Benefits and Risks of Zinc Supplementation in Eating Disorders, ADHD, and Depression

Zinc supplementation may help treat anorexia nervosa, ADHD, and treatment-resistant depression.

Zinc is a metallic element involved in multiple aspects of human cellular function, metabolism, growth, and immune function. It is required for the function of about 100 human enzymes. The human body contains about 2000-3000 mg of zinc, of which about 2-3 mg are lost daily through kidneys, bowel, and sweat glands. The biologic half-life of zinc in the body is about 9 months, so it can take months or years for changes in dietary habits to substantially change zinc status, unless the intake is very high for short periods.

Red meat is a particularly rich source of zinc. Vegetarians may have a harder time getting an adequate amount from the diet. The prevalence of zinc deficiency may be as high as 40% worldwide.

When referring to zinc dosage, it is best to refer to "elemental zinc". Different types of zinc preparations (e.g. zinc gluconate or zinc sulphate) have different amounts of elemental zinc. For example, 100 mg of zinc gluconate contains about 14 mg of elemental zinc. 110 mg of zinc sulphate contains about 25 mg of elemental zinc.

Here are references to articles written by a Vancouver eating disorders specialist between 1994 and 2006, advising supplementation of 14 mg elemental zinc daily (corresponding to 100 mg zinc gluconate daily) for 2 months in all anorexic patients:
http://www.ncbi.nlm.nih.gov/pubmed/17272939
http://www.ncbi.nlm.nih.gov/pubmed/11930982
http://www.ncbi.nlm.nih.gov/pubmed/8199605

Here's a 1987 article from a pediatrics journal, showing improvement in depression and anxiety following 50 mg/d elemental zinc supplementation in anorexic adolescents:
http://www.ncbi.nlm.nih.gov/pubmed/3312133

In this 1990 open study, anorexic patients were treated with 45-90 mg elemental zinc daily, most of whom had significant improvement in their eating disorder symptoms over 2 years of follow-up.
http://www.ncbi.nlm.nih.gov/pubmed/2291418

Here's a 1992 case report of substantial improvement in severe anorexia following zinc supplementation:
http://www.ncbi.nlm.nih.gov/pubmed/1526438

Zinc depletion may lead to an abnormal sense of taste (hypogeusia or dysgeusia). This sensory abnormality improves with zinc supplementation. Here's a reference:
http://www.ncbi.nlm.nih.gov/pubmed/8835055

Here's a randomized , controlled 2009 Turkish study showing that 10 weeks of 15 mg/day zinc supplementation led to improvement in ADHD symptoms in children. However, a close look at the study shows a bizarre lack of statistical analysis comparing the supplemented group directly with the placebo group. When you look at the data from the article, both groups improved to a modest degree on most measures, with perhaps a little bit more improvement in the zinc group. The analysis here was insufficient, I'm surprised a journal would accept this.
http://www.ncbi.nlm.nih.gov/pubmed/19133873

Here's a 2004 reference to a study showing that 6 weeks of 15 mg elemental zinc daily as an adjunct to stimulant therapy improved ADHD symptoms in children, compared to stimulant therapy plus placebo. In this case, there was a valid statistical analysis:
http://www.ncbi.nlm.nih.gov/pubmed/15070418

Here's a 2009 study showing that zinc supplementation improves the response to antidepressants in treatment-resistant depression. The dose they used was 25 mg elemental zinc daily, over 12 weeks.
http://www.ncbi.nlm.nih.gov/pubmed/19278731

Here's an excellent 2008 review article about zinc deficiency, and about the potential role of zinc supplementation in a wide variety of diseases (e.g. infections ranging from the common cold, to TB, to warts; arthritis; diarrhea; mouth ulcers). The review shows that zinc may have benefit for some of these conditions, but the evidence is a bit inconsistent:
http://www.ncbi.nlm.nih.gov/pubmed/18221847

Here is a warning about zinc toxicity:

http://www.ncbi.nlm.nih.gov/pubmed/12368702 {hematological toxicity from taking 50-300 mg zinc daily for 6-7 months. The toxicity was thought to be due to zinc-induced copper malabsorption leading to sideroblastic anemia}

Here is a nice website from NIH summarizing the role of zinc in the diet, in the body, some of the research about health effects, and about toxicity. It sticks to a recommended daily intake of 10-15 mg elemental zinc for adults, or about 5 mg for young children. It states that the maximum tolerable daily intake levels are about 5-10 mg for young children, 20-30 mg for adolescents, and 40 mg daily for adults:
http://ods.od.nih.gov/FactSheets/Zinc.asp

Here is a reference to another excellent review of zinc requirements, benefits, and risks. It makes more cautious recommendations about zinc supplementation, advising no more than 20 mg/day of zinc intake in adults. In order to prevent copper deficiency, it also advises that that the ratio between zinc intake and copper intake does not exceed 10.
http://www.ncbi.nlm.nih.gov/pubmed/16632171

So, were I to make a recommendation about a zinc supplementation trial, I would advise sticking to amounts under 20 mg (elemental) per day for adults, and to ensure that you are getting 2 mg of copper per day with that.

Increasing Anxiety in Recent Decades

Another question from a visitor:

Shifts towards higher anxiety and neuroticism: Twenge** has noted an increase in anxiety and neuroticism in recent decades. Is this the failure of psychiatry/psychology?

Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/11138751

This is a good and important article by Twenge, showing that anxiety and neuroticism (the tendency to experience negative emotion) have increased substantially in the past 5 decades, such that, for example, normal children in the 90's had similar scores on anxiety tests as child psychiatric patients from the 50's. The author finds that economic factors are not associated with this change, but that decreased social connectedness, and an increased sense of environmental danger or threat, are associated.

Here's a related comment:

Baumeister* suggests that purpose, values, sense of efficacy, and self-worth are needed for a meaningful life. Religions and spiritual belief-systems have long provided meaning and more. Nietzsche has supposedly said: "He who has a why to live for can bear almost any how". How do you think one can live a meaningful life? *Baumeister, R. F., & Vohs, K. D. (2002). The pursuit of meaningfulness in life. In C. R. Snyder& S. J. Lopez (Eds.), Handbook of positive psychology (pp. 608-618). Oxford: OxfordUniversity Press.

I have always felt that a strong sense of belonging, safety, meaningfulness, and community is necessary for mental health. Modern culture supports independence. Perhaps modernity also encourages the solitary pursuit of wealth, educational success, etc., in an increasingly competitive and busy culture. People are less likely to join community organizations or visit friends. People are more likely to remain single or live alone for longer periods of their lifetime (in their 20's and beyond). There are more activities that can absorb time and attention while alone (e.g. video games, recreational drugs). Even music--an aspect of life that was previously associated strongly with social connection--has become a medium in which a person can disappear alone, disconnected from the social milieu, thanks to portable music players. A cost of sexual or relationship freedom, particularly in the internet age, can be a tendency for people to have brief, less committed relationships, in the quest for variety, or in the quest for an "ideal mate." Intellectual freedom and advanced knowledge, while possibly allowing for heightened meaningfulness and enlightenment, may also shatter previous bastions of meaningfulness (such as religious dogmas), and may finally cause one to confront the absurdity and seeming empty arbitrariness of the universe. Owen Barfield, in his book Saving the Appearances, described modernity as a "shattering of idols", leaving a spiritual emptiness which science cannot fill.

I guess this is a failure of psychiatry/psychology. Not because the therapies don't work, but because the issue is one of public health and culture. I think this type of evidence emphasizes the importance of encouraging social connectedness and community involvement--to whatever degree is possible--as essentials in a therapeutic prescription for treating anxiety or depression.

In this regard, I encourage involvement in volunteering, community organizations, churches, sports teams, activity clubs, etc. It may be necessary to change one's personal culture in order to change anxiety or depression. You must be wary about being swept up in the prevailing culture, and must instead make active choices about what is healthy and meaningful for you.

*As an addendum here, I have to say that research data of this type may be biased by a variety of factors which differ between one time period and another, including use of language, cultural acceptance of symptoms, etc. Therefore, the children in the 50's may have had lower anxiety scores because they were less familiar with the language associated with anxiety symptoms, were less likely to admit such symptoms on a questionnaire, were more likely to deal with the underlying cause of such symptoms in a different way, etc. We now realize many terrible problems which were going on in the 50's (such as abuse), but which people did not talk about as openly back then. A questionnaire on these issues done at that time might have underestimated the degree of such problems.

