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A combination of prescribed drugs and psychotherapy is often regarded as a superior intervention to the use of these drugs or therapy alone, particularly with depression. The current NICE guidance1 for depression includes recommendations for combined treatment, especially for more severe symptoms and for when previous treatments or various types have been ineffective.

On the other hand, it has long been recognised that the effects produced by taking psychoactive drugs, whether prescribed or illicit, may interfere with the learning and personal development that is an integral part of therapy. For example, if someone is taking benzodiazepines that dampen anxiety, then they may not be able to learn other techniques to manage the anxiety. Any drug that dampens emotions or sensitivity may interfere with efforts to control and manage emotional reactions in non-pharmacological ways.

The idea that combined intervention is more effective is based on several assumptions. Antidepressant drugs are assumed to target the biological causes of depression, whilst psychotherapy separately targets perpetuating psychological factors, with the two interventions leading to a cumulative therapeutic effect.2 However, this is problematic for several reasons.

As outlined in 4.2, there is no convincing evidence for any biological abnormalities underlying depression, which are effectively targeted by antidepressant drugs. In other words, current evidence does not support the idea that antidepressants improve or correct a specific biological component to depression (a disease-centred model), which could act in parallel with psychotherapy.

In addition, the evidence for the actual effectiveness of antidepressants in depression is beset by multiple flaws (see section 4.2.5). Meta-analyses have reported that antidepressants may have slightly more effect than placebo in the short-term reduction of depression symptom scale scores, but it is not clear that such an effect is clinically relevant and could provide an additional benefit to psychotherapy, or that it is a specifically pharmacological effect as opposed to an amplified placebo effect.

NICE suggest that antidepressants can enable more effective therapy through effects such as improved sleep, motivation and cognitive ability.2 Antidepressants do produce psychological and behavioural changes, as described in Section 4.2. Some antidepressants have sedative effects that may improve sleep, but there is no evidence that any antidepressant increases motivation or cognitive ability more than a placebo. From what we know of the alterations antidepressants produce, it is not clear that they would aid psychotherapy, and they may even be counterproductive.

The sedation produced by some antidepressants, for example, may be useful in terms of increasing sleep and reducing anxiety, but may hamper therapy by impairing clarity of thinking and cognitive function during the day. The emotional restriction associated with SSRIs may, in theory, numb intense hopelessness and feelings of depression, which may help people to engage in therapy, but may also prevent people from learning how to manage their emotions in other ways.

Questions remain about the psychological effects of taking antidepressants and how they may impact on therapy. Many people understand antidepressants to work by reversing the underlying biological causes of depression, because, despite the lack of evidence for this position, this is what they have been told. Therefore, taking antidepressants can signal the idea that depression is a biological condition, over which the individual has little control. This position is logically inconsistent with the aims of therapy to enable people to gain more control over their feelings and behaviour and this is explored in section 3.

Multiple individual studies have looked at whether combined antidepressants and psychological intervention is superior to antidepressants or therapy alone. Overall, the results are contradictory. For example, when comparing a psychological intervention alone to a combined intervention, some studies found the combined intervention to be more effective,3,4 others found no difference,5–7 and others found the psychological intervention alone more effective.8,9 Similarly, when comparing a combined intervention to the drugs alone, some studies found a combination to be more effective,10–12 whilst others did not.13–15

As a result of this confusing overall picture, several meta-analyses of randomised studies have been performed, with many reporting an advantage, of varying degrees, for the use of a combination of antidepressants and psychotherapy over either drugs or psychotherapy alone.16–19 However, judging by two recent meta-analyses, the quality of the individual studies included in these studies varies greatly, leading to questions about the reliability of their results.

For example, one 2009 meta-analysis combined studies that compared antidepressants alone to a combination of antidepressants and psychotherapy for depression.18 It included 25 randomised trials and found that combination was better than antidepressants alone in the short term, in term of changes in depression symptom scores. However, the effect size was small, and whilst statistically significant, possibly not clinically relevant. There was insufficient data to look at longer-term outcomes. The number of studies included was limited, and the individual trials were also fairly small. The average number of patients per study was 81, and 15 studies contained fewer than 50 patients. The trials varied in their target population, with 16 looking at adults in general with depression, and others focusing on more specific groups, such as bereaved older people, and people with other physical or psychiatric conditions in addition to depression.

Many of the studies contained crucial flaws. Understandably, no study could blind participants to their treatment allocation, but only 18 reported blinding of assessors. In addition, only 16 studies conducted intention to treat analysis, in other words including the outcomes of all people who entered the trial. As the dropout rates varied significantly between combined and individual treatment groups, this may have impacted on results.

Another 2009 meta-analysis combined 19 studies comparing combination treatment to psychological treatment alone.19 This also found a small difference in favour of combined treatment between the two groups in the short term, similar in magnitude to the other meta-analyses, which the authors admitted may be too small to be clinically relevant. Some limited follow up data were available, with no difference found between the two groups after three to six and 12 months.

