Caffeine & Coffee : Health Benefits

So, is coffee good for you? Or is it bad for you?
How about decaf?

It seems that there are mixed messages out there, about health effects from things such as coffee or caffeine.

What does the evidence tell us?

The evidence base is extremely compelling --

Here is a link to a study by Lopez-Garcia et al. from Annals of Internal Medicine in 2008, involving over 100 000 people, over 18 years of follow-up. Such massive studies with long follow-up time are incredibly informative:

http://www.ncbi.nlm.nih.gov/pubmed/18559841

In the study, it shows clearly that coffee drinkers have lower overall mortality rates, mainly due to a reduction in rates of cardiovascular disease. It showed a modest reduction in mortality rates associated with decaffeinated coffee as well. The authors conclude that the potential health benefits from coffee are due to components in the coffee other than caffeine.

The graph on the top is copied from the paper, and summarizes the results from the study. You can click on the graph to expand it. Actually, the data as presented on the graph suggests that people are healthier who have 2-3 cups of coffee per day, compared to those who have just 1.
Perhaps the less desirable effects from just a single cup per day are due to the more pronounced "jolt" of caffeine that would happen in a person who is not used to drinking as much coffee. Perhaps this effect would offset the health benefit, at low doses. At higher doses, the body may become more tolerant to caffeine's anxiogenic effects.


Unfortunately, this study did not look at mental health effects from drinking coffee, or from caffeine intake.

In another large epidemiological study of over 1400 people followed over 21 years, it was found that those who consumed coffee in mid-life had a substantially lower risk of developing dementia. This association was true after adjustment for demographic differences, lifestyle, and vascular disease.
http://www.ncbi.nlm.nih.gov/pubmed/19158424

This case-control study from Archives of Neurology in 2007 showed an inverse association between coffee intake and development of Parkinson disease (i.e. this relationship suggests that coffee could protect the brain from disease such as Parkinson's). However, smaller case-control studies such as this one are much weaker than the large prospective studies cited above:
http://www.ncbi.nlm.nih.gov/pubmed/17420321

The following 2008 article from Sleep Medicine Reviews presents a more cautionary account of caffeine's effects, particularly with respect to causing a dependence phenomenon, and to disrupting sleep quality. However, a lot of the data cited in this article is absurd, such as showing that a dose of caffeine immediately before sleep causes sleep disruption! Bedtime doses of coffee are not a realistic reflection of most people's caffeine intake!
http://www.ncbi.nlm.nih.gov/pubmed/17950009

Here's an interesting reference to an article showing that the tendency for caffeine to cause sleep disturbance is a heritable trait. That is, some people might be vulnerable to caffeine-induced insomnia, whereas others could sleep well regardless of their caffeine intake:
http://www.ncbi.nlm.nih.gov/pubmed/17969472

Here's a case report of a person with schizoaffective disorder improving upon discontinuing heavy caffeine intake:
http://www.ncbi.nlm.nih.gov/pubmed/18455857


In summary, it appears that coffee drinking is not harmful. In most cases, it may in fact be good for you. However, pregnant women should minimize their use of coffee. For some people, caffeine may cause or exacerbate anxiety or insomnia, especially at higher doses.

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.

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)

Probabilistic Model of Psychotropic Medication Effects

This is an idea I have considered for many years. It fits with my overall view of a lot of evidence from treatment studies.

For many actions in life, an event either happens, or it doesn't. This seems obvious, I guess. You either throw a ball, or you don't. You either show up for work, or you don't. (Mind you, in my own case, I would say that my own modest level of athletic skill causes me quite often to "sort of" throw a ball, or "sort of" swim.)

In medicine, many actions are similarly unambiguous. The surgical removal of an appendix either happens, or it doesn't. An infection either responds to an antibiotic, or it doesn't. Clear.

Yet, I find that many treatments in medicine are much less clear.

In the case of psychiatric treatments, it has been a theory of mine that the drug (or therapy) may reduce the probability of a symptom occurring, in addition to, or instead of, directly reducing the symptom (or not). This phenomenon may be apparent not only in studies of populations, but in an individual.

Many disease processes are driven by multiple variables, which, together, alter probabilities of symptom recurrence. The variables may include genetic factors, environmental stress, etc. There may be a core phenomenon in nature, as manifest on a chemical, or even quantum-mechanical, level, of minute, truly random events, influencing a cascade of effects. The presence of a medication in the body may be just one more variable, influencing the likelihood of a symptom occuring, or developing, or advancing.

