Low-dose atypical antipsychotics for treating non-psychotic anxiety or mood symptoms

Atypical antipsychotics are frequently prescribed to treat symptoms of anxiety and depression. They can be used in the treatment of generalized anxiety, panic disorder, OCD, major depressive disorder, PTSD, bipolar disorder, personality disorders, etc. At this point, such use could be considered "off-label", since the primary use of antipsychotics is treating schizophrenia or major mood disorders with psychotic features.

But there is an expanding evidence base showing that atypicals can be useful in "off-label" situations. Here is a brief review of some of the studies:

http://www.ncbi.nlm.nih.gov/pubmed/19470174
{this is a good recent study comparing low-dose risperidone -- about 0.5 mg -- with paroxetine, for treating panic disorder over 8 weeks. The risperidone group did well, with equal or better symptom relief, also possibly faster onset. But 8 weeks is very brief -- it would be important to look at results over a year or more, and to assess the possibility of withdrawal or rebound symptoms if the medication is stopped. Also is would be important to determine if the medication is synergistic with psychological therapies, or whether it could undermine psychological therapy (there is some evidence that benzodiazepines may undermine the effectiveness of psychological therapies) }

http://www.ncbi.nlm.nih.gov/pubmed/16649823
{an open study from 2006 showing significant improvements in anxiety when low doses of risperidone, of about 1 mg, were added to an antidepressant, over an 8 week trial}

http://www.ncbi.nlm.nih.gov/pubmed/18455360
{this 2008 study shows significant improvement in generalized anxiety with 12 weeks of adjunctive quetiapine. It was not "low-dose" though -- the average dose was almost 400 mg per day. There is potential bias in this study due to conflict-of-interest, also there was no adjunctive placebo group}

http://www.ncbi.nlm.nih.gov/pubmed/16889446
{in this 2006 study. patients with a borderline personality diagnosis were given quetiapine 200-400 mg daily, for a 12 week trial. As I look at the results in the article itself, I see that the most substantial improvement was in anxiety symptoms, without much change in other symptom areas. The authors state that patients with prominent impulsive or aggressive symptoms responded best}

http://www.ncbi.nlm.nih.gov/pubmed/17110817
{in this large 2006 study (the BOLDER II study), quetiapine alone was used to treat bipolar depression. Doses were 300 mg/d, 600 mg/d, or placebo. There was significant, clinically relevant improvement in the quetiapine groups, with the 300 mg group doing best. Improvements were in anxiety symptoms, depressive symptoms, suicidal ideation, sleep, and overall quality of life.}

Here's a reference to a lengthy and detailed report from the FDA about quetiapine safety when used to treat depression or anxiety:
http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4424b2-01-FDA.pdf


In summary, I support the use of atypical antipsychotics as adjuncts for treating various symptoms including anxiety, irritability, etc. But as with any treatment (or non-treatment), there needs to be a close review of benefits vs. risks. The risks of using antipsychotics for treating anxiety are probably underestimated, because the existing studies are of such short duration. Also the benefits over long-term use are not clearly established either.

For risk data, it would be relevant to look at groups who have taken antipsychotics for long periods of time. In this group, antipsychotic use is associated with reduced mortality rates (see the following 2009 reference from Lancet: http://www.ncbi.nlm.nih.gov/pubmed/19595447, which looks at a cohort of over 60 000 schizophrenic patients, showing reduced mortality rates in those who took antipsychotics long-term, compared to those taking shorter courses of antipsychotics, or none at all--the mortality rate was most dramatically reduced in those taking clozapine. Overall, the life expectancy of schizophrenic patients was shown to have increased over a 10-year period, alongside substantial increases in atypical antipsychotic use)

It is certainly clear to me that all other treatments for anxiety (especially behavioural therapies, lifestyle changes, other forms of psychotherapy) be optimized, in an individualized way, before medication adjuncts be used.

But I recognize that suffering from anxiety or other psychiatric symptoms can be severely debilitating, can delay or obstruct progress in relationships, work, school, quality of life, etc. The risks of non-treatment should be taken very seriously. My view of the existing evidence is that adjunctive low-dose antipsychotics can have significant benefits, which can outweigh risks for many patients with non-psychotic disorders. As with any medical treatment decision, it is important for you and your physician to regularly monitor or discuss risks vs. benefits of ongoing medication therapies, and be open to discuss new evidence which is coming out.

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.

Prazosin and other treatments for PTSD-related nightmares

Nightmares are a common symptom of post-traumatic stress disorder (PTSD).

Various psychotherapeutic approaches can help people to deal with nightmares, both to be more psychologically prepared for them, and to be able to let them pass with a smaller amount of distress. Techniques include simply keeping a written record of the nightmares, with or without doing some cognitive therapy exercises based on this record; practicing relaxation techniques; exposure therapy during the daytime (by evoking the imagery of the nightmares, possibly "rescripting" the sequence of events); or by planning for a "rescripting" of the nightmare during the nightmare itself. Here is a reference to a review article about psychotherapy for nightmares: http://www.ncbi.nlm.nih.gov/pubmed/18853707

Sedative drugs can change dreaming activity, but often times these medications are problematic: tolerance or oversedation may develop, or sometimes the nightmares continue despite other types of sleep improvement.

