If a man does not keep pace with his companions, perhaps it is because he hears a different drummer. Let him step to the music which he hears, however measured or far away.
Henry David Thoreau (1817 - 1862), Walden,
Conclusion, 1854
Bipolar Disorder: Background Readings.
The Australian Bipolar Website, FyrenIyce,
is worth a visit at:-
ìhttp://users.wantree.com.au/~fractal/fhello.htm FyrenIyce
The NYTimes Science
Section (click
here for simple text version) ran a story on the theory that mood disorder
can be related to interhemispheric switching and hemispheric asymmetries.
Fish oil and bipolar
disorder: Paper by Stoll et al.
Creating the Elimination of Bipolar Disorder? A marker trait might enable the recognition of vulnerable individuals before the first episode of depression or mania. Although still theoretical, this possibility might eliminate the worst aspects of the disorder altogether, since there is good evidence that the early episodes are triggered by life stressors, (small as these may seem to those who do not have thextreme sensitivity of the bipolar temperament), while later ones may be much more spontaneous because of "kindling". Could one eliminate the worst aspects of the disorder without also eliminating the positive aspects? Should one?
Slaying the Dragon
of Depression?
In this article I draw attention to the underdiagnosed conditon of
bipolar
depression which responds better to mood stabilisers than to antidepressants.
"Sticky" Switch Hypothesis:
Pettigrew
JD and Miller SM 1998 Proc. Roy. Soc. B 265: 2141-2148A "sticky" interhemispheric
switch in bipolar disorder?
This paper is a little technical, but is not intended purely for a clinical readership (There is even a yin-yang symbol, for the complementarity of the cerebral hemispheres, in one of the figures that gets Jack into hot water in some stodgy settings!).
The important new finding is that bipolar subjects switch more slowly between rivalling perceptual alternatives. This "slow switching" trait seems to have a large genetic component, based on a high correlation in identical twins The trait seems accurately to position a subject in the bipolar spectrum, with slower rates of switching involving proportionately greater risk of bipolar disorder. The finding continues to be replicated in larger numbers of subjects in different centres. In addition, we discovered a study from the days before medication, that has essentially the same message (Hunt et al J. Abnormal Soc. Psychol 27: 443.1933).
Unexpected Confirmation of Unihemispheric Effect on Mood:
Bejjani B-P, Damier P, Arnulf I, Thivard L, Bonnet A-M, Dormont D,
Cornu P, Pidoux B, Samson Y, Agid Y 1999 New England J Medicine 340:1476-1480
Transient acute depression induced by high-frequency deep-brain stimulation.
This recent paper provides dramatic confirmation of the hemispheric
switch hypothesis by showing that acute depression can be turned on and
off at will by electrical stimulation of only one side of the brain in
the substantia nigra/ventral tegmental area. When the electrical stimulation
(7 min) was stopped, the 7 min of severe depression was followed by 5 min
of "rebound mania"!! The probable involvement of an aminergic structure
(these are all midline paired putative bistable oscillators) and the sidedness
conform nicely to the predictions. A negative mood effect of stimulation
on the Left is the opposite side of the prediction....Scanning studies
help illuminate this by showing that the Left-sided structures activativated
by the electrical stimulation are mostly sub-cortical. There was very strong
parieto-temporal activation of the Right cortex...reminiscent of the activation
pattern produced by Left caloric stimulation. Another important possibility
is that the stimulation is disruptive of a tonic pattern of activity. The
rebound shown at the end of stimulation is consistent with a disruptive
effect
Perceptual Alternations=Interhemispheric
Switching.
We have produced a new explanation for perceptual rivalry that is based
on the concept of interhemispheric switching. If one accepts this thesis,
then the slower perceptual alternations of bipolar subjects have a number
of clinical implications.
Two analogies have been provided by colleagues:- a spinning top and
a boat rocking at anchor.
You can choose the one that is most familiar.
A slowly spinning top is more likely to wobble and fall over. Put another
way, it is possible for a top that has stopped spinning to stay upright,
..........but extremely difficult to maintain that equilibrium.
Even the slightest perturbing input will cause it to fall over on one
side.
Similarly, among a group of boats of the same size, the boat that rocks at high frequency at anchor will be the least likely to capsize in a big sea. (Read "The Perfect Storm" if you want a dramatic account of this).
In the case of the bistable oscillators responsible for switching in
the brain, if all else is the same, the slower switch will be more easily
perturbed by external synaptic influences. Much research remains to be
done on interhemispheric switches to to flesh out the details, but it is
clear that a major synaptic influence on the switch will be driven by input
from the hemispheres themselves.
The idea therefore is that the switch may be held in one phase by hemispheric
activity on one side and that such a bias is much more likely to occur
if the switch is slower.
In this context, please note the remarkable recovery from an extreme
stroke-induced hemispheric asymmetry that was produced by caloric stimulation.
The authors draw attention to the recovery of multiple cognitive impairments,
thus emphasising the general hemispheric activation produced by caloric
stimulation. The data so far indicate, even in this patient who had renewed
"emotional emphasis', that Left hemispher activation via caloric stimulation
can produce positive changes in mood, whereas Right hemisphere stimulation
produces negative changes.
Portrayals and Characterisations of Manic-Depression.
A. Books:
'A Brilliant Madness' Patty Duke and Gloria Hochman, Bantam
1992
An Oscar-winning star (for her role in ìThe Miracle Workerî)
tells first hand of her experiences with the disorder while a medical reporter
provides accurate, clear and fairly current information about bipolar disorder
in parallel chapters.