Some medications may appear not to be working, if a short-term view is taken. But in a longer-term view, it may be seen that symptom frequency and intensity is diminished. This is consistent with the theory that the medication affects probabilities.

This theory supports the idea that medications, and other psychiatric treatments, could have an important preventative role, beyond their role in an acute situation. And it encourages giving treatments a long period of time to work--at least months, if not years-- in order to most accurately assess effectiveness.

There have been some long-term studies which support this idea, but unfortunately most of the treatment studies in psychiatry have been relatively short-term (only a few months of follow-up, rarely more than a year).

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).

Lithium

I'd like to develop this post gradually, as there is a lot of evidence to summarize and refer to.

But here is a start:

"Mood stabilizers" are drugs which are thought to help treat the symptoms of bipolar disorder. It is hoped that these drugs might reduce manic symptoms, prevent recurrence of manic symptoms, while also reducing or preventing symptoms of depression.

The first treatments for manic episodes were sedatives, including barbiturates and antipsychotics.

The first "mood stabilizer" though, was lithium carbonate.

Lithium itself is the third-simplest element in the universe, after hydrogen and helium. It tends to form salts. It is structurally very similar to sodium, which is a salt-forming element essential to most every life function (that is why we find sodium ions abundantly in all body fluids, and in a similar concentration in the ocean; table salt consists of sodium and chlorine atoms which join together as crystals). Yet, lithium is not normally present in the human body, and is much less common in the universe as well, compared to hydrogen, oxygen, carbon, sodium, etc.

The mechanism of lithium's action in the body, when used as a drug, is still poorly understood. Its similarity to sodium is probably essential to its mechanism. I'll add to this commentary later, but for now I will say that the mechanism of lithium salts probably involves multiple actions inside of nerve cells; these actions may modulate cellular activity.

Here are some of the clinical actions of lithium carbonate, when used as a medication in those with bipolar disorder (I will list the actions in order of how clearly proven and substantial the effect is):

1) It reduces symptoms of mania
2) It may reduce the length of a manic episode (note that just because a treatment reduces symptom severity, it may not reduce the duration of the symptoms).
3) It may prevent the recurrence of manic symptoms
4) It may prevent the recurrence of depressive symptoms
5) It may reduce depressive symptoms when they occur

There are other uses for lithium carbonate as well:
1) It can be combined with an antidepressant to improve symptom control in unipolar depression
2) It may help treat specific symptoms such as irritability and rage
3) It helps prevent cluster headaches (a type of severe, recurrent headache)

Lithium is probably most useful in "classic bipolar disorder", in which individuals experience manic episodes with elevated mood (as opposed to irritable or "dysphoric" mood), and in which the mood episodes are not recurring frequently during an average year (i.e. there is no "rapid cycling").

Here are some of the side-effects of lithium:
1) thirst, increased urine production
2) tremor (shaky hands)
3) nausea
4) sedation -- usually it is a much less pronounced type of sedation compared to antipsychotics, benzodiazepines, or other "sleeping pills". But there can be feelings of reduced energy, reduced clarity of thinking, or lethargy
5) toxicity to the kidneys -- this is not common, but needs to be checked for regularly
6) inhibition of thyroid function -- this is not permanent, nor is it harmful to the thyroid gland (in fact, it may "rest" the thyroid gland); but diminished thyroid levels, if present, requires treatment with a thyroid supplement)
7) acne or other skin rashes
8) toxicity in overdose

There have been a few studies questioning the effectiveness of lithium, particularly in terms of its value in preventing recurrent mood episodes. But for many people it does appear to be very effective, both as an acute treatment and as a preventative agent. It probably works much better as an "anti-manic" agent than an "anti-depressant".

There are various forms of lithium, and various dosing regimes. In most cases, it can be dosed simply: once at bedtime. The concentration of lithium in the blood needs to be measured periodically. Levels which are too high can increase the likelihood of toxicity (mind you, excessive levels could usually be assessed on the basis of side-effect complaints); levels which are too low may not be effective.

In my experience, some people may benefit from staying on lithium, but adjusting the dose to a point that is more tolerable for them. It may not necessarily be true that everyone needs to have a full therapeutic concentration of lithium in order for it to work. For some people, the side effects may outweigh the benefit at full doses.

However, it is a frequent situation in an emergency room, or on a mood disorders hospital ward, that people with clear histories of bipolar disorder, stable on medication, end up having a recurrence of severe mania a few weeks or months after tapering or stopping their medication (often lithium). In some of these cases, the manic symptoms may have already been building up, leading the person to discontinue their medication (rather than the other way around). But in many of these cases, it seems to me that the lithium had been protecting them, and that the recurrence of mania happened because of medication discontinuation.