Prazosin is a cardiovascular drug which blocks alpha-receptors, and is commonly used to treat high blood pressure. Alpha receptors are stimulated by adrenaline, which causes constriction of blood vessels, therefore increased blood pressure. In the brain, increased stimulation of alpha-receptors may be one of the mechanisms driving PTSD-related sleep disturbances such as nightmares. Prazosin has been shown to help reduce PTSD-related nightmares. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/18447662 {a good review article}

http://www.ncbi.nlm.nih.gov/pubmed/17069768 {a 2007 randomized, controlled, crossover study published in Biological Psychiatry, showing pronounced reduction in PTSD-related nightmares with 10-15 mg bedtime doses of prazosin}

http://www.ncbi.nlm.nih.gov/pubmed/12562588 {a 2003 randomized study published in The American Journal of Psychiatry showing substantial benefit in PTSD-related sleep symptoms with prazosin at an average of 10 mg/d}

There is the suggestion in these studies that prazosin, if dosed in the daytime as well, could help treat other PTSD symptoms.

Prazosin has been used for over 35 years in the treatment of hypertension. Interestingly, it is also one of the treatments of choice in the medical management of severe scorpion stings. It may also be a promising option in the treatment of alcoholism (reference: http://www.ncbi.nlm.nih.gov/pubmed/18945226).

Prazosin is well-tolerated by the majority of people taking it. It appears to have minimal psychiatric side-effects. Sedation does not seem to be common. If the dose is too high, too soon, it can cause excessive postural blood pressure drops, with dizziness and a risk of fainting (syncope). It may cause nasal congestion or headache. Priapism (a medically dangerous sexual side-effect) is possible but very rare.

Melatonin: benefits and risks

Melatonin is a hormone synthesized in the pineal gland, and is thought to be important in the regulation of circadian (day-night) rhythms.

It has been used to treat insomnia and sleep-phase abnormalities.

The most interesting study I found regarding long-term use of melatonin was published in JAMA in 2008: http://www.ncbi.nlm.nih.gov/pubmed/18544724
In this prospective, blinded study, elderly patients with dementia were given 2.5 mg melatonin near bedtime, over an average of 15 months of follow-up. Patients in another group were exposed to bright light during the day (approximately 1000 Lux indoors, from 10:00 AM to 6:00 PM). A third group received both melatonin at night and bright light in the day. Placebo groups received no melatonin, or were exposed to typical indoor office lighting, of about 300 Lux.* Interestingly, caregivers were not able to tell whether their site had the ordinary lighting or the bright light (the increased light intensity was measurable with a meter, but was not noticeable subjectively).

The results showed that melatonin consistently improved sleep, particularly helping reduce the time required to fall asleep, and increasing total sleep time.

However, the group receiving melatonin alone showed worsening mood (less positive affect & more negative affect).

The group exposed to bright light in the day, plus melatonin at night, did not show worsened mood.

The authors conclude that bright light in the day helps with mood, cognition, and function in elderly dementia patients. Melatonin alone helps with sleep but has a negative impact on mood. Bright light plus melatonin had a positive impact on all the symptoms studied.

Based on this study, I would encourage anyone using melatonin at night to ensure that they get plenty of bright light during the daytime. It also suggests that any study looking at melatonin treatments should also consider daytime bright light exposure as an important variable which could affect response to melatonin.


Here's a reference to a study showing that 2 mg of sustained-release melatonin improves sleep:
http://www.ncbi.nlm.nih.gov/pubmed/18036082

In this study, children with intellectual disabilities experienced relief of their insomnia (including reduced time to fall asleep, reduced time awake, and increased total sleep time) with 5 mg melatonin supplementation over a 4-week period:
http://www.ncbi.nlm.nih.gov/pubmed/18261024

Here's a study showing improved sleep, with no adverse effects, due to melatonin administration to autistic children:
http://www.ncbi.nlm.nih.gov/pubmed/18182647

Here's a study showing improved sleep in children with epilepsy who were treated with adjunctive melatonin (6-9 mg). There were no significant side-effects:
http://www.ncbi.nlm.nih.gov/pubmed/15794175

High-dose melatonin (1 mg/kg body weight) has been used experimentally to treat intractable epilepsy, but more research is needed to evaluate effectiveness & safety. Here is one reference:

http://www.neurology-asia.org/articles/20043_114.pdf

This study showed improved sleep in adolescents with ADHD, when they were given 5 mg melatonin over a 30-day trial. However there was no improvement in ADHD symptoms:
http://www.ncbi.nlm.nih.gov/pubmed/16670647

Melatonin has been associated with autoimmune conditions. Here is a case report associating melatonin use with autoimmune liver disease:
http://www.ncbi.nlm.nih.gov/pubmed/9412927

Here is an article about melatonin possibly exacerbating rheumatoid arthritis (various reports show increased melatonin levels in rheumatoid arthritis patients):
http://www.ncbi.nlm.nih.gov/pubmed/19069959

Yet, in various other reports, melatonin has been shown in animals to protect the liver from various forms of artificially-induced toxicity. (e.g. http://www.ncbi.nlm.nih.gov/pubmed/15386534)


In conclusion, melatonin appears to be have a reasonable safety profile, and is a potentially effective treatment for insomnia, particularly "initial insomnia" in which there is difficulty falling asleep at the beginning of the night. Typical doses of melatonin range from about 2 mg - 6 mg.