**Here's another article, showing increasing life satisfaction over the past decades:
http://www.ncbi.nlm.nih.gov/pubmed/19227700

Inositol

Inositol is chemically similar to glucose (the type of sugar required by the brain for energy). It is a precursor in a so-called "second messenger system," which cells require to communicate with each other. In the brain, these second messenger systems are activated by various neurotransmitters including serotonin. There is some evidence that brain levels of inositol are reduced in depression and anxiety disorders. Inositol is present in a typical diet, in amounts of about 1 gram per day. Doses of supplemental inositol are typically 10-20 grams per day.

A Cochrane review from 2004 concluded that there was no clear evidence of supplemental inositol being beneficial in the treatment of depression:
http://www.ncbi.nlm.nih.gov/pubmed/15106232

Here's a 2006 reference from Bipolar Disorders showing that supplemental inositol could help treat bipolar depression in some patients already taking lithium or valproate. In 4 out of 9 patients taking 6-20 grams per day of inositol, their depression substantially improved over 6 weeks, with continuing improvement over an additional 8 weeks. However, the other 5 out of 9 patients either did not improve, or actually had worse symptoms. The patients who got worse had more manic or irritable symptoms at the beginning of the trial. When the results were averaged, the inositol did not appear to help significantly--however, it is notable that a subgroup of patients appeared to benefit significantly.
http://www.ncbi.nlm.nih.gov/pubmed/16542187

This 2001 study from the Journal of Clinical Psychopharmacology compared 1 month of inositol (up to 18 grams per day) with fluvoxamine (up to 150 mg per day) in the treatment of panic disorder. Both groups improved similarly. The fluvoxamine group had more side effects of tiredness and nausea. The study is limited by its short duration.
http://www.ncbi.nlm.nih.gov/pubmed/11386498

This 1995 study from the American Journal of Psychiatry compared 12 grams per day of inositol with placebo, for one month, in the treatment of panic disorder. The authors conclude that inositol was effective with no significant side effects. Mind you, when eyeballing the chart of data from individual patients, the results did not look very impressive.
http://www.ncbi.nlm.nih.gov/pubmed/7793450

Here's a negative study, showing no difference between inositol and placebo, when added to antidepressant therapy for OCD:
http://www.ncbi.nlm.nih.gov/pubmed/11281989

The same author as above published a study in 1996 showing that inositol on its own was superior to placebo for OCD treatment. However, despite "statistical significance" being found, eyeballing the data from each patient (presented in the body of the paper) reveals doubtful clinical significance (that is, the amount of benefit looked quite unimpressive to me):
http://www.ncbi.nlm.nih.gov/pubmed/8780431

Here's a reference to a 2001 study showing that inositol was superior to placebo in treating binge eating and bulimic symptoms. In this case, I found the data to be clinically significant. However, the study was limited by its small size.
http://www.ncbi.nlm.nih.gov/pubmed/11262515

Here's a small 1995 study showing that 4weeks of inositol (12 grams per day) was superior to placebo in treating depressive symptoms. The data appeared clinically significant, though modest.
http://www.ncbi.nlm.nih.gov/pubmed/7726322

Here's a 2004 reference from a dermatology journal showing that inositol supplementation led to improvement of psoriasis in patients taking lithium:
http://www.ncbi.nlm.nih.gov/pubmed/15149510

In conclusion, inositol may be modestly effective for treating anxiety, eating disorder, and depressive symptoms. It may perhaps be quite variable in its effectiveness, i.e. some individuals might have much more benefit than others. It appears to be well-tolerated with few side-effects. I could not find good data on long-term safety though. The quality of the evidence is not very robust-- the studies have involved only small numbers of patients, for short periods of time. More research is needed.

Antidepressant Combinations for Resistant Depression

In many cases, a single form of therapy does not relieve symptoms of depression or anxiety. For every person, I recommend a range of healthy lifestyle changes, and I usually would encourage psychotherapy. For many, I encourage trials of antidepressant medication as well. For a significant number of people, a single medication does not relieve symptoms. In these cases of treatment-resistance, it can help to search for an effective combination of several medications. In this post, I will discuss the evidence-based foundation for combining antidepressants.

I find that several different antidepressant combos are worth trying, including an SSRI + mirtazapine, venlafaxine + mirtazapine, or an SSRI + bupropion. Adding trazodone to another antidepressant can be helpful for sleep, although I am less convinced of this combination substantially improving depressive symptoms. Combining newer antidepressants with older tricyclics is another area of interest, which I think we should be open-minded about, but I don't tend to prescribe tricyclics very often, mainly due to concerns about safety and side-effects. There are far fewer careful studies of antidepressant combinations compared to studies looking at single medication treatments, so the level of evidence in this area is not very strong yet. But here are a few references to existing articles from the research literature (I will try to expand my list over time):

http://www.ncbi.nlm.nih.gov/pubmed/19345072
This is a 2009 article from a Montreal group (Blier et al.) showing that a combination of mirtazapine + SSRI (paroxetine) led to significantly more improvement in depressive symptoms over 6 weeks, compared to groups taking either medication alone. The combination was well-tolerated for the most part-- in particular there was little difference in side effects experienced by the combination group compared to the group taking mirtazapine alone. Unfortunately, there are conflict-of-interest problems here: the study was funded by Organon, the mirtazapine manufacturer. And several authors of the study were "consultants" paid by the drug manufacturers for speaking engagements. The continued behaviour of psychiatrists accepting corporate money to give "educational lectures" is unfortunate. Usually large sums of money are involved. Please see my posts on industry-sponsored research: http://garthkroeker.blogspot.com/2008/11/biases-associated-with-industry-funded.html and http://garthkroeker.blogspot.com/2009/05/my-experiences-with-industry.html

Here's another recent article (2010) by Blier et al, again making a strong case for using combination antidepressants right from treatment initiation: http://www.ncbi.nlm.nih.gov/pubmed/20008946

http://www.ncbi.nlm.nih.gov/pubmed/18832958
This is an open study looking at combining escitalopram (Cipralex) with bupropion in chronic depression. There was no placebo or comparison group, so the study has a weak design. But it shows the combination was quite well-tolerated, and led to 50-60% of patients experiencing a remission of symptoms after 12 weeks, which in general is a better result than most single-agent trials, especially in chronic depression. The study was funded by NIMH, which reduces the likelihood of bias.

http://www.ncbi.nlm.nih.gov/pubmed/16165100
This is a 2006 review from Biological Psychiatry looking at combinations of bupropion with SSRIs. It is a good paper, but really most of the evidence presented is of mediocre quality. It does support the idea of using bupropion-SSRI combos, to improve treatment response in depression, and also to reduce SSRI-induced sexual side-effects such as delayed or inhibited orgasm.

http://www.ncbi.nlm.nih.gov/pubmed/15539864
This interesting 2004 paper is looking at the treatment of patients with depression plus chronic headache, using citalopram alone, or amitriptyline (a tricyclic antidepressant) alone, for 16 weeks. Then, a combination of the two medications was given to non-responders, for a further 16 weeks. The combination group showed substantial improvement in both headache and depression.

http://www.ncbi.nlm.nih.gov/pubmed/14744472
This is an important 2004 study from Biological Psychiatry showing that 6 weeks of a fluoxetine (SSRI) + desipramine (tricyclic) combination was more effective than either drug alone, in treating depressed patients admitted to hospital. While similar proportions (about 35-50%) of patients failed to respond to any of the three treatments, those patients who did respond improved much more with the combination. That is, the combination treatment led to a significantly higher chance of total remission compared to either single antidepressant treatment. The study was funded by NIMH.

http://www.ncbi.nlm.nih.gov/pubmed/12172337
This 2002 study looked at several options to treat non-responding depressed patients taking fluoxetine: the first group took a higher dose of fluoxetine (40-60 mg/d), the second group took a combination of regular-dose fluoxetine + desipramine, and the third group took fluoxetine + lithium. The results favoured the first strategy, of maximizing the dose of fluoxetine, instead of combining with something else. However, this result is not very useful, since normally we would maximize the dose of a single agent first anyway, before resorting to a combination. Yet the study does show that combining is not necessarily the best first step in addressing treatment-resistance. It was funded by NIMH.

http://www.ncbi.nlm.nih.gov/pubmed/8988452
This is one of the few studies looking at trazodone combinations: in this case, trazodone+fluoxetine showed some promise in treating resistant depression.

http://www.ncbi.nlm.nih.gov/pubmed/1548249
A weak old study from 1992 showing that trazodone can sometimes help as a combination with an SSRI (in this case, fluoxetine). 3 out of 8 depressed patients in this study improved with the combination (of course, this means that 5 out of 8 did not improve).

http://www.ncbi.nlm.nih.gov/pubmed/19415584
This is a 2009 review article on combining antidepressants. It is in German, which makes it hard for me to read!

