N-acetylcysteine for OCD

I've written a post about N-acetylcysteine before (http://garthkroeker.blogspot.ca/2009/09/n-acetylcysteine-for-treatment-of.html), 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: http://www.ncbi.nlm.nih.gov/pubmed/23131885

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. 

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:  http://www.ncbi.nlm.nih.gov/pubmed/22198456   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:

http://www.ncbi.nlm.nih.gov/pubmed/21311704
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. 

http://www.ncbi.nlm.nih.gov/pubmed/23212058
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. 

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. (  http://www.ncbi.nlm.nih.gov/pubmed/22864465 )   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:  http://www.ncbi.nlm.nih.gov/pubmed/16814437 ).    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 http://www.ncbi.nlm.nih.gov/pubmed/11356982

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. 

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: http://garthkroeker.blogspot.com/2009/03/active-placebos.html)  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:

http://www.ncbi.nlm.nih.gov/pubmed/17015814
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. 

 http://www.ncbi.nlm.nih.gov/pubmed/20074703
This is a replication of the study mentioned above, published in Biological Psychiatry in 2010. 

 http://www.ncbi.nlm.nih.gov/pubmed/20736989
Another similar study, this time showing a greater effect in women; again a 4 mcg/kg infusion protocol was used. 

http://www.ncbi.nlm.nih.gov/pubmed/20926947
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.

http://www.ncbi.nlm.nih.gov/pubmed/21306419
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.

http://www.ncbi.nlm.nih.gov/pubmed/16719539
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.

Antidepressants = Psychotherapy = Placebo ?

Jacques Barber et al. have recently published the results of a randomized, controlled study conducted between 2001 and 2007, comparing antidepressant therapy, short-term dynamic psychotherapy, and placebo in a 16-week course of treatment for 156 depressed adults.  Here is a link to the abstract: http://www.ncbi.nlm.nih.gov/pubmed/22152401


The bottom line in the study was that there was no significant difference between antidepressants, psychotherapy, or placebo. Response rates were 31% for medication,   28% for psychotherapy, and  24% for placebo -- which has a low probability of being statistically different.  Remission rates were 26% for medication, 22% for psychotherapy, and 20% for placebo. 

Critics trying to explain these findings might attempt to argue that the psychotherapy or the medication regime was not sufficient, etc. -- but I do not see this to be true.  The medications (venlafaxine or sertraline) were given at quite sufficient doses for good lengths of time.  The psychotherapy was not CBT (which has a larger research evidence base) but there is little reason, in my opinion, to believe that the therapy style was inferior.

The authors attempt to do some secondary analyses looking for explanations, but their conclusions seem quite weak to me (e.g. regarding race or gender).   The fact that they spin these conclusions into a prominently framed set of "clinical points" seems quite inappropriate to me -- this is a negative study, there are no "clinical points" to be found here, unless they recommend placebos and cessation of other therapies!

There are a number of issues from this study that I do find very important to discuss:

1) despite a massive amount of data showing that various therapies (e.g. antidepressants or psychotherapy) are effective for various problems, there are examples of carefully-conducted negative studies, such as this one.  These results cannot simply be explained away as statistical aberration:  there must be a reason why one group of people responds to a treatment, while another does not.  Many of these reasons are poorly understood.  It may be that the diagnostic category of "major depressive disorder" is inadequate, in that it correlates poorly on its own with treatment responsiveness.

2) the subjects in this study had a high degree of comorbidity (e.g. substance abuse problems, anxiety disorders, and axis II problems).  While the severity and chronicity of depression was not found to actually correlate with treatment responsiveness, I suspect that the comorbidities would substantially affect response to a relatively short-term course of therapy. 

3) the subjects in this study were socioeconomically disadvantaged; while the effect of SES was also not found to "influence the initial findings,"  I believe that low SES is not necessarily a direct negative influence upon mental health; rather it is an indirect factor which for many people increases the likelihood of some profound mental health negatives (e.g. unemployment, lack of meaningful or satisfying employment, lack of healthy or safe community, lack of availability to do healthy or meaningful leisure activities, not enough money to eat healthily, etc.).  I believe that the environmental adversities need to be looked at very closely in a study of this type.

This leads to what I believe is an obvious explanation for the findings here:  there is no therapy for depression that is likely to help unless ALL contributing factors (including obvious environmental contributing factors) are addressed.   By way of analogy, I believe it is pointless to treat insomnia using a powerful sedative if a person is sleeping in a room which is continuously noisy, cold, and prone to break-ins by violent intruders.  The environmental issues need to be addressed first!  Another analogy I have often used is of trying to repair a water supply system for a city:  it is a waste of effort to pipe in more water from rivers, or to dig a deeper reservoir, if the walls of the reservoir and the pipes are leaking or bursting because of structural defects.   In order for a therapeutic strategy to work, the "leaks" have to be repaired first.  For a person with anemia, it is not an appropriate strategy to simply give a blood transfusion:  while a transfusion may be necessary, it will not be sufficient--and could even make matters worse-- if the underlying cause of blood loss is not addressed and treated.

In the case of medications or psychotherapy, I believe these can be very helpful, but only if environmental adversity is also remedied.  In some instances, of course,  relief of a psychiatric symptom could help a person to improve the environmental circumstances.  But in most other cases, I think the issue is broader, and could be considered a political or social policy matter.

Another related issue is that I do not believe "depression" can be treated on its own without addressing all psychiatric and medical comorbidities at the same time.  Ongoing substance abuse, in my opinion, is often a powerful enough factor--psychologically as well as neurophysiologically--to completely dominate and dissolve the positive influences of psychotherapy or effective medication.  In this study, 30-40% of the cohort reported substance use problems. 

As a final thought, I think the "5 axis" model of diagnosis in the DSM system deserves some affirmation; many times, however, we only pay attention to Axis I (diagnoses such as depression or schizophrenia, etc.) or Axis II (personality disorder).  I think that studies such as this one highlight the necessity to look closely at Axes III (medical illnesses) and IV (social, community, financial, and relational problems).  It is likely that issues on these latter two axes can prevent any resolution of problems on the first two.

Piracetam

Piracetam is a so-called "nootropic" drug, a substance which supposedly helps improve cognitive functioning.  It is available without prescription as a sort of supplement in many parts of the world.  In Canada it is not illegal, but must be imported (such as by ordering over the internet from U.S. suppliers).

The mechanism of action is not clear.   There is no obvious single receptor-mediated mechanism.  There may be various effects on ion channels, cell membrane characteristics, etc. but of course such statements are quite vague.

It is quite clear that there are few side-effect problems or toxicity risks with this agent.  Doses are typically 2-5 grams per day.

I became interested in this agent after encountering a case example of someone who reported quite a dramatic improvement in mood and overall functioning attributed to piracetam supplementation.