The one main concern about adverse effects concerns possible exacerbation of autoimmune diseases such as rheumatoid arthritis, although the evidence is not clear on this point. Other types of toxicity, while possible, appear to be rare. Melatonin may even protect cells from a variety of different types of harm. But it is important to recognize the possibility that there could be other unknown adverse effects over long periods of time.

As with any treatment, we have to balance risks against benefits: insomnia itself clearly has a variety of negative long-term health effects (ranging from increased risk of physical and psychiatric illness, to increased risk of accidents). Other treatments for insomnia have their own risk/benefit profiles.

Cognitive-behavioural therapies for insomnia are clearly the safest and most beneficial, and should be optimized before any other medical therapy. But it appears to me that melatonin ought to have a place in the medical treatment of insomnia, alongside other established therapies.

*here are some measures of light intensity in different settings, to help give you some reference points to compare:

50 Lux -- family living room

100 Lux -- very dark overcast day

300-500 Lux -- recommended office lighting

400 Lux -- sunrise or sunset on a clear day

1000 Lux -- overcast day

10 000 Lux -- clear day (not direct sun)

100 000 Lux -- direct sun

Psychologists Prescribing Antidepressants?

Here's another question from a visitor:

Your views on psychologists' obtaining the right to administer antidepressant.

I don't have any problem with this. If psychologists, or anyone else, were to have prescribing privileges, I do think there should be an educational program with a licensing exam, with continuing education requirements for maintaining licensure, etc., to ensure that the prescribers are up-to-date and knowledgable about the medications and risks, etc. At that point, it could be up to an informed patient to decide whether to trust and accept a prescription from a psychologist. As far as I'm concerned, this is a fair balance between regulation and individual rights in a freedom-oriented society.

I think some psychiatrists' opposition to psychologist prescribing has a lot to do with wanting to hold on to more influence, authority, power, or perhaps a greater sense of importance or exclusivity. There may be elements of narcissism and insecurity which underlie this position. It reminds me of the history of modern medical opposition to midwifery.

While many patients need complicated regimes of medication, may have complex comorbid medical problems, and may therefore require a highly specialized expert in psychopharmacology to prescribe for them (actually, the level of expertise in this area among psychiatrists is very inconsistent), the majority of patients who might benefit from antidepressants require a very simple regimen. Such a regimen does not require many years of advanced education to competently administer. It seems a waste of time and health-care expense for those individuals to have to seek out an MD for their prescriptions.

Furthermore, many antidepressant prescriptions are currently written by a gp who may have only seen the patient for a few minutes--if psychologists were prescribing, this would most likely be in the context of knowing the patient very well, with hour-long appointments, and offering very good follow-up care.

There are risks associated with prescription antidepressants, and there are bound to be patients who run into problems after being prescribed antidepressants from a psychologist. But I am doubtful that these risks would be higher than if antidepressants were only available from an MD, particularly if prescribing privileges required passing a licensing exam, etc.

Future of personalized antidepressants

Another question from a visitor:

Advances in psychiatrist medications: Holsboer has recently elaborated on the future of personalized antidepressants designed using genotype and biomarkers. Where do you think psychiatry is headed, in terms of ideology, but also medications and treatments?

Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/18628772

It's an interesting and important subject. In current practice, it can be hard to find medications or other types of therapy which are helpful. It would relieve a great deal of suffering much more quickly to have some way of determining, in advance, which particular treatment for psychiatric illnesses might help best.

Also, the article emphasizes the need to search for treatments outside of the current pharmacological paradigms; we probably have enough medication choices affecting serotonin uptake, etc. It will probably be important to search for pharmacological treatments which affect other systems in the brain.

I don't feel very well-informed about the cutting edge of this science (translating genetic research into pharmacological treatments), but I can see this being a huge advance in the coming decades.

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!

Antidepressants and Bone

There is some evidence that antidepressants, particularly the serotonin reuptake inhibitors, can reduce bone density, and increase the risk of fractures. This risk would be most pertinent in an elderly population.

Serotonin is a relevant factor in bone metabolism, so it is important to consider the potential impact of serotonergic antidepressants on bone health.

Here's a study showing an association between depression and reduced bone mineral density. Depression itself is an understandable cause for bone mineral loss, since it is associated with fatigue, therefore less exercise, worse nutrition, and increased stress hormones such as corticosteroids. In this study, antidepressant use was independently associated with bone mineral density loss in women. It is a retrospective analysis from a large catchment area study involving over 1000 people, who were followed since 1981.
http://www.ncbi.nlm.nih.gov/pubmed/19126857

There are some other studies showing an association between antidepressant use (especially SSRIs) and fractures due to fragile bone. One of the better such studies was published in 2008, looking at the incidence of fractures in a large population-based cohort involving 7983 people aged 55 and over. Importantly, the authors attempted to control for the impact of depression itself on fracture incidence, and basically showed that current SSRI use approximately doubles the risk of fractures:
http://www.ncbi.nlm.nih.gov/pubmed/18626268

There is one important prospective animal study, which shows a small effect of SSRI treatment on bone quality over a 6-month period:
http://www.ncbi.nlm.nih.gov/pubmed/17163489

In conclusion, it is important to know that antidepressants could possibly reduce bone density, and therefore contribute to an increased risk of fractures in the elderly. If antidepressant therapy is needed, it is especially important to encourage activities which protect bone health, such as regular exercise, and good nutrition (including ample calcium and vitamin D in the diet). Non-SSRI antidepressants such as tricyclics may have a smaller effect than the SSRIs. Bone density testing could be indicated, as could medication treatments to protect bone mineralization. These issues should be discussed with your family physician and your psychiatrist.