Good News

Here are a few "good news" websites:

http://www.happynews.com/index.aspx
http://www.goodnewsnetwork.org/
http://www.only-positive-news.com/archives
http://globaldialoguecenter.blogs.com/jbgoodnews/

There is so much bad news in the world today...

Yet, of course, the bad news is accurate: many people are doing many horrible things; whole nations are behaving badly; the whole planet is at risk for irreversible deterioration... It is important and healthy for us to be aware of the truth, even if the truth is difficult to hear.

This reminds me of the way depression can work, particularly chronic depression: the negative, cynical, painful, or pessimistic thoughts associated with depression may represent accurate truths about one's life or about the world.

It can feel frustrating, irritating, and shallow to simply ignore the negative thoughts or negative truths, and focus strictly on "happy thoughts." It can feel like mental manipulation to try to convert a negative observation into a positive one.

I believe that part of the solution is not necessarily to try to negate negative thinking. This would be like refusing to learn about the realities of global hunger, environmental pollution, or about a child being bullied in your neighbourhood, and just simply carrying on with a smile as though everything was fine. This is just denial--things have to be done about hunger, pollution, and bullies.

But I do believe that part of the solution is to be informed about positive news that is going on in the world...this requires very deliberate effort.

Human nature, and the human brain, tends to focus on things that are going wrong. This is a vital safety mechanism...it has kept us safe from predators and other environmental dangers over millions of years of evolution. This tendency shows up in news reporting--headlines are all about disasters, not about moments of sublime beauty or courage or hope. Disaster reporting sells more papers, it grabs our attention more strongly--that's the way our brains are made.

In order to have a healthy and balanced lifestyle we must actively inform ourselves of things that are going right, alongside whatever information comes to us about things that are going wrong. We must do this on a global scale, a local community scale, and on a personal scale (within our own thoughts or minds).

Many anxious negative thoughts represent strong over-estimations of risk (e.g. a fearful airline passenger may feel that the likelihood of crashing is 90%, when in fact the likelihood is 0.0001%); in cases like this an objective "cognitive therapy style" analysis and challenging of thoughts can be therapeutic and reassuring.

Cognitive therapy need not discount negative thoughts. An acknowledgment of a very negative reality may be an honest and frank therapeutic step.

But I think cognitive therapy for depression must allow space for seeking out things that are positive.

I invite you to check out some of the websites above, and seek out more (or better) sources of good news (let me know if you find some). I also invite you to pay attention to examples of "good news" in your community, in your daily life, and in your thinking.

Long-term antidepressant therapy to prevent relapse

Maintenance antidepressant therapy is likely to reduce the probability of depressive relapse. This would involve continuing to take an antidepressant, long-term, even when feeling better. I would restrict such a recommendation to those who have had recurrent or severe depressions. Such maintenance therapy is best indicated for those who have actually had an acute benefit from a specific antidepressant.

I emphasize the importance of psychotherapy and healthy lifestyle change, which also reduce relapse rates (in the case of CBT, for example, the reduction in relapse rate persists long after the course of CBT is over).

This is a 2008 link to findings from the so-called PREVENT study, which showed that 67% of patients on venlafaxine remained well over 2.5 years of follow-up, compared to 41% of patients on placebo:

http://www.ncbi.nlm.nih.gov/pubmed/18854724

A weakness of this study is that they did not allow for an extremely gradual taper of venlafaxine in the group randomized to receive placebo maintenance; therefore the worse outcome in the placebo maintenance group could have partly been due to withdrawal symptoms. However, there is a brief discussion of this possibility in some letters from the Journal of Clinical Psychiatry (2008 May; 69(5): 865-866) , and the authors of the PREVENT study make some good points about why withdrawal symptoms are not likely to account for the worse outcome in the placebo group.

There are a variety of older studies showing reduced relapse rates in patients taking long-term antidepressant maintenance. Here is an example, using imipramine:
http://www.ncbi.nlm.nih.gov/pubmed/8478502

Withdrawal effects are unlikely to account for the worse outcome in the control group, because the control group actually still received the active antidepressant, but just at a lower dose. The point of this study is that a full dose of the antidepressant is probably required in a long-term maintenance phase.

Here is another study from 1992 in Archives of General Psychiatry, showing significant preventative effects from taking full-dose imipramine over 5 years of follow-up, with or without adjunctive psychotherapy:
http://www.ncbi.nlm.nih.gov/pubmed/1417428

Here is a link to a 1990 study in Archives of General Psychiatry showing that full-dose imipramine had substantial preventative effects, moreso than interpersonal therapy, over 3 years of follow-up:
http://www.ncbi.nlm.nih.gov/pubmed/2244793

For this study, I need to go back and look carefully over the full text, which I can't find at this moment.

This study is another compelling piece of evidence, from JAMA in 1999, supporting antidepressant maintenance, and it had an excellent design:
http://www.ncbi.nlm.nih.gov/pubmed/9892449

It showed that elderly patients who had recovered from a bout of recurrent depression, who then received placebo, had a relapse rate of 90% over 3 years. Treatment with interpersonal psychotherapy alone reduced the relapse rate to 64% over 3 years. Treatment with the antidepressant nortriptyline alone reduced this relapse rate to 43% over 3 years. Nortriptyline plus interpersonal therapy combined, led to a relapse rate of only 20% over 3 years. Withdrawal effects from notriptyline are unlikely to have substantially favoured the nortriptyline group, since the follow-up was over a 3 year period, which is way beyond any period of withdrawal effects.

Here is another 2007 review paper, from The Canadian Journal of Psychiatry, summarizing strong research support that long-term antidepressant therapy reduces relapse rate in major depression by about 50%:
http://www.ncbi.nlm.nih.gov/pubmed/17953158

St. John's Wort

St. John's Wort is a herbal antidepressant. Its mechanism is not well-understood, and at this point is in the realm of speculation, but may involve multiple compounds rather than just a single ingredient (one of the many ingredients in St. John's Wort extracts, for example, is hyperforin).

There is an evidence base in the research literature, supporting its use. However, I find many of the articles to be published in minor journals, and to be of questionable quality.

I will restrict my present survey to a few studies that I consider to be of higher quality:

Here is an article abstract discussing possible mechanisms of action:
http://www.ncbi.nlm.nih.gov/pubmed/12775192

This is a reference to a Cochrane review from 2008.
http://www.ncbi.nlm.nih.gov/pubmed/18843608

It supports the use of St. John's Wort for treating major depression, and concludes that response rates were similar, compared to SSRIs and tricyclic antidepressants. It also concludes that St. John's Wort was much better-tolerated than other antidepressants, with a greatly reduced risk of side-effects or of discontinuing the medication due to side-effects. The authors note that studies from German-speaking countries tend to report a greater benefit from St. John's Wort.

I note that this review was written by authors from a "Centre for Complementary Medicine Research" in Germany. It may be that researchers at such a site could have a biased view in favour of complementary therapies.

This review from the major journal BMJ in 2005 gives much less enthusiastic conclusions about St. John's Wort:
http://www.ncbi.nlm.nih.gov/pubmed/15684231

It gives a rigorous analysis of the data, and concludes that there is evidence, mainly from older, smaller, lower-quality studies, that St. John's Wort is beneficial compared to placebo, particularly for mild to moderate depression. More recent, larger, more rigorous studies, and studies including patients with more severe depression, show smaller treatment effects.

It does strongly emphasize that different preparations of St. John's Wort may differ in quality, especially since it is an over-the-counter product in most places, and therefore may lack the guaranteed quality control of regulated pharmaceutical products.