Here are the results of my survey through the research literature:


http://www.ncbi.nlm.nih.gov/pubmed/16007238  -- a 2005 review

http://www.ncbi.nlm.nih.gov/pubmed/1794001  -- a 1991 review looking specifically at its use  in treating  dementia; the data is really not impressive at all for dementia treatment.  

http://www.ncbi.nlm.nih.gov/pubmed/11084917  -- a 2000 Japanese study affirming the effectiveness of piracetam combined with clonazepam  for treating myoclonus  (myoclonus is a neurological problem in which muscles are twitching involuntarily). 


http://www.ncbi.nlm.nih.gov/pubmed/8914096  -- a 1996 study from Japan also showing benefit in treating myoclonus;  there were also improvements in motivation, attention, sleep, and mood (possibly secondary to improvement in the movement disorder). 


http://www.ncbi.nlm.nih.gov/pubmed/11346373 -- 2001 study from Archives of Neurology again affirming that piracetam is effective over 12 months of follow-up for treating myoclonic epilepsy. 

http://www.ncbi.nlm.nih.gov/pubmed/10796585 -- this 2000 Cochrane review stated that the data on piracetam are inconclusive, with studies not being of good quality


http://www.ncbi.nlm.nih.gov/pubmed/10338110 - this 1999 article reviewed studies of piracetam for treating vertigo, concluding that it was useful for reducing frequency of recurrence, at doses of 2-5 grams per day. 

http://www.ncbi.nlm.nih.gov/pubmed/17685739  -- this is a 2007 randomized placebo-controlled study from The Journal of Clinical Psychiatry,  in which piracetam 4800 mg/d for 9 weeks led to substantial improvements in tardive dyskinesia, with large differences from placebo.


http://www.ncbi.nlm.nih.gov/pubmed/10338108  -- piracetam has some antiplatelet function, which could be used in managing or preventing recurrences of vascular disorders.  This is a 1999 review of this subject.


http://www.ncbi.nlm.nih.gov/pubmed/8061686  -- this is a broad review of nootropics, published in 1994.


http://www.ncbi.nlm.nih.gov/pubmed/3305591  -- this 1987 study from The Journal of Clinical Psychopharmacology shows that children treated with piracetam may show improvements in dyslexia.
Doses were 3.3 grams daily x 36 weeks (dosed twice per day).  However, as I look at the results, I see that there is a statistical difference, but the numbers really look very similar between placebo and piracetam.    The placebo group improved substantially; the piracetam group improved only slightly more.  For example, the raw scores in the Grey Oral Reading Test increased from 17.1 to 22.5 in the placebo group; in the piracetam group it increased from 14.8 to 22.9.   It is true that the piracetam was well-tolerated, with minimal side-effect problems.

http://www.ncbi.nlm.nih.gov/pubmed/12394531
this is a 2002 study which attempted to show whether piracetam could prevent ECT-induced cognitive problems.   The dose was 7.2 g/day for a 2-week loading phase, then 4.8 g daily for the remaining 2 weeks.  They concluded that piracetam had no effect on cognition in this group; but the piracetam group did slightly better than the placebo group in terms of overall clinical improvement. 


http://www.ncbi.nlm.nih.gov/pubmed/16878489
this 2006 study described anxiolytic effects of piracetam which were blocked by flumazenil (a benzodiazepine receptor blocker), suggesting that piracetam has some GABA-like activity. 

http://www.ncbi.nlm.nih.gov/pubmed/12809069
a Hungarian study describing successful use of piracetam to treat alcohol withdrawal delirium

http://www.ncbi.nlm.nih.gov/pubmed/7906672
a 1993 Indian study showing that piracetam has anti-anxiety effects when administered on a longer-term basis in rats.  


http://www.ncbi.nlm.nih.gov/pubmed/95599
a 1979 article from Journal of Affective Disorders describing anti-anxiety effects from piracetam similar to a benzodiazepine, but without sedation.


http://www.ncbi.nlm.nih.gov/pubmed/6415738
in this 1983 study, piracetam 2.4 g/day or 4.8 g/day was compared with placebo in treating 60 elderly psychiatric patients; the 2.4 g/day group showed increased socialization, altertness, and cooperation, and had some improvement on memory and IQ tests, compared to the placebo group.

http://www.ncbi.nlm.nih.gov/pubmed/360232
in this 1977 study, elderly psychiatric patients were given 2.4 g/day of piracetam or placebo, for 2 months.  The piracetam group did not improve in any cognitive tests or mood symptom scores compared to placebo, but interestingly 52% of subjects in the piracetam group showed overall improvement (CGI) compared to only 25% in the placebo group.

http://www.ncbi.nlm.nih.gov/pubmed/11687079
a Cochrane review from 2001 concluding that there is evidence that piracetam may improve the course of aphasia after stroke; however, the evidence was found to be weak. 

http://www.ncbi.nlm.nih.gov/pubmed/6128331
this 1982 study shows that 40 g of IV piracetam caused greater reduction than placebo in antipsychotic-induced Parkinsonian side-effects.



http://www.ncbi.nlm.nih.gov/pubmed/488520
a small 1979 study which showed that refractory depressed patients improved with the addition  of 2.4 g piracetam. 



http://www.ncbi.nlm.nih.gov/pubmed/10338106
a look at toxicity risk due to piracetam, when given in higher doses (12 g/day) for 12 weeks, to stroke patients.  The paper concludes that there is no significant toxicity risk at this dose for this population.


In conclusion, piracetam appears to be clearly effective for a few uncommon conditions, such as myoclonus.  There is possible effectiveness for some other problems such as tardive dyskinesia.  The evidence for effectiveness as a "cognitive enhancer" appears to be quite shaky, but not absent.

I am particularly interested in some of the evidence which suggests that it could be useful as a safe, well-tolerated adjunct to treat depression or anxiety.  Some of the studies quoted above appear to support this possibility.  This theme also intersects with my recent thoughts about considering cognitive function in chronic mood, anxiety, ADHD, or personality disorders. A weakness in working memory capacity or executive functioning could substantially interfere with recovery from psychiatric illness; I suspect that a treatment which could specifically help with cognitive function could be a unique angle to augment treatments for these other psychiatric problems.  (see my previous post, which discusses an association between rumination & working memory dysfunction: http://garthkroeker.blogspot.com/2011/08/chronic-pain-rumination.html).  Here's another link about this: http://www.ncbi.nlm.nih.gov/pubmed/21742932)

I do think it would be worthwhile for research groups to consider doing some new, careful, large trials of piracetam as an augmentation for managing depression, anxiety disorders, etc.

Pregabalin for generalized anxiety

There have been a variety of studies in the literature showing that pregabalin is effective for treating generalized anxiety.


The latest of such studies I have seen is published by Mark Boschen in the September 2011 issue of The Canadian Journal of Psychiatry (p.558-565).  

This article is a meta-analysis, and shows generally that pregabalin is effective compared to placebo, and has similar, if not greater, effectiveness than other medication options for treating generalized anxiety, such as SSRIs, venlafaxine, and benzodiazepines.

The most common doses have been in the 600 mg/day range, which I consider quite high, particularly since a reasonable dose range for pregabalin could be around 75-300 mg/day.  