Long-term stimulants & ADHD

The long-term use of stimulants such as methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall), in the treatment of attention or behaviour problems in children and adults, has been a controversial issue.

Symptoms of so-called ADHD include inability to sustain attention while doing academic, social, domestic, or work activities; restlessness, and inability to sit quietly or wait patiently. Of course, everyone has difficulties in these domains at times. The diagnosis of ADHD is intended to apply to individuals whose symptoms are so severe in these areas that it causes serious, ongoing problems functioning socially, academically, and with other life tasks. Those with an ADHD diagnosis are much more likely to drop out of school, to be unable to maintain jobs, to have difficulty maintaining friendships, and to have conduct problems ultimately leading to problems with the law, etc.

It is abundantly clear, from careful research, that stimulants improve symptoms of ADHD, and associated problems with social behaviour and disordered conduct.

I do not see good evidence that stimulants adversely affect personality traits or sense of self. Rather, in many cases, the experience of having severe untreated ADHD symptoms adversely affects personality traits and sense of self.

I will add to this post later, to discuss potential adverse effects from stimulant therapy. But stimulants are generally well-tolerated, with a low risk of serious adverse effects for most people.

Existing psychosocial treatments can help ADHD symptoms as well, but they do not work as well as stimulants, and--surprisingly--combining psychosocial treatments with stimulant therapy does not work much better than stimulants alone, except possibly for some individual cases. Here is some evidence, from a 2008 meta-analysis, for this finding:
http://www.ncbi.nlm.nih.gov/pubmed/18068284
Here are a few other important studies pertaining to long-term stimulant use:

This 5 year prospective study shows that stimulant therapy substantially reduces the rate of smoking and substance use disorders in adolescents with ADHD:
http://www.ncbi.nlm.nih.gov/pubmed/18838643

About 20% of ADHD adolescents treated with stimulants over 5 years developed a substance use disorder, compared to 55% of ADHD adolescents not treated with stimulants.

Stimulant-treated adolescents also had much lower rates of smoking. This is a very strong and compelling study, showing profound reductions in addictive disorders as a result of long-term stimulant treatment.


This 2008 study looked at a group of 169 children with ADHD, and followed up on them 9 years later:
http://www.ncbi.nlm.nih.gov/pubmed/18928410

The children who had taken stimulant treatment for their ADHD fared better than those with ADHD who had not taken stimulants, in terms of academic performance (as measured in several different ways). Neither ADHD group performed as well as a comparison group without ADHD.


This 2007 study from the Journal of Developmental and Behavioral Pediatrics is particularly strong, in that it looks at an entire birth cohort (all 5718 children born in Rochester between 1976-1982, of whom 370 with ADHD were identified):
http://www.ncbi.nlm.nih.gov/pubmed/17700079

It looked at long-term outcomes, over an average of 18 years. The study shows reduced absenteeism, reduced likelihood of being held back a grade, and slightly higher reading test scores, for ADHD children receiving long-term stimulant therapy.

Reading scores were particularly higher in the children who had received high doses of stimulants for longer periods of time.

The stimulant group did not differ from the non-stimulant group with respect to sociodemographic variables or duration of follow-up. The study was retrospective and was not randomized, yet it remains a very strong piece of evidence about long-term effects of stimulant treatment for ADHD.


I think these findings emphasize a number of things:
1) stimulants work very well for ADHD symptoms
2) stimulants unfortunately only have a slight effect on long-term academic outcomes
3) existing psychosocial treatments work modestly well on their own, but for most people do not add to the benefits of stimulants. The psychosocial treatments did not improve long-term academic outcomes. The duration of psychosocial treatment did not correlate with better improvement in symptoms, so the weakness of existing psychosocial treatments is not likely due to inadequate length of treatment.
4) long-term stimulant therapy may substantially reduce the risk of ADHD kids getting into alcohol use, substance use, or smoking problems. This finding is strong evidence against the idea that stimulant use increases the risk for subsequent addictive disorders.

I do think we need to keep working on better psychosocial treatments. I suspect that intensive, long-term, individualized treatment, with a style which suits the personality and strengths of each person, will be most effective. And I suspect that such treatments would need to be combined with positive, supportive milieux at home, school, work, and in peer relationships.

I will add to this post, or write a sequel post, to discuss other treatments for ADHD, such as atomoxetine, antidepressants, EEG biofeedback, dietary modification, and some newer psychosocial treatment ideas.

