuing medical education at the Austen Riggs Center in Stockbridge, Mass. He reports no conflicts of interest concerning the subject matter of this article._

*References:*

Klerman GL, DiMascio A, Weissman M, et al. Treatment of depression by drugs and psychotherapy. Am J Psychiatry. 1974;131:186-191.
Luborsky L, Singer B, Luborsky L. Comparative studies of psychotherapies. Is it true that "everywon has one and all must have prizes"? Arch Gen Psychiatry. 1975;32:995-1008.
DiMascio A, Weissman MM, Prusoff BA, et al. Differential symptom reduction by drugs and psychotherapy in acute depression. Arch Gen Psychiatry. 1979; 36:1450-1456.
Hollon SD, DeRubeis RJ, Evans MD, et al. Cognitive therapy and pharmacotherapy for depression singly and in combination. Arch Gen Psychiatry. 1992;49:774-781.
Jindal RD, Thase ME. Integrating psychotherapy and pharmacotherapy to improve outcomes among pa- tients with mood disorders. Psychiatr Serv. 2003;54 :1484-1490.
Blackburn IM, Eunson KM, Bishop S. A two-year naturalistic follow-up of depressed patients treated with cognitive therapy, pharmacotherapy, and a combination of both. J Affect Disord. 1986;10:67-75.
Teasdale JD, Fennell MJV, Hibbert GA, Amies PL. Cognitive therapy for major depressive disorder in primary care. Br J Psychiatry. 1984;144:400-406.
Bowers WA. Treatment of depressed in-patients: cognitive therapy plus medication, relaxation plus medication, and medication alone. Br J Psychiatry. 1990;156: 73-78.
Conte HR, Plutchik R, Wild KV, Karasu TB. Combined psychotherapy and pharmacotherapy for depression: a systematic analysis of the evidence. Arch Gen Psychiatry. 1986;43:471-479.
Thase ME, Buysse DJ, Frank E, et al. Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles. Am J Psychiatry. 1997;154:502-509.
Prusoff BA, Weissman MM, Klerman GL, Rounsaville BJ. Research diagnostic criteria subtypes of depression: their role as predictors of differential responses to psychotherapy and drug treatment. Arch Gen Psychiatry. 1980;37:796-801.
Arnow BA, Constantino MJ. Effectiveness of psychotherapy and combination treatment for chronic depression. J Clin Psychol. 2003;59:893-905.
Hellerstein DJ, Little SA, Samstag LW, et al. Adding group psychotherapy to medication treatment in dysthymias: a randomized prospective pilot study. J Psychother Pract Res. 2001;10:93-103.
Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazedone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000; 342:1462-1470.
Miller IW, Norman WH, Keitner GI. Cognitive-behavioral treatment of depressed inpatients: six- and twelve-month follow-up. Am J Psychiatry. 1989;146: 1274-1279.
Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54:1009-1015.
Fava GA, Grandi S, Zielesny M, et al. Cognitive behavioral treatment of residual symptoms in primary major depressive disorder. Am J Psychiatry. 1994;151: 1295-1299.
Paykel ES, Scott JD, Teasdale J, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56: 829-835.
Teasdale JD, Segal ZV, Williams JM, et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol. 2000;68:615-623.
Reynolds CF 3rd, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999;281:39-45.
Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34-41.
Mayberg HS. Modulating limbic-cortical circuits in depression: targets of antidepressant treatments. Sem Clin Neuropsychiatry. 2002;7:255-268.
Castren E. Is mood chemistry? Nat Rev Neurosci. 2005;6:241-246.
Basco MR, Rush AJ. Compliance with pharmacotherapy in mood disorders. Psychiatr Ann. 1995;25: 269-279.
de Jonghe F, Kool S, van Aalst G, et al. Combining psychotherapy and antidepressants in the treatment of depression. J Affect Disord. 2001;64:217-299.
Vergouwen AC, Bakker A, Katon WJ, et al. Improving adherence to antidepressants: a systematic review of interventions. J Clin Psychiatry. 2003:64:1415-1420. 
Mintz DL, Belnap BA. What is psychodynamic psychopharmacology? An approach to psychopharmacologic treatment resistance. J Am Acad Psychoanal. In press.
Seligman ME. The effectiveness of psychotherapy: the Consumer Reports study. Am Psychol. 1995;50: 965-974.
Krupnick JL, Sotsky SM, Simmens S, et al. The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome: findings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psychol.1996;64:532-539.
Mintz D. Meaning and medication in the care of treatment-resistant patients. Am J Psychother. 2002;56: 322-337.
Dewan M. Are psychiatrists cost-effective? An analysis of integrated versus split treatment. Am J Psychiatry. 1999;156:324-326.
Goldman W, McCulloch J, Cuffel B, et al. Outpatient utilization patterns of integrated and split psychotherapy and pharmacotherapy for depression. Psychiatr Serv. 1998;49:477-482.
Fava GA, Rafanelli C, Grandi S, et al. Six-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1998;155: 1443-1445.
Browne G, Steiner M, Roberts J, et al. Sertraline and/or interpersonal psychotherapy for patients with dysthymic disorder in primary care: 6-month comparison with longitudinal 2-year follow-up of effectiveness and costs. J Affect Disord. 2002;68:317-330.
Miller IW, Norman WH, Keitner GI. Treatment response of high cognitive dysfunction depressed inpatients. Compr Psychiatry. 1990;31:62-71.


----------