The "limitations" admitted by the author include issues about dosing, and the fact that Pfizer has funded every published randomized study quoted in the article.

I believe that pregabalin could be a very useful option to try, if a medication trial is being considered for generalized anxiety treatment (of course, the first lines of therapy for generalized anxiety are CBT, relaxation-oriented therapies, meditation, exercise, etc.--but for many people these approaches are not sufficiently helpful).  Pregabalin has the advantage of having a quite different--and generally mild--side effect profile compared to other medications, and a what appears to be a fairly low (but I do not think zero) risk of addictiveness/dependence problems, particularly compared to benzodiazepines.

However -- the most obvious limitation of the literature findings is only mentioned briefly in passing by the author in the discussion:  it is hard to make a good conclusion about a treatment for anxiety when the duration of follow-up is only 4-8 weeks!  I believe that a study for this problem needs to extend for a year or more.  First of all, many treatments for anxiety can be acutely helpful, but then wear off substantially over time.  Arguably, having a beer every 4 hours could reduce GAD scores over a 4-week trial--but obviously this is not an acceptable long-term treatment!  (not only would there be multiple physical harms caused by this over a period of many months or years, but there would be substantial tolerance to anxiety reduction effects, which might only become apparent over many months; furthermore,there would be new psychiatric symptoms induced over a period of months and beyond).

It is not clear from the literature whether the acute benefits over 4-8 weeks from pregabalin would persist over a year or more, whether there would be tolerance, whether there would be longer-term emergent physical or psychiatric side-effects, dependence phenomena, trouble with withdrawal or discontinuation, etc.

Research of this type could be used --spuriously--to justify giving GAD patients benzodiazepines on a routine basis as well, despite the frequent and obvious problem of tolerance, dependence, cognitive problems, etc.  Most benzodiazepine studies are of similarly short duration, hence have very limited value to guide us for the long-term treatment decisions which are most important.

Yet, I do think that pregabalin is promising, and could be worth a cautious try, particularly if other approaches are not working well.

Atomoxetine for ADHD

 Atomoxetine (Strattera) is one of the pharmacological options for treating ADHD symptoms (attention or concentration problems, hyperactivity, impulsivity) in children and adults.  I think it is a good drug, quite safe, quite effective.  It is not likely to help with mood or anxiety symptoms.  Its effect is probably not quite as robust, for most people, compared to stimulants, but it has the compelling advantage of working continuously throughout the day, instead of wearing off (as the stimulants do) after a few hours.  It takes at least 2 weeks of daily dosing for it to work, which differs from the immediate effect of stimulants. 

While it has only a 5-hour half-life in the body, it probably works just as well if dosed once-daily compared to twice-daily.  Side-effects are usually quite mild, including possible dry mouth and reduced appetite.  

It is quite expensive, and is not covered well by medication funding plans in BC.

Here is a brief survey of some of the research literature about atomoxetine that I found interesting:

http://www.ncbi.nlm.nih.gov/pubmed/20665133
This 2010 article demonstrates that once-daily atomoxetine is superior to placebo for treating adult ADHD symptoms, over a 6-month follow-up period.   Treated patients typically had about a 30% reduction in their symptom scores.  Doses were about 80 mg/day.

http://www.ncbi.nlm.nih.gov/pubmed/18448861
This is an important study, with 4 years of follow-up, treating adult ADHD patients on an open-label basis.  The medication was tolerated well, again with ADHD symptom reductions of about 30%.  Depression and anxiety symptoms were not affected.  I tried unsuccessfully to find a clear statement about average doses used in the study; the dosing regime was similar to other studies, with a maximum of 160 mg/day.   From the authors' previous paper on the interim results of this study, the mean dose was about 100 mg/day, the median about 120 mg/day.  So these are higher doses than in some of the other studies, which typically had 80 mg/day dosing.  

http://www.ncbi.nlm.nih.gov/pubmed/20070786
This was a 6-week open study, showing that adults with "atypical ADHD" showed improvement with atomoxetine treatment, doses averaging about 80 mg/day.


http://www.ncbi.nlm.nih.gov/pubmed/20051220
This is an important 2008 meta-analysis, comparing effect sizes of different therapies for adult ADHD.  Short-acting stimulants were best; long-acting stimulants similar (no advantage--if anything, not quite as high an effect size compared to short-acting stimulants); non-stimulants such as atomoxetine significantly helpful, but not quite as large an effect size as stimulants.


http://www.ncbi.nlm.nih.gov/pubmed/17110824This study shows modest but significant improvement in quality-of-life ratings for adult ADHD patients treated with atomoxetine 80 mg/day for 6 weeks.  

http://www.ncbi.nlm.nih.gov/pubmed/20642391
This study shows reduction in high-risk behaviours in adolescents treated with atomoxetine over a 40-week period.  Looking quickly at the results, I see significant differences between atomoxetine and placebo, but the absolute differences were quite modest in size (typically about a 10% change).  Also the study design has a variety of weaknesses. 


http://www.ncbi.nlm.nih.gov/pubmed/17474814
This is one of many studies showing that atomoxetine does not help with depressive symptoms.  In this case, it was used as an adjunct to an SSRI.

http://www.ncbi.nlm.nih.gov/pubmed/19358788
This study showed no improvement in cognitive function in patients with schizophrenia treated with atomoxetine over 8 weeks.  There were no adverse psychiatric effects, however.   This is an important area to study, to determine if ADHD treatments such as atomoxetine are psychiatrically safe for those with other major mental illnesses, such as schizophrenia or bipolar disorder. 

http://www.ncbi.nlm.nih.gov/pubmed/20679638
This 2010 article from Neurology shows that atomoxetine is not useful for treating depression in Parkinson Disease patients.  I find this type of study useful, to look at psychiatric symptoms in medical illnesses.  In such situations, the biological impact of the treatment often seems more clear to me, perhaps with fewer confounding psychological factors.    The study did find that patients treated with atomoxetine (target dose 80 mg/day) had significantly less daytime sleepiness, and significant improvement in "global cognitive function."

http://www.ncbi.nlm.nih.gov/pubmed/19025777
This similar study shows a possible improvement due to atomoxetine treatment--averaging about 90 mg/day--of executive dysfunction in Parkinson Disease patients.  I note also that there was a reduction in other symptom domains, such as apathy and emotional lability; these problems can be difficult to address in those with mood disorders. 


http://www.ncbi.nlm.nih.gov/pubmed/17900980
Here's another interesting study, using atomoxetine to treat sleep apnea patients, averaging about 80 mg/day over 4 weeks.  The atomoxetine did not help reduce apnea, but it did significantly reduce subjective sleepiness.   There are only a couple of fragmentary mentionings of atomoxetine in treating narcolepsy, another disorder of excessive sleepiness; here is one case report: http://www.ncbi.nlm.nih.gov/pubmed/16268387 Excessive sleepiness is another challenging symptom I see a lot of in young adult depression; antidepressants often don't help with the sleepiness, and tolerance tends to develop for stimulants.  So atomoxetine may be another useful option. 