My Experiences with Industry Sponsorship

Around 2001, when I was a mood disorders fellow, I was asked to do an educational lecture by Organon, the manufacturer of the antidepressant mirtazapine. The company clearly wanted one of the more prominent mood disorders research psychiatrists to do the lecture--but since no one else was available, they settled for me. It was common practice for research psychiatrists or other perceived "leaders in the field" to be paid by drug companies for "educational lectures" attended by family physicians or other psychiatrists, usually at expensive restaurants or lavishly-catered hotel conference rooms (the drug company footing the bill, of course); I think this common practice remains. To be fair, I think everyone assumed that this was all fine, even a useful educational service. Probably many of those involved in this practice still believe that. And perhaps many of these lectures are useful educational services to some degree, it's just that both the lecturers and the recipients may be unaware of the biases involved. Anyway, my lecture was supposed to be about treating resistant depression. I was provided by the company rep with numerous powerpoint slides about mirtazapine to include in my lecture. I did the lecture, and was paid generously for it. I included a few of the slides about mirtazapine, but I truly tried to give a lecture broadly about treating resistant depression, and discussed mirtazapine for only about 20% of the talk. Clearly the company rep was not impressed with my performance, and I was never again asked to do a lecture for them. I'm glad of that, since the more one does these things, the more one can be convinced that it is professionally appropriate, despite the obvious biases involved.

Around 2000-2001 I was involved in a clinical study of a new drug. The drug company sponsored the study, flew everyone business-class to Monaco (on the French Riviera), and put us up in a lavish 5-star hotel, to attend an introductory meeting regarding the study. Such meetings, in my opinion, are utterly needless expenses. Introductions and instructions about a study can be done without transcontinental travel. Training for rating scales, etc., could be done in some other simple, standardized way, without any need for travel. I did enjoy the trip, and I wouldn't doubt that it contributed to my having a more favourable view of that company's products in the following years.

Also around 2000-2001 I was involved in another clinical study. The drug company, also sponsoring the study, flew everyone business-class to Miami, Florida, and put us up in a famous 5-star hotel. By this time I was starting to have more questions about the neutrality of the research, under these circumstances. Something that struck me during that trip was my observations of the company reps meticulously preparing their video presentation for us -- they were preparing a show; it was basically a slick info-mercial, sound-effects and all. I was also struck by the fact that no one around me seemed to notice this or have a critical view of it. I felt like, on the one hand, we were being treated like royalty, but on the other hand we were simply being bought. I realize that it is good for companies to make participation in research projects attractive to everyone involved. It can be frustrating work to recruit patients for clinical studies, and many psychiatrists would rather not take time away from other aspects of work to participate in research. Research is important, and maybe travel & adventure could be fair aspects to enjoying the life of a researcher. BUT -- the travel is really not necessary at all. It is an extravagance. Information and training about a research protocol can happen locally. Other communication can happen over the phone, over the net, or over a video link. The other expensive extravagances just reduce the neutrality of the study, and also bias all participants (many of whom are "leaders in the field" who often influence other practitioners) to have and convey a more favourable view of the company's products, irrespective of the results of the particular study.

I think it would be interesting to have disclosures in research papers not only about the authors' affiliations with, or income received from, the drug companies, but also about the travel expenses paid by the companies for meetings pertaining to the study in question.

A more mundane aspect of industry sponsorship, during my residency between 1995-2000, was the weekly phenomenon of the "drug lunch." Basically, during almost every group meeting or rounds, food would be provided by a drug rep--usually quite a tasty lunch.

A continuing aspect of industry sponsorship is the distribution of free samples. At times I find this quite useful, to help someone get started on something right away, without the time or expense of a pharmacy visit. At other times, people have not been able to afford medication (the most common psychiatric medications are available for free in BC, through a government plan, but many more exotic medications are not covered by this plan): in some cases, the drug companies have provided a free "compassionate release" supply of medication for extended periods of time. Yet, I recognize that these phenomena lead to bias. The presence of a particular sample can influence the choice of which particular medication to recommend, particularly when the different choices are all similarly effective.

I realize this post may come off sounding like some kind of anti-corporate rant. I don't want to slam corporations too much though -- thanks to large companies, we have many more treatments which can profoundly improve quality of life, and which can save many lives. Profit-oriented motivations can drive productivity, competition, and better research. It's just that we can't be swept into the current of advertising and other biased persuasive tactics which companies use to sell more of their products. We can sympathize with the reality that companies behave this way, but as health care professionals, or as individuals contemplating whether or not to take a particular medication or other treatment, we need to have information which is clear, unbiased, as objective as possible.

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.

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

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}

Ferritin & Iron

Ferritin levels in the blood correlate well with the amount of iron available in the body's "reservoir". If ferritin levels are low, the body has very low reserves of iron. (the converse may NOT be true -- if ferritin levels are high, the body may still have low iron reserves, because there are a variety of conditions, such as inflammatory states, that can cause ferritin levels to rise)

Anemia is a condition in which the body does not have enough iron-containing red blood cells, therefore the body cannot deliver oxygen to the tissues (including the muscles, heart, and brain) as efficiently. One of the most common symptoms of anemia, not surprisingly, is fatigue.

Sometimes, iron reserves can be low, without actually causing anemia. It is like a low water reservoir: water may still be flowing into people's homes despite the water levels being low.