There is also some evidence that sudden lithium discontinuation can provoke increased mood instability. So, while there are no overt withdrawal symptoms from stopping lithium, it should be tapered slowly if possible (I would say over 1-2 months at least).

It should be emphasized that lithium is not a perfect drug, either in terms of side effects or in terms of effectiveness. Many people on full doses of lithium still experience relapses of mania. But it is quite clear, from decades of experience, that lithium can be helpful for many people with bipolar disorder.

References:

http://www.ncbi.nlm.nih.gov/pubmed/17547586
(a 2007 Cochrane review of mood stabilizers, showing good evidence for lithium, but also encouraging use of other mood stabilizers--which for some people could be superior to lithium-- such as valproate and atypical antipsychotics)

http://www.ncbi.nlm.nih.gov/pubmed/8120960
(a 1994 JAMA article showing the effectiveness of lithium and valproate, compared to placebo, in acute mania)

http://www.ncbi.nlm.nih.gov/pubmed/10807488
(a negative study, comparing lithium, valproate, and placebo; published in the major journal Archives of General Psychiatry in 2000--it shows very little difference between lithium, valproate, and placebo treatments with respect to relapses in bipolar patients over a 1-year period; however this study was probably biased in favour of high placebo effects and lower medication treatment effects, for a variety of reasons)

http://www.ncbi.nlm.nih.gov/pubmed/10891035
(a randomized, placebo-controlled study from Archives of General Psychiatry in 2000, showing a pronounced effect of lithium in reducing aggression in hospitalized children with conduct disorder)

http://www.ncbi.nlm.nih.gov/pubmed/16924942

http://www.ncbi.nlm.nih.gov/pubmed/3314489

(a Dutch review article from 2006, and an older article from a U.S. nephrology journal, summarizing the risk of kidney disease associated with lithium; about 15-20% of people taking lithium long-term may experience a decline in kidney function. While this decline is usually mild, I think that an alternative mood stabilizer should be strongly considered if someone is developing signs of reduced kidney function while on lithium).

Noise Pollution

Peace and quiet are important for mental and physical health.

Here are a few links to references:

http://www.ncbi.nlm.nih.gov/pubmed/14757721

http://www.ncbi.nlm.nih.gov/pubmed/15936421
(A 2005 study published in Lancet which showed that noise causes increased irritability, and a negative impact on cognitive development in school-aged children)

On a related note, the use of music players such as iPods can cause permanent hearing loss, particularly if people have the volume turned up very high. People are more likely to use higher iPod volumes if the background noise level is also high. Here are some links to information and evidence:

http://www.hearinglossweb.com/Medical/Causes/nihl/mus/ipod/ipod.htm#fast

http://www.ncbi.nlm.nih.gov/pubmed/19124629

http://www.ncbi.nlm.nih.gov/pubmed/17430434

http://www.ncbi.nlm.nih.gov/pubmed/17711774

Also, the sound volume at a rock concert or a nightclub is sufficient to cause hearing damage, especially if this is an activity done regularly without hearing protection. I recommend using earplugs at rock concerts (yes, I'm serious!) Here is some evidence:

http://www.ncbi.nlm.nih.gov/pubmed/8499785

http://www.ncbi.nlm.nih.gov/pubmed/16825883

http://www.ncbi.nlm.nih.gov/pubmed/12176760

Imaginary Numbers - a metaphor

One of my favourite mathematical metaphors comes from an area called "complex analysis".

I can't resist the metaphor, because of the nature of the mathematical language involved.

I've always loved mathematics. It is enchanting, beautiful, yet infinitely challenging. There is no area within mathematics that cannot be developed into an almost impossibly esoteric branch of its own. Its theoretical abstraction must surely exceed the complexity of the physical universe (unless we consider abstract mathematical ideas to actually be part of the physical universe).

The appreciation of mathematics as an art form or as a form of esthetics has, unfortunately, been hampered by an educational approach which often leads people to experience mathematics with dread, anxiety, or despair.

Anyway, here is the mathematics:

1) A "square root" of a number is another, smaller number, which, when multiplied by itself, gives the first number. So, for example, the square root of 25 is 5--since 5 times 5 equals 25. I suppose we could add that 25 in fact has 2 square roots, since (-5) times (-5) also equals 25. This idea of a "second" square root already involves a higher degree of abstraction.

2) There are some numbers which do not seem to have any possible square root. For example, what would be the square root of (-25)? There does not seem to be any number which, when multiplied by itself, yields a negative number.