Dopamine Agonists in Psychiatry

The dopamine agonists pramipexole and ropinirole are drugs used in the treatment of Parkinson Disease.

These drugs are now well-established in treating restless legs syndrome (RLS) and periodic limb movement disorder of sleep (PLMS), which are frequent problems afflicting about 10% of the population, and which can negatively impact quality of life & mood symptoms.

There is a small body of evidence showing possible benefits of dopamine agonists in the treatment of depression.

Unfortunately, dopamine agonists can exacerbate addictive/compulsive behaviour: http://www.ncbi.nlm.nih.gov/pubmed/20484726 

Here are some references about the role of dopamine agonists in RLS and PLMS:

http://www.ncbi.nlm.nih.gov/pubmed/20120624

Here's a good review article on the use of ropinirole to treat these conditions: http://www.ncbi.nlm.nih.gov/pubmed/20421915
Here's a recent review of dopamine agonists in general to treat RLS: http://www.ncbi.nlm.nih.gov/pubmed/20206780
Here's a 2008 meta-analysis comparing ropinirole with pramipexole for treating RLS.  Pramipexole is shown to be slightly superior:
http://www.ncbi.nlm.nih.gov/pubmed/18226947

In this 2010 study, gabapentin was compared to ropinirole for treating RLS.  While ropinirole was superior in reducing objective measures of periodic limb movements, subjects taking gabapentin had a higher subjective benefit:
http://www.ncbi.nlm.nih.gov/pubmed/20049491


Here's a case study showing remission of depressive symptoms with ropinirole used as an augmenting agent:
http://www.ncbi.nlm.nih.gov/pubmed/20188777 

Here's a 2005 study looking at ropinirole augmentation in treating depression:
http://www.ncbi.nlm.nih.gov/pubmed/15999953
This 2010 review in Lancet showed a direct antidepressant effect of pramipexole in Parkinson Disease patients:  http://www.ncbi.nlm.nih.gov/pubmed/20452823
Here's a rather weak but positive 2010 paper describing a group of patients with bipolar depression who appeared to benefit from longer-term pramipexole treatment; doses averaged about 1 mg/d:  http://www.ncbi.nlm.nih.gov/pubmed/20425143


The side effects from these drugs include frequent nausea and dizziness, possibly some daytime sleepiness.  Psychiatric adverse effects can include hallucinations, and increased compulsive or impulse-control problems.

In summary, I think dopamine agonists have a role in selected psychiatric conditions, particularly if there are restless-legs symptoms contributing to insomnia or nocturnal discomfort.  They may help treat refractory depression, but there is a risk of causing impulse control problems or hallucinations in predisposed individuals. 

Naturalistic study comparing quetiapine, ziprasidone, olanzapine, and risperidone

This study caught my eye recently (here's a link to the abstract:)

http://www.ncbi.nlm.nih.gov/pubmed/20334680

It's a naturalistic study, published in BMC Psychiatry in 2010, prospectively following 213 patients with symptoms of psychosis, who were randomized to receive one of four antipsychotic medications (quetiapine, ziprasidone, olanzapine, or risperidone), then apparently followed for up to 2 years.  

My prediction with such a study would be that all four medications would have similar effectiveness, with a slight edge in favour of olanzapine.

In fact, the results showed a slight edge in favour of quetiapine.  There were no substantial differences in tolerability.

The problems with this study, though, include the following:

1) Most of the data was actually for patients who had only been followed up for 6 weeks (not 2 years!).  Only 8 of the 213 patients were followed up for 2 years.  Of these 8, 5 were taking olanzapine, 2 were taking ziprasidone, and 1 was taking risperidone.  Perhaps one might be tempted to conclude that olanzapine is the drug that has the highest chance of being acceptable for long-term use.

 2) The results were presented in a type of "refined" fashion, for example the changes in symptom scores for each drug over time were presented as graphs with a single straight line for each drug, plotted over a 300-day period.  This type of graph omits a tremendous amount of relevant data:  first of all, there were very few patients who were actually followed for 300 days, most of them were only followed for 6 weeks.  A graph like this implies that there are strong data points stretching out over the entire period.  Secondly, the linear plots do not show the degree of scatter in the data points.  There were no direct reports of the raw data in the study, only refined statistical distillations.  It would be much more informative to show all of the data points plotted out over time:  then one could see the times where most of the data were derived, the various courses of symptom change for each individual in the study, etc.  It would be a messier graph! -- but it would not mislead the viewer to immediately conclude that one medication is obviously better than the others.

In conclusion, the study really grabbed my attention when I first looked at it, but I found it to be much weaker than I thought, after reading it closely.

It does, however, provide a little bit of support for the idea that any one of these four antipsychotic medications are reasonable to try, in the treatment of psychotic symptoms.  I agree that quetiapine is a reasonable first choice, though the others could be reasonable also, depending on personal preference, past experience, side effect risks, etc.  I would still lean towards olanzapine for anticipated long-term treatment of severe symptoms.

Antidepressant + CBT superior to either treatment alone for treating social anxiety

Blanco et al. published this study in the March 2010 issue of Archives of General Psychiatry.  Here's a link to the abstract:
http://www.ncbi.nlm.nih.gov/pubmed/20194829 

Patients with social anxiety were divided into four groups in this randomized prospective 24-week study:  placebo; cognitive behavioural group therapy; phenelzine medication; combined CBT + phenelzine.

CBT was modestly effective, phenelzine only slight more effective, but the combination of CBT + medication was substantially more effective, more or less additively so, particularly in terms of total remission rates.  There was a very low placebo response.

Findings of this type are not surprising.   An interesting aspect to this particular study is that it makes use of phenelzine, an old MAO inhibitor.  This shows that sometimes these old drugs can still be quite useful.

This study does not necessarily demonstrate that CBT is the only form of psychotherapy which would work adjunctively to help social anxiety.  I do think that components of CBT, such as emphasizing exposure to anxiety-provoking situations, and practicing social initiatives in a systematic way, are necessary.  But, other forms of psychotherapy might adjunctively help the CBT to work better!  

Antidepressants only effective in severest depression?

A recent article in JAMA by Fournier et al. is a meta-analysis of antidepressant treatment effects assessed in relation to depression severity. Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/20051569

The results show that antidepressants work significantly well, compared to placebo, only for very severe depression (corresponding to Hamilton Depression Rating Scale scores of at least 25).

The analysis is quite well-done, and the results are also presented in a graphical form clearly showing a linear increase in antidepressant effect as baseline depression scores increase.

The authors observe that antidepressants are most commonly prescribed to people who have milder depressions--a population in which they show that medications arguably do not work.

Here are a few of my criticisms of this study:

1) the duration of each trial included in the meta-analysis was between 6 and 11 weeks. In my opinion, depressive disorders are long-term, highly recurrent problems, which have a natural period over at least 6-11 months, not 6-11 weeks. Treatments to address mood disorders of any severity require much longer durations. The short duration could cause a significant under-estimation of treatment effects.