Here is a 2003 study from the major journal, BMJ, which shows that iron supplementation improves fatigue in non-anemic women with low ferritin:
http://www.ncbi.nlm.nih.gov/pubmed/12763985

This study, from the major medical journal Lancet in 1996, shows that iron supplementation given to non-anemic girls with low ferritin improved their verbal learning and memory:
http://www.ncbi.nlm.nih.gov/pubmed/8855856

Low ferritin levels are associated with a disease called "restless legs syndrome" (RLS), which causes discomfort and insomnia at night, and which can often give rise to a substantial reduction in quality of life. I suspect there are many milder cases of RLS which could be contributing to insomnia, and therefore contributing to resulting anxiety and mood problems. Here are some studies showing the association, and demonstrating that iron supplementation can improve RLS:

http://www.ncbi.nlm.nih.gov/pubmed/15854860

http://www.ncbi.nlm.nih.gov/pubmed/8085504

http://www.ncbi.nlm.nih.gov/pubmed/19200780


In this recent study from the Journal of Pediatric Neurology, children with ADHD and low ferritin levels showed improvement in their ADHD symptoms after receiving iron supplements:

http://www.ncbi.nlm.nih.gov/pubmed/18054688
In conclusion, I believe it is very important to evaluate ferritin levels, particularly in women, since the levels are frequently low; low ferritin is associated with fatigue, restless legs, ADHD, and reduced cognitive function. It could be a contributing factor to mood disorders and other psychiatric problems.

Usually, low ferritin levels are easily remedied by iron supplementation. Most daily multivitamins contain iron, but the amount of iron in these is usually enough only to maintain your iron stores, not to build them up. Similarly, increasing iron-rich foods in the diet will help to maintain or build iron stores, but this could take a very long time. In order to build up your iron stores more quickly, higher doses of iron salts, such as ferrous sulphate, need to be taken daily for several months.

I recommend aiming for a serum level of at least 50 micrograms / litre (50 ug/L). Many labs give a normal range starting at 20 ug/L, and therefore you may not hear from your physician if the level comes back at 25. It is important to know that the average for women is at least 50, and the average for men is about 100. Exceptions include children, whose ferritin levels are a little lower, and women in advanced stages of pregnancy, who have average ferritin levels of only about 20.

If you do have low ferritin, then further investigation could be warranted, to assess for other causes of iron deficiency (e.g. chronic blood loss from the digestive tract, from heavy menstrual flow, or from the kidneys). So your decisions on this matter should be discussed and followed-up with a primary care physician.

Pathological & Therapeutic Crying

This post is in response to a previous comment:

...So, maybe if there was a medication that would stop you from crying, depression levels could be taken down?

----
Antidepressants can directly reduce crying, probably independent of other effects on emotion.

There is a condition called "pathological crying" which can occur after a stroke or other brain damage; in this condition the afflicted person may be weeping uncontrollably, with or without a subjectively sad or negative emotional state. SSRI antidepressants can help greatly with this, here is a reference:

http://www.ncbi.nlm.nih.gov/pubmed/10576464

Here is a reference showing that mirtazapine could be an alternative:

http://www.ncbi.nlm.nih.gov/pubmed/16239769

A similar antidepressant-induced "reduction in crying" may sometimes be one of the sources of relief in depression. But such an effect could be unwelcome if it leads to a subjective restriction of emotional range.
Are tears therapeutic? Most of us would agree that crying is often a relief, or even a necessary emotional outlet. Many psychotherapists would consider a patient's tearfulness in a session to be therapeutic.

In my opinion, tears can sometimes be a relief, and can sometimes be very therapeutic -- but sometimes tearfulness can feed a cycle of exhausting, out-of-control sadness or despair. And sometimes tearfulness can be so reflexive that almost any event or trigger in daily life can bring it on. Occasionally tearfulness may be a type of "defence" which prevents dialog (with self or others) about an underlying experience or emotion.

I would add, as a formal personal opinion, that tearfulness need not be a sign of "loss of emotional control" (though sometimes it could be). A person who is confident, stable, mature, and sensitive may feel quite at ease with tearfulness. Tearfulness, in this case, is a normal, and often healthy, emotional display. For some individuals, tearfulness happens more naturally, for others they may be more comfortable experiencing emotion without tearfulness.


What does some of the evidence have to tell us:
http://www.emotionalprocessing.org.uk/tears/is%20crying%20good%20for%20you.htm
(a website with an introduction to the subject)

http://www.ncbi.nlm.nih.gov/pubmed/18509370
(here's a case study showing that crying can be therapeutic -- even if it is the therapist who cries; this is a position I strongly support, for a variety of reasons, most of all because I believe in the "Rogersian" idea of genuineness and transparency, also I believe that crying need not be considered a form of weakness, but a symbol of sensitivity and compassion, whether the tear is shed by the patient or by the therapist. Too many therapists are, in my opinion, so defended by various tactics of emotional detachment, that they become aloof, and in some cases ironically afraid of emotional intensity--this may in some cases lead to dismissive, or ineffectively cold, postures towards tearful or suffering patients. Of course, if the therapist is not functioning, and is tearful due to emotional fragility or depression, then the tearful therapist needs to take a break and seek therapy himself or herself.)

