Friday, January 11, 2013

Lamotrigine review: bipolar depression, unipolar depression, borderline personality, OCD

Lamotrigine is a novel anticonvulsant.  Clearly it is useful for treating epilepsy, in terms of reducing seizure frequency in difficult cases, with a better side-effect profile than many other anti-seizure medications. 

It has been used in psychiatry for over 10 years, mainly to treat bipolar depression.  Initial studies were quite encouraging.  More recent studies have been a bit more mixed. 

Here are a few recent references: 
this was a large study of using lamotrigine as an augmentation to treat unipolar depression.  It did not show that lamotrigine was useful overall.  But it appeared much more effective in a subgroup of  patients with much more severe depression.  Average doses were about 200 mg/d, maximum 400 mg.
this study showed improvements in affective lability with lamotrigine vs. placebo, in patients with borderline personality, using a flexible dose (average about 100 mg/day).  200 mg/d lamotrigine  helpful for bipolar depression as add-on with lithium x 8 wks
no difference in depression scores with lamotrigine vs placebo  as add on for bipolar patients  adding lamotrigine 100 mg to an SSRI improved symptoms (about 30% reduction in YBOCS score) in OCD patients, compared to placebo, after 16 weeks.

In conclusion, I think lamotrigine is in the "why not give it a try" category for a variety of problems.  It might possibly help for treating depression in bipolar patients, or even as an augmentation in unipolar depression.  It might be useful in OCD patients, and in borderline personality.  It may be one of those agents which helps some individuals very well, even though the average effect for a group of similarly afflicted individuals may be unremarkable.  Another possibility is that it could help with certain symptom domains, such as obsessionality, ruminativeness, etc. which could occur more prominently in some but not all patients with mood or personality disorders. 

I think the big advantage of lamotrigine is that it is quite well-tolerated, with a benign side-effect profile, except for a small risk of a dangerous rash and a few other rare serious problems, which just need to be watched for carefully. 

Thursday, January 10, 2013

N-acetylcysteine for OCD

I've written a post about N-acetylcysteine before (, which suggested that it could be useful in treating compulsive behaviour disorders such as skin-picking. 

A recent 2012 study by Afshar et al. has shown that NAC is useful for treating obsessive-compulsive disorder (OCD).  Here's the reference:

In this study, 48 patients with OCD who had not responded to an SSRI were given NAC up to 2400 mg/day or placebo, in addition to a continued dose of the same SSRI, for 12 weeks. 

The NAC group had about a 40% reduction in YBOCS score (a quantitative measure of OCD symptoms) after 12 weeks, compared to a 20% reduction in the placebo group.  This is a good, clinically relevant symptom change especially for a treatment-resistant group. 

Mild gastrointestinal complaints were more common in the NAC group, but there was not a big difference in drop-out rates between placebo and NAC. 

NAC works as as a glutamate-modulating agent, with possible anti-inflammatory effects.  It is metabolized to the amino acid cystine after entering the brain. 

So it appears that NAC could be a simple, low-risk, effective adjunct, or even a primary treatment modality, for obsessive-compulsive disorder. 

I would be curious to see more research looking at NAC for other anxiety disorders, or for ruminative depression. 

Wednesday, January 9, 2013

Long-term clonazepam for panic disorder

The treatment of anxiety disorders, particularly panic disorder, should emphasize behavioural and cognitive therapy, exercise, lifestyle factors, etc. 

But medication treatments can often be very helpful if these other therapies are not helping.  The trend of thinking on this matter over the past few decades has been to preferentially use SSRI antidepressants, and to minimize the use of benzodiazepines such as clonazepam, due to concerns about side effects and dependence. 

This study challenges that notion:   It is a 3 year followup study (an excellent duration for a psychiatric study!) -- and compares paroxetine 40 mg/d with clonazepam 2 mg/d (all doses taken at bedtime) for treatment of panic disorder. 