2) the study, like many, looks at "depression alone." In most real-life situations, outside of a research study, individuals have several different problems, such as mild depression + social anxiety, or mild depression + panic attacks, etc. The presence of other symptoms, particularly anxiety symptoms, most likely would increase the likelihood of antidepressants helping.

3) Milder depressions, just like more severe depressions, may actually improve more consistently with a "second step" such as combination with psychotherapy, or combining two different antidepressants. The mildness of a medical syndrome does not necessarily mean that the effective treatments need only to be "mild."

4) Milder depressive syndromes may be more prone to misdiagnosis.

5) current "resolution" to measure treatment effects in depression is quite poor. "Depression" is a very broad category. An analogy could be considering "abdominal pain" to be a diagnostic category. If "abdominal pain" is the only category, and is simply rated on a severity scale (rather than subcategorized to obtain a precise diagnosis), and the treatment offered for "abdominal pain" is appendectomy, then we would probably see no difference in treatment effectiveness between appendectomy and placebo. This is because appendectomy is only effective to treat appendicitis (a subset of the abdominal pain population), and is either ineffective or harmful in treating abdominal pain patients without appendicitis (except, perhaps, for those patients who have a placebo improvement of psychosomatic or factitious abdominal pain, an improvement which they attribute to having surgery).

We currently do not have the science to subcategorize depression in a more clinically meaningful way (there are subcategorization schemes, but they don't have much relevance in terms of treatment).

But we do have a research method which could improve "resolution":
-instead of comparing two populations of depressed individuals, one group receiving antidepressant (or some other treatment), and the other receiving placebo (or some other alternative), the study design could instead be to offer every individual courses of placebo, alternating with antidepressant (or "treatment one" alternating with "treatment two"). Each course of treatment would have to last an adequate length of time. The analysis would aim to show whether there is a subset of individuals who respond to the antidepressant, or a subset of individuals who do better with placebo. The averaged results over the whole group might show that antidepressant effects do not differ from placebo (just like appendectomy might not differ from placebo in treating "abdominal pain"), but the individualized result could show that some individuals improve substantially with the antidepressant (just like appendectomy would save the lives of the small group of "abdominal pain" patients who have appendicitis).

---

In the meantime, though, I think it is reasonable to recognize that antidepressants are less consistently helpful when symptoms are less severe.

Non-human Primate Models of Psychiatric Treatment Effects

Before starting the main body of my post, here's a little introduction:

I've been doing quite a bit of reading lately about the history of psychiatry (in particular, an excellent book by Lisa Appignanesi; I'll write a post about it when I've finished, which could be in a while, since the book is 5 cm thick!). Also I've been reading about cultural psychology (another very interesting field), after finding a free set of university lecture notes published online. I'd like to write another post about this subject as well, when I get around to it.

What does this have to do with "non-human primate models of psychiatric treatment effects?" Well, I'm becoming more strongly aware of the powerful effects of culture upon the manifestations of psychological (and, possibly, physical) health and distress. The book I'm reading deals with cultural change through history; these changes have influenced the presentation, management, and course of many psychiatric phenomena. Even terms like "psychiatric phenomena" or "symptoms," etc. are culturally influenced jargon. The cultural psychology subject also deals, of course, with cultural differences, but in this case mainly with the way different groups of people in the present era around the world experience or perceive emotions, psychological distress, social interactions, or cognitive processes. I suspect that cultural differences may exist between families as well, within the same geographical area.

These factors complicate the study of psychiatric therapies, perhaps in many ways that could be subtle but powerful.

I've been interested in finding more evidence about the effect of physical and psychological treatments for psychiatric symptoms in non-human primates. In this case, cultural or personal history biases could be much more carefully controlled.

There are a lot of studies done in rodents, of behavioural therapies and of medication, including a very questionable rodent "model" of antidepressant effectiveness. I think that possible conclusions are much more limited, about human therapies based on research done in mice, etc.

Monkeys or apes are much closer to humans, in terms of genetic similarity and brain structure. They may exhibit behavioural problems that are much more closely analogous to psychiatric symptoms in humans. So, I have been looking for good research about medication and "psychotherapy" effects in primates. Here's a start:

http://www.ncbi.nlm.nih.gov/pubmed/19383215

This 2009 article describes self-injurious behaviour in rhesus macaques. These animals may bite themselves severely; this is thought to be due to an underlying vulnerability combined with social deprivation in infancy or being isolated in captivity. About one-third of macaques experiencing solitary captivity exhibit self-directed stereotypic behaviour. The behaviour is exacerbated by separation from the social group, by disruption of daily routines, or by exposure to a fear-provoking stimulus (for animals, this could be an unfamiliar person trying to interact with them closely). It is interesting to consider that analogous behaviours in humans are probably related to similar vulnerabilities, deprivations, or triggers.

The experiment described in the article is about treating these self-injuring monkeys. Each group started off with 4 weeks of baseline observation, followed by 4 weeks of placebo, before randomization to fluoxetine, venlafaxine, or placebo for the final 4 weeks.

The individuals in the fluoxetine groups, at higher doses in particular, had substantial reductions in self-injurious behaviour (at least 50-75% less self-injury than the placebo group). The venlafaxine group did not improve as much.

There were no changes in "general behaviour" aside from a reduction in "aggressive displays." In particular, there were no signs of sedation or reduced engagement, etc.

I don't mean to make too much of results of this type, but I do think that this is strong evidence that the effect of an SSRI is not simply of an elaborate active placebo, influenced by cultural expectation. Also, just because a symptom is reduced doesn't necessarily mean a problem is solved...however, reducing a problematic behaviour such as self-injury may be a necessary prerequisite to resolving other types of psychological problems.

This type of study would be strengthened if it was extended for a year or more, and if it was to include data about other "quality of life" indicators, such as social integration, longevity, physical health, etc.

Here's another study, showing that tryptophan administration over a 4-week period substantially decreased self-injurious behaviour (again, by 50-75%) in small monkeys. There was also a decrease in previously high levels of cortisol. The dose of tryptophan was over 100 mg/kg per day, which would be a bit inconvenient to administer to humans:
http://www.ncbi.nlm.nih.gov/pubmed/19383216

Here's another study of self-injury in macaques. In this case, housing the animals outdoors led to significant reductions in self-injury. I think the message here could be that a healthy environment which optimizes freedom of movement, space, and natural sensory cues (e.g. of light, sound, and temperature), leads to diminished stress and and diminished symptoms of psychological distress. We could confidently generalize this statement to humans, I think.
http://www.ncbi.nlm.nih.gov/pubmed/16995645

Here is a relevant review on the subject of self-injury in human vs. non-human primates:
http://www.ncbi.nlm.nih.gov/pubmed/16713051

Here's an amusing (and, unfortunately, not very strong) study showing that hearing music leads to increased affiliative behaviour and decreased aggressive behaviour in chimpanzees. There were different degrees of responsiveness to different types of music:
http://www.ncbi.nlm.nih.gov/pubmed/17203919


I'll try to add to this post later. In the "psychotherapy" realm, some of the first important animal studies in primates were done by Harlow. I'm interested to find some more recent stuff in the research literature. I guess there won't be much on cognitive therapy in monkeys, since there is a bit of a problem encouraging non-human primates to keep written diaries with thought records...similarly, psychoanalytic studies are probably in short supply (!) Yet, in all seriousness, I suspect that the key elements for successful therapy in non-human primates involve positive, gentle, consistent relationships; and gentle, non-punitive behavioural education & modeling.

