2004 overview: Combined pharmacotherapy and psychotherapy for depression

In this overview Professor Lars Kessing, Denmark, discusses one of the issues in the treatment of depression that attracted special interest in 2004.

Cognitive Behavioural Therapy (CBT) is one of the most well validated psychological treatments for depression and is increasingly being used in the treatment of patients with depression.

For mild to moderate depression, CBT may be used as monotherapy. For acute moderate to moderately severe depression, CBT may primarily play a role in combination with antidepressive pharmacological treatment.

However, as concluded in two recent reviews from this year (ref. 1, ref. 2), the evidence for a better effect of combined psychotherapy and pharmacotherapy than of monotherapy with either of the treatments is still not strong due to rather small sample sizes and poor methodology in most studies.

The tendency seems to be that the more severe or chronic depressive episodes, the more is to gain from combination therapy.

Strange situation

We are currently in the rather strange situation that the evidence of combination therapy of CBT and pharmacotherapy is better for the treatment of adolescents with depression than for the treatment of adults with depression. This is due to a single study published in 2004 (ref. 3).

This study is remarkable as it satisfies most modern demands for a randomised controlled trial. In fact, no other study has investigated the effectiveness of combined CBT and antidepressive medication for depression in youth, but due to the extraordinary high quality of this study, it outnumbers, in my opinion, all other studies investigating combined CBT and pharmacological treatment among adults.

Sufficient sample size

The study included a sufficient sample size of 439 patients based on power calculations made during the planning of the study. Randomization was done at a central computer stratifying for treatment site and sex.

Independent researchers who were physically isolated from patients, data and treating clinicians, did the assessment of outcome. A placebo group was included.
Primary outcomes were chosen a priory. Patients had mild to severe depression with a low spontaneous remission rate as illustrated by a relatively low placebo response.

More than 50 % of the sample exhibited one or more comorbid disorders in contrast to most industry-funded trials, increasing the generalizability of the findings. Analyses were done according to the "intention to treat" principle.

Patients between 12 and 17 years

The study was conducted at 13 US academic and community clinics. Patients between the ages of 12 and 17 years with depression were randomised to

fluoxetine alone (10-40 mg)
CBT alone
CBT with fluoxetine
placebo

All interventions were given during a 12 weeks course.

The learnings from the study

The learnings from the study are clear:

The combination of pharmacotherapy (fluoxetine) with CBT produces the greatest improvement in depressive symptoms compared with pharmacotherapy alone and compared with CBT alone.
Pharmacotherapy alone is more effective than CBT and more effective than placebo.
CBT alone is not more effective than placebo.
Suicidal ideation improved in all four treatment groups, but most in the combined pharmacotherapy and CBT group.

An interesting question is whether CBT has similar effects on brain function and metabolism as antidepressants. Findings from a few recent studies suggest that interpersonal psychotherapy (IPT) is associated with a variety of changes in brain function - as illustrated by brain imaging - and that these changes mimic the changes seen following pharmacologically treatment.

Effect on CBT on brain function

The first study to investigate the effect of CBT on brain function was published in 2004 (ref. 4). In this study, 17 unmedicated patients with moderate to severe depression were treated with CBT.

These patients were in post hoc analyses compared to 13 patients treated for depression with paroxetin in a prior study. Both groups of patients underwent PET glucose metabolism scans (FDG) in the resting state less than a week before and after treatment.

The results were, however, somewhat curious as the expected frontal hypometabolism found in many prior studies of depression not was confirmed in either of the treatment groups in the pre-treatment PET scans.

Most significantly, scans in patients treated with CBT showed increase in metabolism in hippocampus and decrease in frontal cortex while the patients treated with paroxetine showed the inverse changes – frontal increases and hippocampal decreases.

The groups showed similar changes in the ventral lateral frontal region and inverse changes in other regions as well.

Confusing but encouraging

Although the results of this preliminary study thus is somewhat confusing it is encouraging with a study comparing the effect of CBT on brain metabolism with brain changes associated with pharmacotherapy.

We urgently need these studies for better understanding what we are doing in clinical practice. The future scope is to develop more sophisticated brain scanning methods allowing us to differentiate between different types of depression and different kinds of successful psychological and pharmacological treatments.

The ultimate aim is that we as clinicians are able to precisely define the depressive subtype and the corresponding most effective treatment or combination of treatments.