The clonazepam alone group did very similarly well to the paroxetine group, with even a slight edge of superiority over paroxetine.  And there were fewer side effect complaints in the clonazepam group compared to paroxetine.  There was no advantage to combined therapy (clonazepam + paroxetine). 

While I still remain concerned about dependency and abuse problems with benzodiazepines, this type of study affirms that long-term benzodiazepine use may be helpful--and possibly superior to antidepressants--for some patients. 

Interesting Augmentations 2: L-methylfolate

L-methylfolate is an active form of folic acid which enters the brain.  Folic acid supplementation has been considered for decades in treating depression, with varying results (generally mildly positive).  The mechanism in the brain is generally as an indirect enhancer of the production of neurotransmitters, through its involvement in the metabolic pathway. 

Here are some recent studies looking at l-methylfolate as an augmentation:
Here, a dose of 15 mg/day of l-methylfolate (but not 7.5 mg) added to an SSRI led to a doubling of the response rate for depressed patients, after 30 days (about 30% vs. 15%).   These patients had previously been on the same SSRI alone without response.   There were no side effect problems.
Another positive study from 2011.  Again showing a significant improvement in response rate with l-methylfolate augmentation, with no side effect problems (probably fewer side effects in the folate group).  But this is a much weaker study due to it being retrospective. 

As I look further at this I see some controversy about whether there may be bias here, as the methylfolate is quite an expensive product.  I would want to see a comparison study between methylfolate and the much more inexpensive ordinary folic acid.    In discussions I've looked at pertaining to this issue, the argument is made that the dose of ordinary folic acid would be very high to match 15 mg of l-methylfolate.  Maybe so--but it would be very simple to do a comparison study, since if there is no clinical superiority of one over the other, then the more affordable product should be recommended. 

Tuesday, January 8, 2013

Interesting Augmentations 1: creatine + SSRI

From my annual review of articles from psychiatry journals, here is the first of a few which caught my eye: they're very simple studies looking at medication augmentations.  

An augmentation refers to adding some type of therapeutic agent (usually a medication) to help make another therapeutic modality work better.  Usually an augmentation would not be expected to help much on its own--the term implies that it must be used with something else.  Typical augmentations in common use are triiodothyronine (a form of thyroid hormone) or lithium added to antidepressants to treat depression. 

It's always nice to see an article which has an extremely simple premise (e.g. to try some new therapy or other), which could be readily applied in an attempt to help someone immediately. 

The first article is from a Korean group (Lyoo et al.) published in the American Journal of Psychiatry in September 2012. ( )   They looked at treating 52 women having a major depressive episode, with either escitalopram 10-20 mg/day plus placebo, or escitalopram 10-20 mg plus 5 grams of creatine monohydrate daily.  

From the second week of treatment onwards, the creatine group had better symptom improvement.  After 8 weeks, over 50% of the creatine group met criteria for remission, compared to only about 25% of the placebo group. 

Creatine has been used for years as a type of muscle-building supplement.  It may have some benefits for various neuromuscular and other neurological disorders.  Risks and side-effects are minimal, according to my reading of existing evidence, particularly at doses of 5 grams per day or less  (see this risk assessment review: ).    In the brain, the mechanism is of improving ATP availability, thereby improving cellular energy dynamics.  Humans obtain creatine from the diet (about 1 g/day) and from synthesis inside the body (another 1 g/day).  So it makes sense to have therapeutic doses well above the body's baseline supply of 2 g/day.   Here is a reference to an excellent review article by Persky (2001

Creatine is readily available wherever one would obtain nutritional supplements.  If one were to try creatine, I might suggest looking for pure creatine monohydrate, as opposed to some mixture (typically with protein powder), as the mixture would be more expensive, and would often contain unnecessary additives such as artificial sweeteners.  The creatine could be ingested as a partially dissolved suspension in warm water or juice.  The dosing regime could be debated somewhat, as creatine has quite a short half-life in plasma.  This current study used a single large dose daily, but the idea of using divided dosing should be explored.