Is Seroquel XR better than generic quetiapine?

A supplement written by Christoph Correll for The Canadian Journal of Diagnosis (September 2009) was delivered--free--into my office mailbox the other day.

It starts off describing the receptor-binding profiles of different atypical antipsychotic drugs. A table is presented early on.

First of all, the table as presented is almost meaningless: it merely shows the concentrations of the different drugs required to block 50% of the given receptors. These so-called "Ki" concentrations have little meaning, particularly for comparing between one drug and another, UNLESS one has a clear idea of what concentrations the given drugs actually reach when administered at typical doses.

So, of course, quetiapine has much higher Ki concentrations for most receptors, compared to risperidone -- this is related to the fact that quetiapine doses are in the hundreds of milligrams, whereas risperidone doses are less than ten milligrams (these dose differences are not reflective of anything clinically relevant, and only pertain to the size of the tablet needed).

A much more meaningful chart would show one of the following:

1) the receptor blockades for each drug when the drug is administered at typical doses

2) the relative receptor blockade compared to a common receptor (so, for example, the ratio between receptor blockades of H1 or M1 or 5-HT2 compared to D2, for each drug).

The article goes on to explore a variety of other interesting differences between antipsychotics. Many of the statements made were theoretical propositions, not necessarily well-proven empirically. But in general I found this discussion valuable.

Despite apparent efforts for the author to be fair and balanced regarding the different antipsychotics, I note a few things:

1) there are two charts in this article showing symptom improvements in bipolar disorder among patients taking quetiapine extended-release (Seroquel XR).

2) one large figure appears to show that quetiapine has superior efficacy in treating schizophrenia, compared to olanzapine and risperidone (the only "p<.05 asterisk" was for quetiapine!) -- this figure was based on a single 2005 meta-analysis, published in a minor journal, before the CATIE results were published. No other figures were shown based on more recent results, nor was clozapine included in any figure.

I think quetiapine is a good drug. BUT -- I don't see any evidence that quetiapine extended release is actually any better, in any regard, than regular quetiapine. In fact, I have seen several patients for whom regular quetiapine suited them better than extended-release, and for whom a smaller total daily dose was needed.

Here is a reference to one study, done by Astra-Zeneca, comparing Seroquel with Seroquel XR, in healthy subjects: http://www.ncbi.nlm.nih.gov/pubmed/19393840 It shows that subjects given regular quetiapine were much more sedated 1 hour after dosing, compared to those given the same dose of Seroquel XR. It implies that the extended release drug was superior in terms of side-effects. Here is my critique of this study: first of all, sedation is often a goal in giving quetiapine, particularly in the treatment of psychosis or mania. Secondly, problematic sedation is usually the type that persists 12 hours or more after the dose, as opposed to one hour after the dose. In this study, the two different formulations did not differ in a statistically significant way with respect to sedation 7, 8 or 14 hours after dosing. In fact, if you look closely at the tables presented within the article, you can see that the Seroquel XR group actually had slightly higher sedation scores 14 hours after dosing. Thirdly, dosing of any drug can be titrated to optimal effect. Regular quetiapine need not be given at exactly the same dose as quetiapine XR--to give both drugs at the same dose, rather than at the optimally effective dose for each, is likely to bias the results greatly. Fourth, this study lasted only 5 days for each drug ! In order to meaningfully compare effectiveness or side-effects between two different drugs, it is necessary to look at differences after a month, or after a year, of continuous treatment. For most sedating drugs, problematic sedation diminishes after a period of weeks or months. Once again, if immediate sedation is the measure of side-effect adversity, then this study is biased in favour of Seroquel XR. Fifth, the study was done in healthy subjects who did not have active symptoms to treat. This reminds me of giving insulin to non-diabetic subjects, and comparing the side-effects of the different insulin preparations: the choice of population is an obvious strong bias!


Regular quetiapine has gone generic.

Quetiapine extended-release (Seroquel XR) has not.

I am bothered by the possibility of bias in Correll's article.

It is noted, in small print at the very end of this article, that Dr. Correll is "an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Organon, Ortho McNeill-Janssen, Otsuka, Pfizer, Solvay, Supernus, and Vanda." AstraZeneca is the company which manufactures Seroquel XR.

In conlusion, I agree that there are obviously differences in receptor binding profiles between these different drugs. There are some side-effect differences.

Differences in actual effectiveness, as shown in comparative studies, are minimal. But probably olanzapine, and especially clozapine, are slightly better than the others, in terms of symptom control.

Quetiapine can be an excellent drug. Seroquel XR can be an excellent formulation of quetiapine, and might suit some people better.

BUT -- there is no evidence that brand-name Seroquel XR is superior to generic regular quetiapine.

One individual might respond better to one drug, compared to another.

The author, despite including 40 references, seems to have left out many important research studies on differences between antipsychotics, such as from CATIE and SOHO.

(see my previous post on antipsychotics: http://garthkroeker.blogspot.com/2008/12/antipsychotic-medications.html )

Hallucinations

Hallucinations are perceptions which take place in the absence of a stimulus from the peripheral or sensory nervous system.

They may be classified in a variety of different ways (this is an incomplete list):
1)by sensory modality
a) auditory: these are most common, and may be perceived as voices speaking or mumbling; musical sounds; or other more cacophonous sounds
b) visual: these can occur more commonly in delirious states or medical illnesses affecting the brain. Many people experience normal, but unsettling, visual hallucinations, just when falling asleep or waking up.
c) tactile: these are most common in chemical intoxication syndromes, such as with cocaine.
d) olfactory: more common in medical illness

2) by positionality
-when describing hallucinated voices, if the voices are perceived to originate inside the head, or to not have any perceived origin, then they could be called "pseudohallucinations." If the voices are perceived to originate from a particular place, such as from the ceiling or from across the room, then they could be called "hallucinations" or "true hallucinations." This terminology has been used to distinguish between the hallucinations in schizophrenia and psychotic mood disorders (which are typically "true hallucinations") and those experienced in non-psychotic disorders (pseudohallucinations are more typically--though not invariably--associated with dissociative disorders, borderline personality, or PTSD).

3) by insight
An individual experiencing a "psychotic hallucination" will attribute the phenomenon to stimuli outside of the brain. An individual experiencing a "non-psychotic hallucination" will attribute the phenomenon to his or her own brain activity, and recognize the absence of an external stimulus to account for the experience. In most cases, "insight" fluctuates on a continuum, and many individuals experiencing hallucinations will have some intellectual understanding of their perceptions being hallucinatory, but still feel on a visceral level that the perceptions are "real."