Another 2009 meta-analysis combined 19 studies comparing combination treatment to psychological treatment alone.19 This also found a small difference in favour of combined treatment between the two groups in the short term, similar in magnitude to the other meta-analyses, which the authors admitted may be too small to be clinically relevant. Some limited follow up data were available, with no difference found between the two groups after three to six and 12 months.

Overall, evidence that a combination of antidepressants and psychotherapy is superior to either intervention given alone is not conclusive. The assumptions behind this research, for example, that antidepressants are effective, and that antidepressants and psychotherapy provide distinctive, additive mechanisms against depression have not been proven.

3. Ravindran, A.V., Anisman, H., Merali, Z., Charbonneau, Y., Telner, J., Bialik, R.J. … & Griffiths, J. (1999). Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy: Clinical symptoms and functional impairments. American Journal of Psychiatry, 156(10), 1608–1617.
4. Keller, M.B., McCullough, J.P., Klein, D.N., Arnow, B., Dunner, D.L., Gelenberg, A.J. … & Trivedi, M.H. (2000). A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. New England Journal of Medicine, 342(20), 1462–1470.
5. Murphy, G.E., Simons, A.D., Wetzel, R.D. & Lustman, P.J. (1984). Cognitive therapy and pharmacotherapy: Singly and together in the treatment of depression. Archives of General psychiatry, 41(1), 33–41.
6. De Jonghe, F., Hendricksen, M., Van Aalst, G., Kool, S., Peen, V., Van, R. … & Dekker, J. (2004). Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. The British Journal of Psychiatry, 185(1), 37–45.
7. Thompson, L.W., Coon, D.W., Gallagher-Thompson, D., Sommer, B.R. & Koin, D. (2001). Comparison of desipramine and cognitive/behavioral therapy in the treatment of elderly outpatients with mild-to-moderate depression. The American Journal of Geriatric Psychiatry, 9(3), 225–240.
8. Hersen, M., Himmelhoch, J.M., Thase, M.E. & Bellack, A.S. (1984). Effects of social skill training, amitriptyline, and psychotherapy in unipolar depressed women. Behavior Therapy, 15(1), 21–40.
9. Friedman, A.S. (1975). Interaction of drug therapy with marital therapy in depressive patients. Archives of General Psychiatry, 32(5), 619–637.
10. Bellino, S., Zizza, M., Rinaldi, C. & Bogetto, F. (2006). Combined treatment of major depression in patients with borderline personality disorder: A comparison with pharmacotherapy. The Canadian Journal of Psychiatry, 51(7), 453–460.
11. Macaskill, N.D. & Macaskill, A. (1996). Rational-emotive therapy plus pharmacotherapy versus pharmacotherapy alone in the treatment of high cognitive dysfunction depression. Cognitive Therapy and Research, 20(6), 575–592.
12. Blackburn, I.M., Bishop, S., Glen, A.I.M., Whalley, L.J. & Christie, J. E. (1981). The efficacy of cognitive therapy in depression: A treatment trial using cognitive therapy and pharmacotherapy, each alone and in combination. The British Journal of Psychiatry, 139(3), 181–189.
13. Bellack, A.S., Hersen, M. & Himmelhoch, J. (1981). Social skills training compared with pharmacotherapy and psychotherapy in the treatment of unipolar depression. The American Journal of Psychiatry.
14. Browne, G., Steiner, M., Roberts, J., Gafni, A., Byrne, C., Dunn, E. … & Kraemer, J. (2002). 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. Journal of Affective Disorders, 68(2–3), 317–330.
15. Markowitz, J.C., Kocsis, J.H., Bleiberg, K.L., Christos, P.J. & Sacks, M. (2005). A comparative trial of psychotherapy and pharmacotherapy for ‘pure’ dysthymic patients. Journal of affective disorders, 89(1–3), 167–175.
16. Khan, A., Faucett, J., Lichtenberg, P., Kirsch, I. and Brown, W.A. (2012). A systematic review of comparative efficacy of treatments and controls for depression. PloS one, 7(7), e41778.
17. de Maat, S.M., Dekker, J., Schoevers, R.A. & de Jonghe, F. (2007). Relative efficacy of psychotherapy and combined therapy in the treatment of depression: A meta-analysis. European Psychiatry, 22(1), 1–8.
18. Cuijpers, P., Dekker, J.J.M., Hollon, S.D. & Andersson, G. (2009). Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: A meta-analysis. The Journal of Clinical Psychiatry 70(9):1219–1229. doi: 10.4088/JCP.09r05021.
19. Cuijpers, P., van Straten, A., Warmerdam, L. & Andersson, G. (2009). Psychotherapy versus the combination of psychotherapy and pharmacotherapy in the treatment of depression: A meta-analysis. Depression and anxiety, 26(3), 279–288.

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