Here are links to 2 carefully done studies from 2001 and 2002, published in JAMA, showing no therapeutic benefit of St. John's Wort. The first study compared only with placebo, the second study also compared with sertraline, an SSRI--in the latter study the sertraline actually didn't do well against placebo either! I have to wonder if particular samplings of depressed patients are relatively less treatment-responsive compared to placebo, for a variety of reasons. Also, it may be that some preparations of St. John's Wort are more effective than others:

http://www.ncbi.nlm.nih.gov/pubmed/11308434

http://www.ncbi.nlm.nih.gov/pubmed/11939866

Here is a link to a recent German study showing that people who respond to St. John's Wort have lower rates of relapse, compared to placebo, if they continue to take it for a year:
http://www.ncbi.nlm.nih.gov/pubmed/18694635


There are some interactions St. John's Wort may have with other drugs; mainly the concern is that St. John's Wort induces the liver to metabolize other drugs more actively, therefore reducing the levels of other drugs. This could be a danger for some people. Here is a reference about this:
http://www.ncbi.nlm.nih.gov/pubmed/15260917

There are case reports of St. John's Wort causing mania, so it would need to be used carefully in persons with bipolar disorder. But there are no studies that I can find, which give clear estimates of risk for St. John's Wort to cause mania or rapid cycling, particular when compared to other treatments for depression in bipolar disorder.

There is a poor evidence base looking at the safety of combining St. John's Wort with other antidepressants, but there are a few case reports of possibly dangerous states such as serotonin syndrome.

I will add to this posting later, but for now I would say that St. John's Wort is probably quite safe for most people, and is probably easier to tolerate (in terms of side-effects) than prescription antidepressants. It may be effective, for some people, to treat or reduce symptoms of depression and anxiety. It may reduce levels of other medications, including contraceptives, and may interact with other drugs, so these possibilities have to be considered very carefully, and discussed with your prescribing physician.

Also, I should add that different brands of St. John's Wort may differ in quality, differ in the extraction method used, etc. So if you are going to give St. John's Wort a try, it may be worthwhile to try several different brands. Given the abundance of positive research studies from Germany, it might be worthwhile to try a German brand.

Drum Circles

Drum circles are groups where people gather to pound drums together: producing, hearing, and appreciating rhythms.

The perception of rhythm is one of the core elements of human experience.

Over hundreds of thousands of years of human evolution--even before the development of culture--the perception of rhythm must have been a very important part of daily life experience.

Here are some examples of rhythms that have been part of life experience for millions of years:

-The rhythmic pounding of ocean waves
-The beating of the heart (as perceived by feeling the pulses through touch, by feeling a throbbing, excited heart in the chest, or sometimes by hearing one's own or someone else's heartbeat)
-The rhythm of breathing (regular and soft in a calm state, rapid or erratic in anxious or excited states, irregular in various particular ways as a person is crying or sobbing; or when a person is dying, e.g. Cheyne Stokes respiration)
-The chirping of crickets or the croaking of frogs (these rhythms being affected by human proximity)
-The rhythm of work tasks (e.g. preparing some kind of meal or building some kind of structure would involve repetitively pounding, picking, or working with a material, and if this was a monotonous, laborious task, a rhythm would naturally form to help the person "get into it")
-The rhythm of human footsteps (steady and strong when feeling confident and certain, rapid or timid when frightened, stomping when angry)
-The rhythms of the human voice. Before the development of languages over 50 000 years ago, probably a great deal of communicative content between humans would have been based on "non-verbal" vocalizations, which would have emphasized tonal quality but also rhythm. Today vocal rhythms are most obviously part of the expressive content in poetry and song.
-Part of rhythm includes silence. It is the "empty space" between sounds. There was a lot more silence in pre-modern cultures.

Upon the development of human culture, starting perhaps 50 000 years ago, rhythms would have been generated spontaneously as a part of creative expression, as celebration, or as ritual.

In modern culture, perhaps a lot of the ancient, prehistoric aspects of rhythmic perception have been "drowned out". In urban environments, we have a lot of cacophonic, industrial sounds, or multiple sources of sounds all coming at us at the same time. There may not be very much silence at all. I suspect that this cacophony is a contributing factor to life stress, and one of the variables increasing the rate of mental illness (there are certainly many studies showing increased prevalence of various mental illnesses in urban environments). As a corollary, I believe that spending time developing one's musical and rhythmic experiences is beneficial to mental health.

As a therapeutic modality, drumming could help people in various ways:
1) as a form of meditative focus
2) it involves physical action: it is a form of exercise as well as a form of tactile stimulation
3) it helps to focus attention: it is a form of mental exercise, as well as a means to distract mental energy away from anxiety or other negative emotions
4) it can be an endless source of intellectual stimulation, with hearing or producing increasingly complex rhythms and cross-rhythms. This can evolve to become a source of esthetic enjoyment, also leading to appreciating rhythm in other aspects of life and music more richly.
5) it can be a social activity, in which other members of the group can be guides or teachers: in drum circles, individuals need not be skilled in drumming or in generating complex rhythms--exposure to the group permits a social learning experience
6) similarly, a drum circle could be a good setting to deal with performance anxiety or social anxiety, in the comfort of an encouraging and accepting group
7) it can simply be a healthy, enjoyable form of stress management
8) drum circles can be a means to build community: the experience combines elements having to do with conformity (maintaining the same rhythm together) and with individuality (each person may have a separate or special rhythmic role or task) -- both such elements are required to have healthy community life

In Vancouver, I know of one regular drum circle group, which has been open to anyone interested. The leader of this group, Lyle Povah, has done interesting work with drum circles as part of an inpatient eating disorders treatment program. Here's his website:
http://lylepovah.com/

There may be similar groups in other communities across the world, and I encourage people to research this, and to consider checking one out.

Active Placebo Studies show smaller benefits from Antidepressants

In most of the better clinical studies, a "placebo group" acts as a control. The placebo would consist of something totally inert, such as a capsule with nothing inside, or possibly with a small quantity of a sugar such as lactose.

The idea of an "active placebo" is interesting: in this case, the placebo is an agent shown not to have any beneficial or detrimental effect on the disease in question, but which clearly has side-effects.

An example would be using a tablet of Gravol (dimenhydrinate) as the "placebo". It is not an antidepressant, but it has side-effects (sedation, dry mouth, etc.). In this way, it is a more convincing placebo, since a person taking an agent which produces side effects is more likely to believe that they are taking the "active" agent. If a person is taking a placebo they strongly believe to be a placebo (since it produces no side effects) they are less likely to have any "placebo effect" response, and the whole point of the placebo control will be relatively "unblinded."

There is a body of research literature looking at using "active placebo" vs. antidepressants to treat depression.

http://www.ncbi.nlm.nih.gov/pubmed/9614471

{a 1998 meta-analysis from the British Journal of Psychiatry showing that the effect sizes of antidepressant therapy are only about half as large when compared against an active placebo, rather than an inert placebo}

http://www.ncbi.nlm.nih.gov/pubmed/14974002
{a 2004 Cochrane review with similar findings}

These results support the evidence that antidepressants work -- but they suggest that probably most of the studies overestimate how well they work, because they are measured against inert placebos in most cases.

I think that more clinical studies need to include active placebos.

I post this not to be cynical, or to discourage the use of antidepressants--as you can see from the rest of this blog, I strongly support medication trials to treat psychiatric problems--but I believe that we have to always search for the most accurate, least biased sources of information. We need to be wary of exaggerated claims about the effectiveness of anything, especially since I see in my practice that many of the treatments don't seem to work quite as well as the ads claim they should.

Trazodone

Trazodone is another antidepressant introduced in the early 80's. Once again, its use was fashionable for a time, gradually faded, and at this point it is mainly used adjunctively to treat insomnia.

It is notable among antidepressant choices in not causing sexual side effects (other than the rare incidence of priapism, which is a medically dangerous, painful, abnormally sustained penile erection, which occurs in probably less than 1 in 1000).

The trouble with trazodone is that for many people, it causes too much daytime sedation. However, it can be worth a try, to treat insomnia associated with depression or antidepressant therapy, or possibly as an augmentation to treat depression or OCD.

In my experience, about 50% of people find trazodone a helpful adjuct, but the other 50% find it causes too much tiredness or dizziness the next day to be worth continuing.