4) by character
Voices in particular can be described in a variety of ways. So-called "first rank symptoms of schizophrenia" include hallucinated voices which comment on a person's behavior, or include several voices which converse with each other.
The quality of the voice can vary, with harsh, angry, critical tones more common in psychotic depression, and neutral emotionality more common in schizophrenic states.


--all of these above descriptions are incomplete, and associations between one type of hallucination and a specific "diagnosis" are imperfect. A great deal of variation exists--

It is probably true that some hallucinations are factitious (i.e. the person is not actually hallucinating, despite claiming to), but of course this would be virtually impossible to prove. Something like functional brain imaging might be an interesting, though impractical, tool, to examine this phenomenon. People with psychotic disorders or borderline personality might at times describe factitious hallucinatory phenomena in order to communicate emotional distress or need to caregivers. Or sometimes the phenomena may convey some type of figurative meaning. The motivation to do this might not always be conscious.

There are a variety of ways to treat hallucinations.

In my opinion, the single most effective treatment is an antipsychotic medication. Hallucinations due to almost any cause are likely to diminish with antipsychotic medication treatment.

There is evolving evidence that CBT and other psychotherapy can help with hallucinations. Here are some references:
http://www.ncbi.nlm.nih.gov/pubmed/19176275
http://www.ncbi.nlm.nih.gov/pubmed/9827323

Some individuals may not be bothered by their hallucinations. In this case, it may sometimes be more the physician's agenda than the patient's to "treat" the symptom. Yet, it is probably true that active hallucinations in psychotic disorders are harbingers of other worsening symptoms, so it may be important to treat the symptom early, even if it is not troublesome.

Other types of behavioral tactics can help, including listening to music, wearing ear plugs, other distractions, etc. In dealing with pseudohallucinations or non-psychotic hallucinations, "mindfulness" exercises may be quite important. A well-boundaried psychodynamically-oriented therapy structure could be very helpful for non-psychotic hallucinations or pseudohallucinations associated with borderline personality dynamics or PTSD. Care would need to be taken, in these cases, not to focus excessively or "deeply" on the hallucinations, particularly without the patient's clear consent, since such a dialog could intensify the symptoms.

Which is better, a simple drug or a complex drug?

Here is another critique of medication marketing trends in psychiatry:

http://thelastpsychiatrist.com/2009/04/how_dangerous_is_academic_psyc_1.html#more

I agree quite strongly that there has been a collusion between:
- psychiatrists who eagerly yearn to meaningfully apply their knowledge of psychopharmacology, pharmacokinetics, neurotransmitter receptor binding profiles, etc. (to justify all those years of study)
- and pharmaceutical company sales reps

I can think of attending many academic rounds presentations in which a new drug would be discussed, for example a newly released SSRI. During the talk, there would be boasting about how the new drug had the highest "receptor specificity", or had the lowest activity at receptors other than those for serotonin (e.g. for histamine or acetylcholine).

These facts that I was being shown, while enjoying my corporate-sponsored lunch, were true. But they were used as sales tactics, by-passing clear scientific thought. Just because something is more "receptor-specific" doesn't mean that it works better! It may in some cases be related to a difference in side effects. Yet sometimes those very side-effects may be related to the efficacy of the drug.

By way of counter-example, I would cite the most effective of all antipsychotic medications, clozapine. This drug has very little "receptor-specificity." It interacts will all sorts of different receptors. And it has loads of side effects too. Perhaps this is part of the reason it works so well. Unfortunately, this does not sit well with those of us who yearn to explain psychiatric medication effects using simple flow charts.

Similarly, the pharmacokinetic differences between different medications are often used as instruments of persuasion--yet often times they are either clinically irrelevant, of unproven clinical relevance, or even clinically inferior (e.g. newer SSRI antidepressants have short half-lives, which can be advantageous in some regards; but plain old Prozac, with its very long half-life, can be an excellent choice, because individuals taking it can safely skip a dose without a big change in the serum level, and ensuing side-effects).

I should not be too cynical here -- it is important to know the scientific facts that can be known about something. Receptor binding profiles and half-lives, etc. are important. And it can be useful to find medications that have fewer side-effects, because of fewer extraneous receptor effects. The problem is when we use facts spuriously, or allow them to persuade us as part of someone's sales tactic.

So, coming back to the question in the title, I would say it is not necessarily relevant whether a drug works in a simple or complex way. It is relevant whether it works empirically, irrespective of the complexity of its pharmacologic effects.

Pregnancy & Depressive Relapse

I was looking at an article in JAMA from 2006, which was about pregnant women taking antidepressants. They were followed through pregnancy, and depressive relapses were related to changes in antidepressant dose. Here's a link to the abstract:

http://www.ncbi.nlm.nih.gov/pubmed/16449615

The study is too weakly designed to allow strong conclusions. Yet the abstract makes a statement about "pregnancy not being protective" which--while possibly true--is not directly related to the findings from the study. This criticism was wisely conceived by the author of "The Last Psychiatrist" blog:
http://thelastpsychiatrist.com/2006/10/jama_deludes.html

Yet the JAMA study is not uninformative.

And the criticism mentioned above goes a bit too far, in my opinion. The critique itself makes overly strong statements in its own title & abstract.

It appears quite clear that pregnant women with a history of depressive illness, who are taking antidepressants, but decrease or discontinue their medication during the pregnancy, have a substantially higher risk of depressive relapse.

Because the study was not randomized, we cannot know for sure that this association is causal. But causation would be reasonably suggested. It does not seem likely that this large effect would have been caused by women whose "unstable" depressive symptoms led them to discontinue their antidepressants (i.e. it does not seem likely to me that "reverse causation" would be a prominent cause for this finding). I think this could happen in some cases, but not frequently. Nor does it seem likely to me that a woman already taking an antidepressant, who becomes more depressed during the pregnancy, would therefore stop taking her medication. This, too, could happen (I can think of clinical examples), but I don't think it would be common. It seems most likely to me that the causation is quite simple: stabilized depressive illness during pregnancy is likely to become less stable, and more prone to relapse, if antidepressant medication is discontinued.

The critique of this article also discusses the fact that women in the study who increased their doses of medication also had higher rates of depressive relapse, yet this fact is not mentioned very much in the abstract or conclusion. This finding is also not surprising--what other reason would a pregnant woman have to increase a dose of medication which she was already taking during her pregnancy, other than an escalation of symptoms? In this case, depressive relapse (which can happen despite medication treatment) is likely the cause of the increased dose--the increased dose is unlikely to have caused the depressive relapse.

Yet, as I said above, the study only allows us to infer these conclusions, as it was not randomized. And I agree that the authors overstate their conclusions in the abstract. In order to more definitively answer these questions, a randomized prospective study would need to be done.

N-Acetylcysteine for treatment of compulsive disorders

N-acetylcysteine is an antioxidant which modulates the glutamate system in the brain. Glutamate is actually the most prevalent neurotransmitter in the brain, and generally has strongly activating effects on nerve cells.