3) So, how about if we create such a number, imaginatively? Such a number has been invented, and it is called the "imaginary number", signified as "i". The imaginary number i is an abstraction, with the property that i times i equals -1.

4) What is the use of having such an imaginary number? What application could it have? Well, as it turns out, it is enormously useful in understanding and solving problems in physics and engineering. And, I think, it demonstrates a very beautiful link between phenomena that might initially seem completely different.

The exponential functions are phenomena which, if represented graphically, appear to represent rapidly accelerating growth. If something keeps doubling regularly, the growth is "exponential". Many phenomena in nature can be described using exponentials.

The trigonometric functions are phenomena which, if represented graphically, appear to represent waves, which oscillate regularly; in the case of the "sine" function, we have a "sine wave", which fluctuates, forever, between -1 and 1. Many other phenomena in nature can be described using the trigonometric functions.

There appears, at first sight, to be no obvious relationship between the exponentials, which represent unbridled growth (e.g. population growth); and the sine wave, which represents continuous, regular, well-bounded waves (e.g. the swinging of a pendulum).

But if we figure out a formula which can calculate an exponential, and a formula which can calculate a sine wave function, we find that if "imaginary numbers" are allowed, the two types of functions are variations of the same thing. Hence we have the mathematical fact:
exponential (ix) = cos(x) + i sine(x).

So here is the psychological metaphor:

The link between something which rises, escalates, explodes upwards towards infinity, and something which is stable, repetitious, and finite -- is "imagination". They are variants of the same, larger, thing, as long as you can expand your perspective of understanding.

The introduction of imagination may transform a problem of unbridled excess into one which could include stable regularity. Similarly, imagination could transform the monotony of a "sine wave" type of life into something more excitedly or wildly "exponential".

In approaching seemingly impossible life problems, I think it is important to be able to step back, and sometimes to allow an entirely new perspective or way of thinking.

Family Therapy ideas for Individual Therapy

Long ago I found that ideas from the theory and practice of family or group therapy could be well-applied to individual therapy.

In family or group dynamics, individuals can find themselves in particular types of roles (e.g. observer, leader, critic, outsider, social butterfly, scapegoat, etc.). Sometimes these roles can be "typecast", entrenched through repetition. Such entrenchment of roles may not allow a person's full range of emotion & personality to flourish.

Similarly, within one's own individual mind, it is possible to "typecast" oneself, through repetition of assumed roles.

The same tactics that can help in a group or family setting (e.g. encouraging a deliberate exploration of entrenched roles, and experimenting with taking on different role styles) could be beneficial for an individual.

Another dynamic which is explored in family therapy is the type of boundaries that exist between different members, in conjunction with the strength of the bond between each different member.

There may be "detached" relationships (a weak bond and little involvement), or so-called "enmeshed" relationships (in which people are extremely involved in each other's affairs, sometimes not allowing the individual to have an experience of autonomy).

Boundaries may be weak, absent, or atypical (in different cases, leading to different types of abuse, or to young children taking on the role of parent or confidante with their mother or father). Or boundaries may be extremely rigid, lacking flexibility (perhaps leading to an uncomfortable authoritarian atmosphere in the relationship or household).

In family therapy, reflection and work can be done on building healthy relationship bonds, encouraging a relaxation of enmeshments, so as to permit more individual autonomy. And work can be done to encourage healthy boundary formation.

Similarly, in an individual therapy setting, personal boundaries and "inner relationship bonds" can be a source of problems. "Enmeshments" may occur on an inner level, perhaps in the form of ruminative or obsessive preoccupations. "Detached" inner relationships may occur, in which parts of self or behaviour are held separate, and leading to a non-integrated sense of self, or a sense of self consisting of numerous independent facades or personas. Boundaries could be weak (perhaps leading to impulse control problems), or inflexible (perhaps leading to an inability to adapt easily, or to adjust to another person's style in a relationship).

In individual therapy, similar work can be done to build healthy "inner bonds", and healthy "inner boundaries".

I consider this comparison between family/group and individual therapy to be metaphorical. In the theory of so-called "object relations" such metaphorical ideas may be considered quite literally, i.e. that external relationships become literally "internalized" in the formation of a healthy self.

In practice, I think some of the ideas from family therapists can be imaginatively applied in an individual therapy setting.

As a concluding--but practical and concrete-- tangent, an exercise in one form of family therapy is to research your family tree, and to collect information about the life stories of different members of your family tree. This would include immediate relatives, but also more distant ancestors.