Here is a literature review:


http://www.ncbi.nlm.nih.gov/pubmed/19112384
{in this 2008 study from a minor journal, trazodone was shown to increase the amount of slow-wave sleep in treating chronic insomnia}

http://www.ncbi.nlm.nih.gov/pubmed/12930437
{a 2003 urology article showing evidence that trazodone may help treat erectile dysfunction, especially at higher doses}

http://www.ncbi.nlm.nih.gov/pubmed/18978492
{a small 2008 study showing that 50-100 mg of trazodone may reduce SSRI-induced sexual dysfunction}

http://www.ncbi.nlm.nih.gov/pubmed/16968574
{a small 2006 study showing equivalence between trazodone and sertraline in treating depression over 6 weeks}

http://www.ncbi.nlm.nih.gov/pubmed/10507215
{a small 1999 study from a podiatry journal, showing that trazodone can help with painful diabetic neuropathy symptoms}

http://www.ncbi.nlm.nih.gov/pubmed/8010365
{a 1994 American Journal of Psychiatry article showing that trazodone can help with antidepressant-induced insomnia, particularly helping with overall subjective sleep quality, reducing waking in the middle of the night, and reducing early morning waking}

http://www.ncbi.nlm.nih.gov/pubmed/8988452
{this awkardly-designed 1996 study suggests that combination treatment including 100 mg of trazodone may help in treatment-resistant depression}

http://www.ncbi.nlm.nih.gov/pubmed/11518472
{this quite weak 2001 study nevertheless suggests that trazodone helps to reduce nightmares in PTSD patients}

http://www.ncbi.nlm.nih.gov/pubmed/6337131
{an early, 1983 study, of trazodone vs. imipramine for treating moderately to severely depressed outpatients. Despite the weaknesses of the study design, it did have some follow-up over 3 years, showing that trazodone works well for some people, and worked as well as imipramine overall}

http://www.ncbi.nlm.nih.gov/pubmed/18311107
{an example of a small study suggesting that adjunctive trazodone could help improve OCD symptoms. Some studies have shown no anti-OCD effect with trazodone alone, but others have shown trazodone alone to be beneficial in refractory OCD. In any case, I think the evidence base suggests that trazodone could at least be worth a try, either together with an SSRI, or even on its own.}

Moclobemide is a Good Antidepressant

The antidepressant moclobemide is a reversible monoamine oxidase inhibitor. Once again, this is a drug that was frequently prescribed for a time, but has subsequently faded in popularity.

It was released in the late 80's; around 1990 many studies came out, comparing moclobemide with other antidepressants, including tricyclics and fluoxetine, showing that it worked just as well for treating depression. Many of these studies were published in Scandinavia. There have been very few clinical studies since then. Part of the reason may be that moclobemide was never approved in the U.S. (I do not understand why not).

Moclobemide has also been used effectively to treat social phobia.

In my opinion, it is a neglected option in treating depression. Because it has faded in popularity, it is usually tried as a third-line medication. For this reason, it is prescribed to patients who are more likely to have a more refractory depression. For this reason, it is less likely to be seen to help as much; this leads to clinicians pronouncing it ineffective, and not prescribing it. If it was prescribed as a first-line agent, I think we would see that it works pretty much as well as any other antidepressant.

Its advantages relate to the side-effect profile: its side effects in general are probably closest to placebo among all the antidepressants. And there are minimal or no sexual side effects with moclobemide, compared to the SSRI's. Here's a reference:

http://www.ncbi.nlm.nih.gov/pubmed/10974600

Other references:

http://www.ncbi.nlm.nih.gov/pubmed/17168253
{a 2006 meta-analysis showing that moclobemide works as well as SSRI's}

http://www.ncbi.nlm.nih.gov/pubmed/16702988
{a 2006 article from the British Journal of Pharmacology suggesting that moclobemide may have neuroprotective or even neurogenerative effects in the hippocampus}

http://www.ncbi.nlm.nih.gov/pubmed/12595913
{a 2003 review}

Addendum:

There was one case series study published in 2000 by Magder, Aleksic, and SH Kennedy, describing the successful use of very high-dose moclobemide in combination with lithium and/or trazodone for treatment-resistant depressed patients. The doses used were up to 1500-1650 mg/day, which is much higher than the usual maximum of 600 mg. They advocated using an MAOI diet at these doses. Moclobemide was well-tolerated, and the patients appeared to benefit over 1-2 years of follow-up. It's worth looking at this brief article in its entirety, here's a link to the abstract:
http://www.ncbi.nlm.nih.gov/pubmed/10831036

Volunteering Improves Mental Health

Altruistic volunteering is beneficial for mental health.
There are several mechanisms by which this could happen:

1) the experience of giving one's time and energy for another in need is an intrinsic life joy
2) there are opportunities to build new friendships, with others who also are "practicing altruists"
3) the experience may allow you to discover new aspects of yourself, in terms of skills, pleasures, ambitions, etc.
4) the structure of the volunteer experience may be a "benevolent structure" motivating action in your day, challenging depressive symptoms which might keep you inactive or alone

Here is some evidence from the literature:

http://www.ncbi.nlm.nih.gov/pubmed/18381833
{this 2008 study from a gerontology journal, shows that people in their 60's who volunteer moderately have higher levels of well-being, after controlling for variables such as educational level, physical health, etc. People who didn't volunteer, or people who volunteered "too much", had lower levels of well-being}

http://www.ncbi.nlm.nih.gov/pubmed/18321629
{a 2008 study from the London School of Economics, showing that there is a direct causal relationship between volunteering and happiness; weekly volunteering increases the likelihood of being "very happy" by 16%, independent of income level--the data also suggest that the effect is more pronounced for people who volunteer more frequently}

http://www.ncbi.nlm.nih.gov/pubmed/11467248
{a 2001 study looking at data from 2681 people, showing that volunteering is associated with increased well-being in numerous domains, including happiness, life satisfaction, self-esteem, sense of control over life, physical health, and depression}

http://www.ncbi.nlm.nih.gov/pubmed/9718488
{a 1998 study showing that volunteering bolsters well-being in elderly persons who volunteer; also the people who are helped by the volunteers had reduced amounts of depression}


I think there should be some more prospective, randomized studies of volunteering and other altruistic activity in the treatment of mental illnesses.

If you are interested in volunteering in Vancouver, here is a place to start looking:


http://www.govolunteer.ca/cgi-bin/page.cgi?_id=16

Buspirone

Buspirone is another of those medications that was introduced in the 80's, and was marketed for the treatment of anxiety. Most of the published studies on buspirone were done around 1990.

While many antidepressants simply increase the amount of serotonin or other neurotransmitters by blocking neurotransmitter re-uptake into neurons, buspirone works by directly stimulating one of the target receptors for serotonin, called the 5HT-1A receptor.

As with many new drugs, there was a wave of enthusiasm, which eventually faded. At this point buspirone is rarely prescribed.

In my opinion, it could be a useful and well-tolerated adjunct, to try in the following situations:

1) to treat generalized anxiety disorder
2) to augment antidepressants (i.e. to add to an antidepressant which isn't working well enough)
3) to treat antidepressant-induced jaw or tooth grinding (bruxism)
4) to treat aggressive or self-injurious behaviour; it may be particularly helpful in elderly patients with dementia, or in mentally handicapped patients
5) to treat migraine (a common comorbid problem among depressed or anxious patients)
6) to help with opiate withdrawal
7) to help quit smoking

Side effects are usually mild and subside with time; they include dizziness, nausea, sweating, or nervousness. About 10% of people in the clinical trials of buspirone discontinued the medication due to side effects.

Buspirone is metabolized through the cytochrome P450 3A4 system in the liver; because of this its levels in the body can be substantially increased by other medications or grapefruit juice, so these types of interactions have to be considered when choosing a dose.

