Thinking outside the box for ways to treat major depression

Up to 20% of patients with MDD have psychotic symptoms, though their diagnosis is frequently missed because patients do not want to dwell on their “crazy thoughts”. Typically, the delusions are somatic.

It may sound flaky, Professor Shatzberg warned, but Botox treatment could be an antidepressant. Deep furrowing of the brow has been linked to melancholia since the time of Charles Darwin. Now data from Germany and the US suggest Botox injection of the forehead might relieve depressive symptoms. It is thought that depression may not simply be expressed in frowning but also exacerbated by it through feedback from the facial musculature to the CNS. If so, interrupting this cycle makes sense, though the approach has to be further assessed in trials. If these prove positive, the range of uses for Botox could extend from the bladder to the brain.   

Psychotic depression

Psychotic symptoms in MDD are frequently stress related, and characterised by upregulation of the cortisol system. This suggests the possibility of treating them by blocking hypercortisolism. The abortifacient mifepristone has been studied in this role in randomised trials and, unlikely as it may sound, seems to achieve rapid improvement in psychotic symptoms – though only if blood levels of the drug are sufficiently high.

These trials show a placebo response rate of up to 40%, but high rates are not unusual in antidepressant studies. In terms of drug development, this is a major problem and suggests we need harder endpoints than the scales we use at present.

Ketamine uncertainties continue

Ketamine has caused a stir in psychiatry. But there are several concerns. One is the trials.  Most have small numbers of patients, and it is difficult to maintain blinding. There is some doubt about whether ketamine has a sustained effect, as well as about its safety and tolerability. And another issue is that we do not know the mechanism of action. NMDA blockade seems too simple an explanation.

Is the rapid onset of antidepressant effect caused by a surge of glutamate? Or catecholamines? Or is ketamine really an opioid, which would fit with the analgesic effects? The lack of clarity on mechanism of action has practical consequences if we are seeking to use ketamine’s apparent activity to guide development of more effective and better tolerated drugs.  

Deep brain stimulation

For a while, this seemed promising for highly refractory depression. But the premature termination of two randomised trials has led many to question the validity of the approach. It may be that the positioning of the electrodes in the subgenual capsule or the anterior capsule was inconsistent from one centre to another. And maybe the medial forebrain bundle is a better target, as suggested by the pilot study of Thomas Schlaepfer et al. But for now we still await convincing evidence for its benefits in MDD.

Pharmacogenetics

We are on the cusp of introducing pharmacogenomics into clinical practice in depression. But from what we know at present, genetic markers look more promising as a means of predicting side effects than as a means of predicting clinical response, Professor Schatzberg suggested.