I think this is an interesting exercise in individual therapy for a variety of reasons:
1) because psychological symptoms, problems, personality styles, etc. are substantially influenced by genetic factors, it can be interesting to examine the life stories of those who are genetically related to you. It may also be true that the SOLUTIONS that work best for various life problems are also influenced by genetic factors (e.g. there is some evidence that a particular medication, if it works extremely well, has a higher chance of working extremely well for another person who is genetically similar). In a broader, "life story" sense, you may find stories in your family of various adversities that are similar to your own, and you may come to understand how these different ancestors coped. Some of these stories may be cautionary (i.e. warnings about how NOT to cope with certain problems), but some of the stories may be inspiring, and may guide or reassure you in your own pathway to solving your life problems.
2) the process of examining stories from family and ancestors can increase your sense of connectedness, identity, and meaning. Many families in our modern culture have become quite disconnected, and perhaps this disconnectedness fosters loneliness, materialism, or a cultural vacuum. As you gather information about these family stories, you may end up re-connecting with distant cousins, etc. and this could expand or enhance your network of friendships.
3) If many of the stories you find are very negative, this type of information could be upsetting, traumatic, or exacerbate more recent post-traumatic symptoms. If this is the case, such an exploration may need to be taken very slowly, if at all. But sometimes, if you feel ready, the process can become part of healing from the trauma. The exploration of a full story--even if the story is very negative--can sometimes be a prelude to healing. This task encourages the exploration of stories from distant relatives, as well as immediate relatives--this increases the likelihood that you will find some positive, inspirational stories, even if many of the stories are traumatic or turbulent.

Vitamin D & other vitamins

I'm re-posting this as a separate entry, because I think it's important.

I recommend multivitamin supplements as standard advice, because I think there is negligible evidence of risk (other than the effect on your wallet), and potential benefit.

The role of vitamin supplements ought not to be overvalued -- I think they are unlikely to cause a pronounced change in any symptom. But a vitamin deficiency could possibly prevent other treatments for depression from working optimally. Many people with psychiatric symptoms have less than optimal nutrition, for various reasons; therefore I feel that vitamin and mineral deficiencies are more likely.

There is some evidence of vitamin supplements being used to augment antidepressant medications, but the level of evidence is quite weak.

Vitamin D in particular is probably important to supplement, particularly for those of us who experience dark, cold northerly winters (vitamin D is normally produced in the body when our skin is exposed to the ultraviolet rays from direct sunlight). Furthermore, most of us wisely use sunscreen when it is sunny and warm, so most of us are getting less vitamin D from the sun. There is some evidence that the RDA for vitamin D (200-400 IU per day) is too low, particularly when we consider that brief whole-body skin exposure to sunlight generates an equivalent of perhaps 10 000 IU.

Here is a reference to a very interesting and promising recent study suggesting beneficial mood effects from higher-dose vitamin D supplementation (people received the equivalent of about 3000-6000 IU per day, for a whole year); the study is from a major, highly respected internal medicine journal:

http://www.ncbi.nlm.nih.gov/pubmed/18793245
Here is an excellent reference examining the issue of vitamin D safety, dosage, and toxicity:

Vieth, Reinhold. "Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety", American Journal of Clinical Nutrition 1999;69:842–56

A recent study by Bischoff-Ferrari et al. (2009) showed that elderly hip fracture patients given 2000 IU per day of vitamin D for 12 months, had a 60% reduction in fall-related injuries and a 90% reduction in infections leading to hospitalization, compared to a group given only 800 IU per day of vitamin D.

Here's a reference to a 2008 study from a clinical biochemistry journal showing toxicity from prolonged very high-dose vitamin D, of over 40 000 IU/day over several years. It concludes that the lowest dose at which hypercalcemia can occur is about 3800 IU per day:
http://www.ncbi.nlm.nih.gov/pubmed/18275686

Based on the evidence I recommend supplementing with an extra 2000 IU of vitamin D daily (possibly up to 3000 IU), in addition to the 400 IU that is present in most vitamin supplements, unless you have a medical condition associated with abnormal calcium metabolism or abnormal sensitivity to vitamin D (e.g. sarcoidosis).

If you are taking high-dose vitamin D you should have serum calcium levels checked periodically, and possibly a serum vitamin D level.

I do not recommend "mega doses" of any other vitamin, since I do not see a good evidence base for this being helpful, and higher doses of many such nutrients can be toxic or dangerous. A few recent studies have shown that people taking certain vitamin supplements, such as vitamin A or E, actually do more poorly than the control group.