I've been curious to revisit the evidence base for buspirone; here is my review of the literature:

1) Using buspirone as an augmentation to antidepressants, for treatment of depression:

http://www.ncbi.nlm.nih.gov/pubmed/17628435
{a good, important study from NEJM in 2006: 565 depressed patients who had not remitted despite receiving high-dose citalopram, were given augmentation therapy with either bupropion SR or buspirone. That is, the bupropion or buspirone was added onto their daily regimen of citalopram, and the patients were followed over at least 7 weeks. Both groups did similarly well, with about 30% of both groups having a remission. The bupropion group did slightly better in a few ways. Unfortunately there was no placebo augmentation group}

2) Treating generalized anxiety:

http://www.ncbi.nlm.nih.gov/pubmed/8666569
{a small study from 1996 showing that buspirone helps reduce anxiety symptoms in patients who also have mild depression; but the reduction in anxiety symptoms (about 50%) is only modestly different from placebo (about 35%) }

http://www.ncbi.nlm.nih.gov/pubmed/3320034
{this study from 1987 had a one-year follow-up of 700 patients. But it was open-label (no randomization, no placebo group). It did show that the patients taking buspirone for treatment of generalized anxiety showed sustained improvement, and tolerated the medication well}

http://www.ncbi.nlm.nih.gov/pubmed/17984162
{this 2007 study compares the effect sizes of numerous different medication treatments for generalized anxiety; buspirone fares particularly poorly, with a "non-significant" effect size of 0.17; SSRI's and venlafaxine do slightly better, and the novel anticonvulsant pregabalin actually does best. Complementary and alternative medications had a negative effect on symptoms, in this analysis. However, this meta-analysis is limited by the fact that most of the buspirone studies were done over 10 years ago and most of the results are from short-term treatment.}

http://www.ncbi.nlm.nih.gov/pubmed/2211567
{one of the small randomized studies comparing buspirone with a benzodiazepine for treatment of anxiety; the study shows similar effectiveness. Given that buspirone is non-addictive, it makes buspirone a more attractive option}


3) Treating other anxiety conditions:

http://www.ncbi.nlm.nih.gov/pubmed/2407755
{one of the studies showing that buspirone is NOT effective for treating panic disorder}

4) Improving cognitive function in schizophrenia:

http://www.ncbi.nlm.nih.gov/pubmed/17628435
{this 2007 study had a good randomized design, and 6 months of follow-up; it claimed in the abstract that buspirone had a beneficial effect on cognition when added to antipsychotics in schizophrenia -- but if you take a look at the actual data in the article, the differences in buspirone vs. placebo groups are very small. So I'm not impressed.}

5) Treating migraine:

http://www.ncbi.nlm.nih.gov/pubmed/16109114
{a small 2005 study in a headache journal looking at a group of 74 patients with migraine over 6 weeks of treatment; it showed that low-dose buspirone (10 mg) reduces migraine frequency by about 40%, and reduced anxiety scores by about 20%, both of which a substantial difference compared to placebo. The improvement in anxiety did not depend on the improvement in headache, they appeared to be separate, independent effects.}

6) Treating acute heroin withdrawal:

http://www.ncbi.nlm.nih.gov/pubmed/15876901
{an interesting 2005 study showing that 45 mg per day of buspirone can reduce symptoms of heroin withdrawal over a 2-week period; looking at the results directly, it appears that the effect is very substantial, that the buspirone almost eliminated withdrawal symptoms}

7) Helping quit smoking:

http://www.ncbi.nlm.nih.gov/pubmed/1739365
{a small 1992 study from Archives of Internal Medicine showing that buspirone helps with nicotine withdrawal, and may help people quit smoking}

8) Treating ataxia:

http://www.ncbi.nlm.nih.gov/pubmed/8806320
{another interesting study from Lancet in 1996, showing that buspirone helps improve symptoms of cerebellar ataxia, a type of brain disease which causes impaired balance & coordination}

9) Treating aggressive behaviours:

http://www.ncbi.nlm.nih.gov/pubmed/2016248
{a small study suggesting that buspirone can help reduce aggression and anxiety in mentally handicapped adults, without causing sedation or cognitive side-effects}

10) Treating bruxism:

http://www.ncbi.nlm.nih.gov/pubmed/10665633
{a 1999 study of 4 cases of SSRI-induced bruxism improving with buspirone}

11) Treating tardive dyskinesia:

http://www.ncbi.nlm.nih.gov/pubmed/8102622
{a 1993 study showing some improvement in tardive dyskinesia (a movement disorder) after treatment with buspirone for 12 weeks. However there are a few other case reports in the literature of buspirone causing worsened symptoms of various movement disorders, such as dystonias or myoclonus (twitching); but the incidence of such side effects appears to be very low}


12) Animal studies:

http://www.ncbi.nlm.nih.gov/pubmed/17312776
{in this study a badger in a zoo (!) was suffering agitation and engaging in self mutilation; "environmental enrichment" initially helped, but the behavioural problems still recurred. Buspirone ended up helping substantially, over an 18 month period, with no side-effects}

http://www.ncbi.nlm.nih.gov/pubmed/15766212
{in another animal study, buspirone helped reduce self-injurious behaviour in a group of rhesus macaques, and it seemed to help more than fluoxetine, with fewer side-effects}

Brainstem Stimulation - cranial nerves

There are some novel therapies such as vagal nerve stimulation or deep brain stimulation, which can improve symptoms of depression. These treatments may be increasingly important sources of relief for chronically suffering depressed patients-- particularly as the technology advances, becomes safer and more refined.

Here are a few links to references about these treatments:

http://www.ncbi.nlm.nih.gov/pubmed/16641939

http://www.ncbi.nlm.nih.gov/pubmed/19137233

Of greater interest to me in an outpatient office psychiatry practice, is an idea based on looking at trivially available techniques to accomplish "deep brain stimulation" or "vagal nerve stimulation", etc. All parts of the brain -- even the "deep brain", and even the vagal nerve -- are connected to all other parts of the body! Specific life events can obviously affect deep brain or vagal nerve stimulation, without requiring an implanted electrical device or neurosurgery! Some of these life events could be deliberately sought out as therapeutic strategies.

Something I've noted about some of these new, radical techniques, is that they involve stimulation of brainstem structures, often involving the cranial nerves. It seems to me that the cranial nerves are an extremely visceral set of portals through which stimuli are exchanged between the environment and the deep structures of the brain which regulate mood and consciousness. Here's a summary of all the cranial nerves, with speculations about techniques to "stimulate" them in a way that might be therapeutic:

Cranial Nerve I (olfactory): Stimulation of this nerve requires exposure to different scents. Aromatherapy is a familiar component of alternative health strategies. Here is some evidence from the mainstream medical literature, showing that aromatherapy can be helpful:
http://www.ncbi.nlm.nih.gov/pubmed/19125379
(a review article)
http://www.ncbi.nlm.nih.gov/pubmed/18178322
(a randomized study showing that the scent from lemon oil improves mood, compared to water or lavender, and regardless of expectancies or past experience with aromatherapy)
http://www.ncbi.nlm.nih.gov/pubmed/18713168
(a study showing improvement with lavender oil aromatherapy vs. controls in neuropsychiatric symptoms of elderly dementia patients)
http://www.ncbi.nlm.nih.gov/pubmed/17342790
(another study showing improvements in dementia patients with lavender)

Given the fact that there is virtually no risk to aromatherapy treatments, why not give it a try? It could help with sleep, relaxation, studying, or as a conditioning device (e.g. associating a particular odor with sleep, or with studying a particular subject, etc.)

Cranial Nerve II (Optic): Bright light therapy has a considerable evidence base. Probably looking at beautiful things in nature is good for your mood (I'll need to find a reference to prove this!). These images would have to pass through Cranial Nerve II, on their way to your brain.

Cranial Nerves III, IV, and VI: these innervate the muscles which move the eyes. There is a type of therapy called "EMDR" which calls upon patients to move their eyes back and forth as an essential part of the therapeutic technique. I suspect this acts as a conditioning phenomenon, which at once distracts the person, while perhaps permitting exposure therapy regarding uncomfortable thoughts or PTSD symptoms to take place in a more relaxed state, or in a state associated with therapeutic benefit. But maybe the "brainstem stimulation" from eye movements is an integral part of EMDR's therapeutic effect.

Here are some links to review papers or meta-analyses looking at EMDR:
http://www.ncbi.nlm.nih.gov/pubmed/16740177
(here, EMDR and CBT are both shown to be substantially and similarly effective in the treatment of post-traumatic stress disorder)

http://www.ncbi.nlm.nih.gov/pubmed/17636720
(a Cochrane review also showing EMDR and CBT to be the psychological treatments of choice in post-traumatic stress disorder)


Cranial Nerve V (trigeminal): this nerve transmits tactile sensations from the face into the brainstem. I do not know of any deliberate psychiatric therapy involving this nerve. But there is acupuncture. Also, there is massage, and in particular "facial treatments" (involving massage, aromatherapy, moisturizing creams, etc.) available in health spas--these seem to have a positive effect on overall well-being. I'd be curious to see a controlled study on this: in the meantime, though, it seems another risk-free thing to try.
http://www.ncbi.nlm.nih.gov/pubmed/19129675
(well, this is a pretty weak study -- but it's a start, and it involves a totally harmless treatment -- it shows reduction of anxiety in women receiving facial massage)

Cranial Nerve VII (facial): this nerve innervates the muscles of the face. As noted in a previous post, actions which affect facial musculature can affect emotion, just as emotion changes facial muscle tone (it's always interesting how these phenomena can work both ways). A branch of Nerve VII also conducts information about taste (gustatory sensation) from the tongue to the brain. I have no doubt that enriching one's culinary sensations in life has a positive impact on mood. But I'll have to look for a study to prove it.

