Monday, February 6, 2012

Scopolamine for Depression

Scopolamine is an acetylcholine-receptor blocker, which is usually used to treat or prevent motion sickness. Some recent studies show that it might be useful to treat depression.  Here is some background, followed by a few references to research studies:  

The old tricyclic antidepressants (such as amitriptyline) were shown over many years to work very well for many people.  Unfortunately, they are laden with side-effect problems and a significant toxicity risk (they can be lethal in overdose).  The side effects are due to various different pharmacologic effects, particularly the blockade of acetylcholine and histamine receptors.  Newer antidepressants, such as those in the SSRI group, have very few such receptor blockade effects.

In some studies, however, the old tricyclics actually are superior to newer antidepressants, especially for severely ill hospitalized depression patients.

It is interesting to consider whether some of the receptor blockade effects which were previously considered just nuisances or side-effect problems, could actually be part of the antidepressant activity.  Or, in some cases, drugs which primarily have receptor blockade side effects may actually be indirectly modulating various other neurotransmitter systems.

A clear precedent exists in this regard:  clozapine is undoubtedly the most effective antipsychotic, but it is loaded with multiple side effects and receptor blockades.  It may be --at least in part-- because of the receptor blockades, not in spite of them, that it works so well.  

Another example of this effect, quite possibly, is related to what I call the "active placebo" literature (I have referred to it elsewhere on this blog:  The active placebos used in these studies usually had side effects  due to acetylcholine blockade, and the active placebo groups usually improved quite a bit more than those with inert placebos.  This suggests another interpretation of the "active placebo" effect:  perhaps it is not simply the existence of side-effects that psychologically boosts a placebo effect here, it is that the side-effects themselves are due to a pharmacologic action that is actually of direct relevance to the treatment of depression.

Here are some studies looking at  scopolamine infusions to treat depression:
This 2006 study from Archives of General Psychiatry showed that 4 mcg/kg IV infusions of scopolamine  (given in 3 doses, every 3-5 days) led to a rapid reduction in depression symptoms (halving of the MADRS score), with a pronounced difference from placebo.   Of particular  note is that the cohort consisted mainly of chronically depressed patients with comorbidities and unsuccessful trials of other treatments.  Surprisingly, there were few side effect problems, aside from a higher rate of the expected anticholinergic-induced dry mouth and dizziness.
This is a replication of the study mentioned above, published in Biological Psychiatry in 2010.
Another similar study, this time showing a greater effect in women; again a 4 mcg/kg infusion protocol was used.
evidence from an animal study that scopolamine --or acetylcholine blockade in general-- affects NMDA-related activity, in general antagonizing the effects of NMDA.   This is consistent with a theory that scopolamine may work in a similar manner to the NMDA-blocker ketamine (which has been associated with rapid improvement in depression symptoms) but without nearly as much risk of dangerous medical or neuropsychiatric side-effects.
This article looks at the pharmacokinetics of infused scopolamine, and also gives a detailed account of side-effects.  There are notable cognitive side-effects, such as reduced efficiency of short-term memory.
This study looks at dosing scopolamine as a patch.  The patch is designed to give a rapidly absorbed loading dose, then a gradual release to maintain a fairly constant level over 3 days.  My own estimation, based on reviewing this information, is that a scopolamine patch would roughly approximate the IV doses used in the depression treatment studies described above, though of course the serum levels would be more constant.

Transdermal scopolamine (patches) are available in Canada from pharmacists without a physician's prescription.

While this is an interesting--though far from proven-- treatment idea, it is very important to be aware of anticholinergic side effects, which at times could be physically and psychologically unpleasant.  At worst, cognitive impairment or delirium could occur as a result of excessive cholinergic blockade.  Therefore, any attempt to treat psychiatric symptoms using anticholinergics should be undertaken with close collaboration with a psychiatrist.


superactionRN said...

Dr. Kroeker,

Do you have any patient experience specific to the efficacy of the scopolamine transdermal patch for the treatment of MDD? If not, have you ever considered it as primary or adjunctive therapy? If so, what influenced your decision to rule it out as an option? Thanks in advance.

GK said...

I've seen a bad reaction to the patch. But I don't rule it out as an option. The trouble with scopolamine patches, compared to IV scopolamine, is that they produce a relatively continuous serum level for days at a time, while the IV dosing produces a spiking level over a few hours. It may be that brief spikes of serum level are more effective or more tolerable in terms of side-effects. I suppose that experimenting with using a scopolamine patch just for 6 hours at a time, every few days, might be a valid alternative dosing strategy. Another problem with this, though, is that no one has done a good controlled study of such a strategy. So in the meantime, it must be considered a third-line possibility to be approached cautiously with good medical supervision.

Anonymous said...

Do you know any doctors in the US that rx scopolamine for depression? I contacted NIH about their clinical trial for scopolamine and b/c I live outside Maryland, I would have to go inpatient for 1 1/2 to 3 months to be in the trial. This is something that I don't really want to do. I am trying to find a doctor in my area that would rx scopolamine. Thank you.

GK said...

I don't know about the specific practices of individual doctors outside of Vancouver (and even here, my knowledge of others' practices is quite limited).

Some individual physicians might more willing than others to try something a bit different, provided there is some evidence-based support. I encourage you to be equipped with copies of research studies to discuss with your physician around such matters.