A recent study in Archives of General Psychiatry described groups of individuals with compulsive hair-pulling behavior (trichotillomania), randomized to receive either placebo, or N-acetylcysteine 1200 mg/day, then up to 2400 mg/day, over 12 weeks:
http://www.ncbi.nlm.nih.gov/pubmed/19581567

The N-acetylcysteine group had about 50% reduction in hair-pulling behaviour, with no change in the placebo group. Those in the N-acetylcysteine group did not report any side effects. In fact, the only side effects were among those in the placebo group.

The same author published a study in 2008 showing a substantial improvement in compulsive gambling behavior in a group given NAC at an average dose of about 1500 mg/d:
http://www.ncbi.nlm.nih.gov/pubmed/17445781

A very preliminary study showed that NAC may have some promise in treating cocaine addiction:
http://www.ncbi.nlm.nih.gov/pubmed/17113207

NAC has shown some promise as an adjunctive treatment for chronic schizophrenia; in this study the dose was 1000 mg twice daily, over 24 weeks. Once again, there were no side-effects. As I look at the body of the paper, I see that there was a definite favorable effect from the NAC compared to placebo, in several domains, but the size of the effect seemed clinically modest:
http://www.ncbi.nlm.nih.gov/pubmed/18436195

So NAC appears to be an appealing therapy for a variety of frequent, and often difficult-to-treat psychiatric symptoms. There do not appear to be side effect problems.

At this point, NAC can be obtained from health food stores in Canada, as a nutritional supplement.  It is also on the prescription formulary in an injectable form for treating acetaminophen toxicity. 

ADHD questions

Here are some great questions about ADHD, submitted by a reader:

1) You write here that long-term use of stimulants has NOT been shown to improve long-term academic outcomes. Why do you think this is, given that symptoms of ADHD improve on medication? (It actually really depresses me to think that individual symptoms can improve, yet no real change takes place...though I know that this might not apply to all patients.

2) What are some effective non-drug treatments for ADHD? I am particularly interested in dietary measures, and also EEG biofeedback.

3) I have read about prescribing psychostimulants as a way of basically diagnosing ADHD...i.e., the diagnosis is based on your response to the medication. I am just wondering how precise this would be, given that stimulants would probably (?) impove most people's concentration, etc. Or is there any role for neuropsychological testing in trying to establish a diagnosis? Is there any way of definitively establishing this kind of diagnosis?

4) I have read that there are many differences between ADD and ADHD, i.e. not just in symptom presentation but in the underlying brain pathology. Is that true? I'm not sure how to phrase it, it seemed like the suggestion was that ADD was more "organic", although maybe that doesn't make sense. Does that have implications for prognosis or treatment strategies?

5) I have read that one red flag that suggests ADD in the context of MDD treatment is a good response to bupropion. If a patient did not have a really good response to bupropion-- or if the response was only partial-- does this usually mean that treatments with psychostimulants like Ritalin, Adderall, etc. will be ineffective (or only partially effective) also?

6) If ADD is not diagnosed/treated until adulthood, is it usually more difficult to treat than if it is diagnosed/ treated in early childhood? Is the response to stimulant treatment just as good? I guess I am wondering if there are certain structural changes that occur in the brain that result from untreated ADD-- kind of like long-term depression and hippocampal atrophy?

7) Is there a certain type of patient who usually does poorly on psychostimulants, or who experiences severe side effects on psychostimulants?

I don't know the answers to a lot of these, but I am interested to keep trying to learn more. Here's my best response I can come up with for now:

1) First of all, the bottom line of whether something is helpful or not may not be some specific thing, like academic performance. Perhaps "well-being" in a broad, general sense is a more reasonable goal. Yet, things like academic performance are important in life. Perhaps stimulants or other treatments for ADHD are "necessary but not sufficient" to help with ADHD-related academic problems over the longer term. It appears to me from the data that stimulants are actually helpful for academic problems, it's just that the size of the effect is much smaller than what most people would hope for.

2) I wrote a post about zinc supplementation before. Also adequate iron stores are probably important. A generally healthy diet is probably important. I've encountered some people with ADHD who have reduced tolerance for irritation or frustration, and may be particularly bothered or distracted by hunger; yet they may not be organized to have meals prepared regularly through the day. So it can help them manage their ADHD to make sure they always have snacks with them, so that they are never in a hungry state. Other than that, I think there are a lot of nutritional claims out there which have a poor evidence base. The link between sugar intake and hyperactivity is poorly substantiated--I've written a post about that.

Food additives or dyes could play a role in exacerbating ADHD symptoms. Based on this evidence, it makes sense to me to limit food dyes and sodium benzoate in the diet, since such changes do not compromise quality of life in any way, and may lead to improved symptoms. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/17825405
(this is the best of the references: it is from Lancet in 2007)

http://www.ncbi.nlm.nih.gov/pubmed/15613992
http://www.ncbi.nlm.nih.gov/pubmed/15155391

I once attended a presentation on EEG biofeedback. I think it is a promising modality. Harmless to give it a try, but probably expensive. It will be interesting once the technology is available to use EEG biofeedback in front of your own home computer, at low cost.

A few of the self-help books about ADHD are worth reading. There are a lot of practical suggestions about managing symptoms. Some of the books may contain a strongly biased agenda for or against things like stimulants or dietary changes, so you need to be prepared for that possibility.

3)The ADHD label is an artificial, semantic creation, a representation of symptoms or traits which exist on a continuum. Even for those who do not officially satisfy symptom checklist criteria for ADHD, they could benefit substantially from ADHD treatments if there is some component of these symptoms at play neurologically. Many people with apparent disorders of mood, personality, learning, conduct, etc. may have some component of ADHD as well: in some cases ADHD treatments are remarkably helpful for the other problems. So I think careful trials of stimulants could be helpful diagnostically for some people, provided there are no significant contraindications.

4) I've always thought about the ADHD label as just a semantic updating of the previous ADD label. Subtypes of ADHD which are predominantly inattentive rather than hyperactive may differ in terms of comorbidities and prognosis.

5) Hard to say. Many people think of bupropion as a "dopaminergic" drug, whereas bupropion and its relevant metabolites probably act mainly on the norepinephrine system in humans (its dopaminergic activity is more significant in dogs). But perhaps bupropion response could correlate with stimulant response. I haven't seen a good study to show this, nor do I have a case series myself to comment one way or the other based on personal experience.

6) I don't know about that. Comorbidities (e.g. substance use, relationship, or conduct problems) may have accumulated in adults who have not had help during childhood. Yet I have often found it to be the case that the core symptoms of most anything can improve with treatment, at any age.

7) Patients with psychotic disorders (i.e. having a history of hallucinations, delusions, or severely disorganized thinking) often seem to do poorly on stimulants. Patients who are using stimulants primarily to increase energy or motivation often are disappointed with stimulants after a few months, since tolerance develops for effects on energy. Patients with eating disorders could do poorly, since stimulant use may become yet another dysfunctional eating behaviour used to control appetite. And individuals who are trying to use stimulants as part of thrill-seeking behaviour, who are using more than prescribed doses, or who are selling their medication, are worse off for receiving stimulant prescriptions.