Cranial Nerve VIII: the cochlear branch of this nerve transmits information about sounds from the ears to the brain. Hearing music, soothing sounds, and speech clearly affect mood and cognition. Noise, as I claimed in an earlier post, has a negative impact on mental health. Silence itself "rests" the cochlear nerve, which could itself be therapeutic (in moderation).
The vestibular branch of nerve VIII seems interesting to me as a prospective therapeutic target. This nerve transmits signals about balance, head position, and head movement to the brain. Sometimes individuals in an autistic or highly agitated psychotic state will stimulate their vestibular nerve by rocking repetitively. The action of a parent rocking a baby to sleep, or calming an agitated, crying baby, involves stimulating the baby's nerve VIII. It would be interesting to see if various stimulations of the vestibular nerve could be useful in adults, to treat anxiety, agitation, insomnia, or mood disorder. Balance exercises could be a start (perhaps some of yoga's therapeutic effects come from this). Maybe something like sleeping in a hammock, which would rock slowly, could be more soothing on this level, compared to a regular bed. Some people might find a boat to be very soothing (for others it would just cause nausea). If there are any engineers out there, reading this, it would be an interesting project to design a device which could be programmed to gently rock an adult back and forth (with different waveforms and frequencies).

Cranial Nerve IX: Glossopharyngeal. This nerve innervates your throat. The action of swallowing involves this nerve. People with anxiety states often have uncomfortable throat sensations, or problems with swallowing. It's hard to come up with therapeutic ideas directly relating to this one. Except perhaps the idea of eating really spicy food -- which stimulates not only taste buds but also sensory nerves (partly from Cranial Nerve V) in the mouth and throat. Strong culinary sensations can be a source of pleasure, and perhaps can also teach one to be more open about new things (I remember taking a long time getting used to wasabi on sushi after being introduced to Japanese food upon moving to Vancouver in 1995).

Cranial Nerve X: This is the vagus nerve that is stimulated electronically in an advanced surgical treatment for depression. The vagus nerve innervates the parasympathetic system of the body's viscera (e.g. it slows the heart, speeds up the bowel, etc.). One can train the vagus nerve through activities such as yoga, meditation, biofeedback, and through physical exercise.

Cranial Nerve XI: this nerve allows you to turn your head back and forth. Perhaps this could be an element not to forget in your exercise regime -- do some stretching and gentle exercises involving rotation of your head.

Cranial Nerve XII: this nerve allows you to move your tongue. Speech, singing, eating, and a variety of other pleasurable activities -- all involve your tongue. In anxiety states, people can have an exaggerated awareness of their tongue movements. Taking voice lessons or attending a voice coach can help build confidence, reduce social anxiety, literally help you "strengthen your voice"--a strong and clear voice, both metaphorically and literally, can be part of a healthy emotional life.

In conclusion, perhaps there are a variety of readily available techniques that can accomplish "deep brain stimulation" in ways that benefit your mental health, without actually requiring a neurosurgical procedure!

Singing

There are a number of reasons why singing (out loud!) can be beneficial for mood:

1) the parts of the brain, as well as the facial and pharyngeal muscles, involved in singing, are similar to those most active in positive mood states. This may seem a trite or ridiculous association, but it is supported by evidence, namely that voluntary actions associated with happiness, even if unconsciously initiated, lead to more positive mood. Here's a link to the abstract of a classic, amusing, 1988 paper by Fritz Strack, published in The Journal of Personality and Social Psychology (another great journal that I recommend following), demonstrating that changing the position of facial muscles leads to a change in emotional response:
http://psycnet.apa.org/journals/psp/54/5/768/

2) singing is active, yet relaxing; potentially social, yet individual; creative, yet structured

3) Fellow singers--if singing is done in a group--are likely themselves to be emotionally positive and encouraging, leading to a positive social environment.

Here's a link to an abstract demonstrating that choir singing leads to improved mood and reduced stress hormone levels:
http://www.ncbi.nlm.nih.gov/pubmed/15669447

Of note, actively singing music -- not merely listening to music -- was required to produce a beneficial effect.

Bipolar Depression

The depression which occurs in the context of bipolar disorder may have a variety of unique features (sometimes such a depression may occur BEFORE a clear manic episode has ever happened, so a depression with these features can sometimes be a warning sign of latent bipolarity, or a risk sign that bipolar disorder may develop in the future):

1) excessive sleep (rather than insomnia), along with marked physical lethargy
2) depression beginning early in life (during teenage or young adult years)
3) depressive episodes of short duration
4) depressive episodes having psychotic features (e.g. delusions)
5) other "atypical" depressive features, such as increased eating
6) Sometimes a very rapid response to antidepressants (e.g. within one or two doses)

Nevertheless, these features are not invariably present in bipolar depression; and many people may have depressive episodes with these features, who do not have bipolar disorder.

Conversely, in my opinion, there is one significant element from a person's history which points strongly away from a diagnosis of bipolar depression:

If a person has taken an antidepressant, especially at a high dose, and especially for a long period of time (over 3 months), and especially a tricyclic antidepressant or venlafaxine -- if a person has taken such an antidepressant on its own, without a mood stabilizer, and WITHOUT developing overt symptoms of mania, this is fairly strong evidence against underlying bipolarity.

Some of the recent evidence about treating bipolar depression leads us to question the role, value, or safety of antidepressants in the bipolar population.

http://www.ncbi.nlm.nih.gov/pubmed/18727689
(a 2008 review, showing little effect of antidepressants when added to mood stabilizers in treating bipolar disorder over at least 6 months of follow-up)

http://www.ncbi.nlm.nih.gov/pubmed/17392295
(this is from the New England Journal of Medicine--one of the world's leading medical journals--in 2007, and it showed, over 26 weeks of follow-up, that adding antidepressants to a mood stabilizer regime did not improve outcome, in fact the antidepressant group did not do quite as well)

Which treatments have an evidence base in bipolar depression?

1) Lamotrigine. It has the advantage of helping modestly with depressive symptoms with a low risk of causing mania. It may be true that some of the studies over the past few years have exaggerated the benefit of lamotrigine, however. In any case, it appears quite safe, and can be helpful for some people. There is a small risk of a very serious skin rash with this drug, otherwise it is quite safe and well-tolerated.

http://www.ncbi.nlm.nih.gov/pubmed/19200421
(a recent study looking at Lithium + Lamotrigine vs. Lithium + Placebo over 8 weeks of follow-up; the benefits of lamotrigine are significant but modest)

http://www.ncbi.nlm.nih.gov/pubmed/15003074
(this study also showed a benefit from lamotrigine, over a whole year, but there was no placebo group, so the results carry much less weight)

2) Other mood stabilizers, e.g. lithium, valproate, and carbamazepine. Unfortunately these drugs are probably more effective for preventing manic episodes than for preventing or treating depression. Yet, the combination of a standard mood stabilizer with another agent such as lamotrigine could be a valid step.

3) Atypical antipsychotics, e.g. olanzapine, quetiapine, and risperidone. These drugs undoubtedly are beneficial as mood stabilizers, possibly more so than the standard mood stabilizers such as lithium or valproate. There is evidence that antipsychotics + other mood stabilizers are additively effective in combination. They can be worth a try for treating bipolar depression. Unfortunately, if the bipolar depression is already characterized by excessive sleep, tiredness, and appetite, antipsychotics can sometimes make these symptoms worse. But if there are psychotic features with the depression, an antipsychotic can be an essential part of the treatment.