http://www.ncbi.nlm.nih.gov/pubmed/17587475
(an interesting look--from an anthropological perspective-- at a phenomenon called "wailing", a type of crying & lamentation which is part of a group ritual of mourning in the Yemenite Jewish community; this article includes interesting perspectives about crying and its theoretical role in bereavement. It suggests that the idea of "healthy bereavement" has been heavily influenced by Freudian, and largely "male", ideas, viewing emotions in a kind of "hydraulic" way -- as forces to be directed, or cathartically released, and in particular pronouncing healthy grief as a process involving letting go of the relational bond with the deceased. In the "wailing" phenomenon the author suggests that the group crying, accompanied by lyricism and dialog, may act to build a kind of emotional or relational "cradle" where the bereaved person may maintain a continuing loving bond with the deceased, rather than aim to let the bond go)

Beta-Blockers

Here's a link to a very interesting study which shows that the beta-blocker propranolol can interrupt the consolidation of fear in humans:

http://www.nature.com/neuro/journal/vaop/ncurrent/pdf/nn.2271.pdf

This study suggests a novel use for beta-blockers, which could facilitate behavioural therapy for PTSD. The study demonstrates a variety of things:
1) as was well-known before, when people experience something fearful or traumatic, it sensitizes them to react more strongly to the same fearful stimulus in the future
2) when people re-experience a fearful or traumatic memory, this re-experience consolidates, or strengthens, the strong fearful reaction. This is consistent with the evolution of PTSD and other anxiety disorders, in which an expanding variety of daily events can trigger and consolidate the fear (e.g. a survivor of a bad traffic accident may constantly re-experience traumatic symptoms when hearing traffic noise, loud sounds, etc.--and may start to avoid these situations. Every time this happens, the anxiety disorder becomes more entrenched).
3) Fears can be "extinguished" by re-experiencing the feared stimulus repetitively, in a safe setting. But the fear can be "re-kindled" after extinction more easily than in non-traumatized people (this suggests a permanence to "emotional memory" that can be only temporarily over-ridden by psychological techniques)
4) If the consolidation phase of fear or traumatic memory could be interrupted, then a person might not develop ongoing post-traumatic symptoms at all. In this experiment, there is evidence that propranolol can interrupt this consolidation.
5) Propranolol may disrupt the "emotional memory" consolidation but not the "declarative memory"--the former process may occur primarily through the amygdala, whereas declarative memory is consolidated mainly in the hippocampus. So, the use of propranolol would not "erase the memory" of a traumatic event--the facts of the event would still be remembered normally--but it might reduce the painful, reflexive feeling of emotional trauma associated with the event.

The study does NOT show that "propranolol erases memories", as some of the news headlines seem to be proclaiming. It DOES suggest that adjunctive propranolol may greatly enhance the effectiveness of behavioural therapy. It requires that the person use propranolol while engaging in exposure therapy. So, for example, a possible technique for treating PTSD or panic (especially new-onset) might be to use a 40 mg dose of propranolol 1-2 hours before a therapy session. In the therapy session, the memories of the upsetting events could be discussed. The propranolol might interrupt the process of these upsetting memories getting further consolidated, might facilitate a behavioural therapy process which would help the person feel emotionally comfortable with their thoughts and memories. This process may occur because of direct beta-blockade in the amygdala, which may interrupt consolidation of emotional memory directly.

Despite this encouraging study, there are a number of negative studies looking at using propranolol similarly, for example:
http://www.ncbi.nlm.nih.gov/pubmed/18761097

http://www.ncbi.nlm.nih.gov/pubmed/19060728

I think the main thing to take from the first study is that propranolol may help, but probably only as an augmentation to enhance the effectiveness of behavioural therapy (or CBT) for treating post-traumatic stress or other anxiety disorders.

Beta-blockers are drugs used primarily in cardiology. Some beta-blockers, such as atenolol, act only peripherally, that is they do not enter the brain very much. Others, especially propranolol, can more easily enter the brain, and therefore can act in the central nervous system as well as peripherally.

In psychiatry, propranolol has been useful to treat performance anxiety, especially if there is a component of tremor (e.g. shaking hands) accompanying the anxiety. Many musicians use doses of propranolol to reduce tremor during performances. The anti-tremor mechanism is most likely peripheral beta-blockade (i.e. outside the brain), but the accompanying reduction of subjective anxiety may also be due to central beta-blockade (i.e. inside the brain). This is consistent with some studies which show that peripherally-acting beta-blockers reduce tremor as well as propranolol, but people subjectively prefer the propranolol.
(Reference: http://www.mdconsult.com/das/citation/body/121508141-4/jorg=journal&source=&sp=6333536&sid=0/N/6333536/1.html?issn= )

Beta-blockers have been studied in the treatment of panic disorder, decades ago. They don't work. Here's a link to one of the many studies showing this:
http://www.ncbi.nlm.nih.gov/pubmed/2651490

Yet, these old studies don't look at the possibility that the beta-blocker could work as an "augmentation" to psychological therapy. Many effective treatments do not work on their own, they work only in conjunction with something else.