4) Omega-3 supplements : see my previous post

5) Light therapy: I have seen this be helpful at times. The light exposure may need to be carefully titrated (e.g. just a few minutes at a time), to prevent overstimulation or agitation. Light therapy requires the purchase of a 10 000 Lux light box, which could cost about $200-300.
http://www.ncbi.nlm.nih.gov/pubmed/18076544

6) Cognitive-behavioural therapy. Elements of CBT help with most anything, it seems to me (from learning to play the violin, to doing mathematics, to treating anxiety or depression from any cause). CBT can be adapted so as to be more tolerable and interesting (some of the workbooks can be hard to get through). I think its core features require daily written work, journaling, conducting a dialog with oneself about thoughts and emotions (hopefully to work at identifying forms of depressive thinking, and being willing to challenge such thoughts if they occur), and deliberately challenging oneself behaviourally to face fears, a little at a time. In bipolar disorder CBT may work best in conjunction with ideas that help to stabilize or structure daily behavioural rhythms (e.g. getting up regularly in the morning, having a routine, eating regularly, exercising, doing some intellectually challenging work, doing some creative work, going to bed around the same time, etc.). Of course, in depression of any sort, it can be extremely hard to initiate or maintain such lifestyle habits--if there is too much fatigue or lack of motivation to get started with very much, I encourage getting started with the very smallest of tasks or daily structures, and building from there; consistency is more important than amount.

http://www.ncbi.nlm.nih.gov/pubmed/18324665

7) Other psychotherapy: basic supportive care can be very important, provided there is a resilient, trusting therapeutic relationship

8) Antidepressants: despite the negative results of late, there are selected individuals for whom antidepressants may be very helpful. Over the past decade, bupropion has perhaps been the first antidepressant to consider, due to its lower rate of causing a manic switch, and possibly its higher likelihood of helping with the low energy states characteristic of bipolar depression. SSRI antidepressants have been the second-choice agents. MAOI's are probably lower risk with respect to causing manic switch, and the reversible MAOI moclobemide could be a good option. Venlafaxine and tricyclic antidepressants have been agents to avoid, due to their high risk of causing a manic switch.

References:
http://www.ncbi.nlm.nih.gov/pubmed/16449476

http://www.ncbi.nlm.nih.gov/pubmed/16880481

9) Stimulants: I have found that stimulants can be quite useful in bipolar depression, provided that they are not increasing psychotic symptoms or agitation. They have the advantage of working quickly, helping immediately with energy and attention, and often helping with mood. Furthermore, they can be withdrawn quickly if manic symptoms or agitation arises; if stimulants are withdrawn quickly, it causes a relative state of sedation. (Note that there is some evidence from a few older studies that stimulant treatment can actually reduce symptoms of mania) There are several older stimulants, such as methylphenidate (Ritalin), and dextroamphetamine (Dexedrine), and several newer formulations of these older drugs (e.g. Adderall). A newer, atypical stimulant called modafinil can be an option as well. However, modafinil is quite expensive and often not covered by medication plans in Canada.

References:
http://www.ncbi.nlm.nih.gov/pubmed/15383134
http://www.ncbi.nlm.nih.gov/pubmed/18980736

http://www.ncbi.nlm.nih.gov/pubmed/16974196

http://www.ncbi.nlm.nih.gov/pubmed/367183

http://www.ncbi.nlm.nih.gov/pubmed/3312177

(the above two references are to older, interesting studies showing that stimulant treatments actually helped REDUCE manic symptoms acutely--I cite this as evidence that stimulants are reasonable to use in bipolar patients, however I would not go so far as to recommend stimulants in the treatment of mania, as other anti-manic treatments are much more effective and accepted as a standard of care)


10) ECT:electroconvulsive therapy is unequivocally effective for treating both depression and mania. However, there may be a higher risk of mild but persistent cognitive side-effects in the bipolar population:
http://www.ncbi.nlm.nih.gov/pubmed/17653292

If there are "borderline" phenomena occuring in the context of bipolar depression, once again some of Dawson's ideas may be helpful (see my previous postings about borderline personality); these involve emphasizing the role and competence of the individual patient in choosing treatment options, and avoiding an authoritarian stance on the part of the therapist.

Other references:

http://www.ncbi.nlm.nih.gov/pubmed/18992784
(A recent study correlating early age of onset for depression with bipolarity, severity, recurrence, etc.)

http://www.ncbi.nlm.nih.gov/pubmed/18199233
(A review of diagnostic issues regarding bipolar depression)

Omega-3 Supplementation

Omega-3 fatty acids are present in a variety of foods.

The fatty acids EPA and DHA are present mainly in fish such as salmon, herring, mackerel, anchovies, and sardines. These fatty acids, especially DHA, are probably important for brain function, and are also found in the retina of the eye.

Another omega-3 fatty acid, ALA, is present from plant sources such as canola oil, flax, and walnuts. ALA may be converted in the body to DHA.

There is some evidence that there are health benefits from diets higher in omega-3 fatty acids, or diets supplemented with extra omega-3.

Of interest for psychiatry, omega-3 supplementation may be a safe adjunct in the treatment of depression. Fish oil is probably the simplest source of extra EPA and DHA.

The only problem with increasing fish consumption is the exposure to environmental contaminants such as mercury and PCBs. Fish oil capsules may actually have less of these contaminants than pure fish, especially if the oil has been refined to remove contaminants. In any case, I think the benefit-risk ratio is very favourable, and that 1-3 capsules per day of fish oil is quite safe. And I feel confident to recommend increased fish intake in the diet. For vegetarians, increased intake of walnuts, canola, and flax could be recommended.

http://www.ncbi.nlm.nih.gov/pubmed/18183532
(a review of the studies over the past decade looking at omega-3 supplements in mood disorders)

http://www.ncbi.nlm.nih.gov/pubmed/16741195
(a nice review from The American Journal of Psychiatry in 2006, summarizing epidemiological data associating low fish consumption with higher rates of mood disorder, and summarizing some of the treatment studies showing antidepressant effects of omega-3 supplements in depression, bipolar disorder, and borderline personality)

http://www.ncbi.nlm.nih.gov/pubmed/19156158
(this is a recent study showing beneficial effects of omega-3 supplements in children with bipolar symptoms;but it was not a randomized or controlled study)

http://www.ncbi.nlm.nih.gov/pubmed/19200125
(this is a recent local study analyzing fish oil supplements for environmental pollutant levels, such as PCBs. Based on this study, one should avoid supplements of products such as seal or shark oils, which have much higher contaminant levels.)

http://www.ncbi.nlm.nih.gov/pubmed/19139352
(one of the articles summarizing evidence that omega-3 intake reduces the incidence or progression of macular degeneration, which is a common cause of visual loss in those over 65 years of age).

http://www.ncbi.nlm.nih.gov/pubmed/19064523
(a huge study, published in 2006, involving data from over
40 000 people over 18 years of follow-up--it shows a slight reduction in cardiac disease associated with higher fish consumption, but no change in overall "major chronic disease risk". But, incredibly, and unfortunately, they did not include mood or other psychiatric disorders in their assessment of "chronic disease" outcomes. Yet, studies of this type exemplify that The American Journal of Clinical Nutrition is an excellent journal, a valuable and practical source of evidence-based health information which could guide nutritional choices).

Zoloft and Cipralex best?

A recent article in the major, prestigious medical journal Lancet concluded that

"Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost."

Here is a link to the abstract: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60046-5/fulltext

Predictably the news headlines about this article read something like this: "Zoloft and Cipralex better than other drugs"

Taking a closer look at the data, as presented in the abstract, reveals the following:
1) mirtazapine (Remeron) was actually the most "efficacious" drug of all the drugs studied. But its side-effect profile/tolerability was less favourable than some of the others.
2) mirtazapine, escitalopram (Cipralex), venlafaxine (Effexor), and sertraline (Zoloft) were all quite similar in terms of "efficacy", and were all significantly superior to duloxetine (Cymbalta), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and reboxetine.

The study is impressive, in that it was a meta-analysis including the data from over 25 000 patients.

But the study is substantially weakened by the fact that it does not look at long-term outcomes (over a year or more).

As I've written before, I feel that the best assessments of effectiveness for conditions such as depression, which recur over a period of years, require data that also cover a period of years, rather than just months.

Oddly, the findings about bupropion are not mentioned in the abstract.

The paper is further weakened by not looking at tricyclics at all.

I think the results of the study should not be overvalued. The study may reasonably guide a first choice of antidepressant, though. A few very particular points to take from this study are that venlafaxine was not shown to be dramatically superior to all other antidepressants (despite what their advertising has inferred quite often), also that the new antidepressant duloxetine is clearly not dramatically superior either (which encourages us to be wary of the marketing hype behind it -- see my previous entry on Cymbalta).

Another result from this study confirms an observation I've had in my practice, that mirtazapine (Remeron) can be a very good antidepressant, provided its side effects can be tolerated (sedation and weight gain).

The authors wisely note that the study ought not to prompt someone to change a medication that is working well for them. The study measures differences between groups; for a given individual sometimes one particular medication can work best (e.g. fluvoxamine, duloxetine, or fluoxetine), even if it is not the most effective for a group.