Beta-blockers have also been used to treat irritability or rage problems. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/15764868
{one of the studies in the geriatric psychiatry literature, showing possible benefit for using propranolol to help agitated dementia patients}

http://www.ncbi.nlm.nih.gov/pubmed/2136070
{an example of a study showing some benefit of propranolol treatment for reducing rage outbursts -- however the study is of low quality}

http://www.ncbi.nlm.nih.gov/pubmed/3546964
{another study from the Mayo Clinic in 1985, showing some success using propranolol to treat patients with rage outbursts}

http://www.ncbi.nlm.nih.gov/pubmed/9196923
{a review paper from 1997, looking at various pharmacologic treatments for aggression; some of the research about beta-blockers is reviewed here}

In summary of the above studies, beta-blockers may help a bit for irritability, aggression, rage outbursts, and agitation, due to a variety of causes, but the evidence base is mainly from before 1990, and the studies are not very rigorous.

Beta-blockers also help diminish a very uncomfortable symptom called "akathisia". Akathisia is a state of external, and internal, restlessness, that can be caused by older antipsychotic drugs.

Beta-blockers are also useful in migraine prophylaxis. Migraine is associated with depression, so a beta-blocker could be a good therapeutic choice in someone with migraines as well as anxious, irritable, or agitated depression.

There were a few studies suggesting beta-blockers could cause or worsen depression, but many of these studies are weak. Here is a review:
http://www.ncbi.nlm.nih.gov/pubmed/16466322

In a more recent major JAMA review, beta-blockers were not found to be causative of depression or fatigue:
http://www.ncbi.nlm.nih.gov/pubmed/12117400

In my opinion, beta-blockers should be used cautiously in people who have or develop depressive symptoms, but I don't think they are contraindicated, since they may be beneficial overall if they help other symptoms. Also, if there are depressive effects, these may be dose-dependent, and may disappear just by reducing the dose.

---

Beta-blockers literally "block" beta-adrenergic receptors in the body. These beta receptors are normally stimulated by the catecholamines adrenaline and noradrenaline (also called epinephrine and norepinephrine), which are hormones secreted by the adrenal glands and by a small area of cells deep in the brain called the locus ceruleus. There is always a little bit of these hormones in circulation (in quantities in the order of parts per trillion, concentrations which would be achieved by adding a single drop of hormone to the volume of 1-10 olympic-sized swimming pools).**

Here is a reference showing resting adrenaline and noradrenaline levels in healthy subjects:
http://hyper.ahajournals.org/cgi/content/abstract/30/1/71

These tiny quantities of hormone are nevertheless enough to stimulate beta receptors; such stimulation is required to maintain or increase the output of the heart, also many other actions in the body, including in kidneys and muscle tissue.

http://www.psychosomaticmedicine.org/cgi/content/abstract/52/2/129
{An excellent study looking at peripheral catecholamine levels (norepinephrine and epinephrine) in groups of patients with anxiety, patients with pheochromocytoma (a disease causing huge increases in catecholamine levels), and normal controls; they found that peripheral norepinephrine levels correlate with anxiety, but NOT in the pheochromocytoma patients; this supports a theory that anxiety states cause central, and secondary peripheral, stimulation of catecholamine release--but the catecholamines themselves do not necessarily CAUSE the anxiety, but are a RESULT of it. Incidentally, Psychosomatic Medicine is another excellent journal worth following}

http://www.psychosomaticmedicine.org/cgi/reprint/66/5/757
{a study showing that norepinephrine levels in the brain correlate highly with blood pressure in normal controls; but do not correlate at all with blood pressure in people with PTSD, suggesting that in PTSD there is an abnormality in catecholamine regulation}

http://ajp.psychiatryonline.org/cgi/reprint/158/8/1227.pdf
{a study from The American Journal of Psychiatry showing that people with PTSD have levels of CSF norepinephrine almost twice as high as normal, and that the norepinephrine levels correlate with the severity of PTSD symptoms}

http://www-personal.umich.edu/~nesse/Articles/AdrenFunctPanic-ArchGenPsychiatry-1984.PDF
{a study from Archives of General Psychiatry in 1984, showing higher levels of plasma catecholamines in panic disorder subjects; but less responsiveness to further adrenergic stimulation in the panic subjects--this suggests that anxious subjects have chronically high catecholamines, and consequently are actually LESS sensitive to catecholamine changes}

http://www.csbmb.princeton.edu/ncc/PDFs/Locus%20Coeruleus/Aston-Jones%20&%20Cohen%20(ARN%2005).pdf
(an article about the role of norepinephrine released in the brain's locus ceruleus, and its importance for optimizing performance of tasks)

**For the math, let us assume that the resting concentration of epinephrine is 100 pMol, or 10^-10 moles/litre; a litre of water has about 55.5 moles of water, so the concentration can be expressed as one part in (55.5 / 10^-10) or one part in 555 billion. A drop of water has a volume of about 1/20 mL. So this concentration of epinephrine corresponds to an analagous concentration of one drop in (555 billion/20) mL, which is about 1 drop in 28 million litres. An olympic swimming pool has a volume of about 2.5 million litres (http://en.wikipedia.org/wiki/Olympic_size_swimming_pool). So this concentration corresponds to 1 drop in a volume of over 10 swimming pools.