'Daughter of the Queen of Sheba Jacki Lyden. Sceptre 1997
Beautifully written from a (normal) daughter's point of view, this
tells a comi-tragic story about a bipolar mother whose diagnosis is not
honed until rather late in life. A GP husband, who perhaps should know
better, plays an important role in the early obfuscations.
An Unquiet Mind Kay Redfield Jamison.
Distinguished as both a sufferer and a Professor of Psychiatry at Johns
Hopkins, Kay Jamison comes from academic psychology rather than from a
medical background. She has made big contributions to bipolar research
(including TheBible....~1K pp Manic Depressve Illness, Goodwin
FK and Jamison KR 1990, Oxford UP, ; and Touched by Fire where she
elaborates the link with creativity and leadership).
This is a gripping and intelligent account from the manic-depressiveís
point of view.
Churchill'sBlack Dog and other phenomena of the human mindAnthony Storr. Flamingo 1989.
A psychiatrist's account of the role of the bipolar spectrum of personality in the achievements of Winston Churchill and Isaac Newton. The portrayals of Churchill and Newton are quite consistent with their being bipolar. Newton's renowned ability to hold one idea or train of thought for extended periods (described by witnesses in this book), is also consistent with the the view that he was a slow switcher and that this trait contributed to his genius (as well as to his prickly personality!).
Perhaps the Battle of Britain and the Principia Mathematica should be borne in mind when one is confronted with the negative side of bipolar disorder!
B. Videos/Movies.
Extracted from Joyís much longer list of movies with mental
disorder as a theme, on FyrenIyce.
The currently-running soapie about Gps, Peak Practicefeatures a GP (played by Adrian Lucas of wicked Wickham fame in the BBC's Pride and Prejudice) who has a bipolar wife. The GP's learning curve about the disorder poses problems for the wife.
Bullworth 1999
Warren Beatty plays a corrupt US politician who becomes manic during
his re-election campaign, with dramatic and sometimes humorous consequences
for his constituents. Hollywood introduces some ambiguities which would
make a valuable source for discussion, concerning, for example, the choice
about when, whether and how to intervene in mania. You will
find a number of different viewpoints are made possible.
Mr. Jones. 1991
Richard Gere is a passable manic. Good interactions with psychiatrist
medico girlfriend.
Title: Tom and Viv
Date: 1995
Actors: Miranda Richardson
Director:
Plot: The story of T.S. Elliot and his wife, who suffered from mental
illness. A full range of cycling is portrayed,
similar in appearance
to manic depression, but never actually described
in a diagnosis.
Great acting.
Title: Mad Love
Date: 1995
Actors: Drew Barrymore, Chris O'Donnell
Director: Antonia Bird
Written by: Paula Milne
Plot: Seattle teenagers fall in love and after parental opposition,
run away together. She is manic-depressive,
and he learns
to be loving, nurturing, and grow in
responsibility. A good
movie for young people. May generate
discussion in this age
group.
Title: Lust for Life
Date: 1956
Actors: Kirk Douglas, Anthony Quinn
Director: Vincente Minnelli
Plot: Story of Vincent Van Gogh. 1950s version.
Title: A Fine Madness
Date: 1966
Actors: Sean Connery, Joanne Woodward
Director: Irvin Kershner
Plot: A manic depressive poet; typical Sixties comedy, but interesting
for its portrayal of the general public
perception of "mad"
artists. Based on a novel by Elliot
Baker.
Title: Cobb
Date: 1994
Actors: Tommy Lee Jones, Robert Ruhl
Director: Ron Shelton
Plot: Story of Ty Cobb, one of the greats in baseball, who was also
very likely manic-depressive. Cobb was on
lithium the last years
of his life; the story is about the writing
of his biography
by sportswriter Al Stump.
Title: Blue Sky
Date: Released in 1994
Actors: Jessica Lange, Tommy Lee Jones
Director: Tony Richardson
Plot: Lange won an Oscar for her portrayal of a manic depressive woman
who is a military wife in Cold War America.
The mood swings are
only briefly discussed. We are to derive
from the character's
behaviour that something is not quite
balanced, although the
diagnosis is unclear.
G-Proteins and Lithium.
The G-protein cell-signalling system, with its complex interlocking pathways and powers of amplification, has an increased gain in bipolar disorder, in the form of elevated levels of Gs alpha. This has been shown in many different cells of bipolar patients, including neurons, leucocytes and platelets. Some consequences of this are:-
. increased responsiveness to cAMP-linked drug actions; (substance abuse is well- recognised in bipolar families and may have a more biochemical explanation than the obvious environmental ones related to "handling the family dramas").
. increased light suppression of melatonin secretion
. increased response to sensory stimuli
These effects all appear to be downstream of the fundamental basis of bipolar disorder, since there have been no studies that find a genetic link between bipolar disorder and G-proteins, despite the intense work in this area.
Since one important action of lithium ions is to put a ceiling on G-protein activation, this may be one important site of lithium's therapeutic action.(The other medications used to treat bipolar disorder, such as Valproate, carbamazepine and omega 3 & 6 fatty acids, also act on the G-protein signalling pathway, but at different sites from lithium) At first sight this action of lithium looks implausible, since millimolar concentrations of lithium ion are needed to have this action, while the therapeutic levels reached in extracellular fluids are only in the micromolar range. But recent work by Roger Papke and colleagues, at Gainesville (UFlorida School Med), has shown that lithium is concentrated inside post-synaptic spines following action spikes. Spikes lead to cation influxes, including lithium ions, with the result that millimolar concentrations of lithium are found exactly where they are needed most in the bipolar brain.......inside neuropil that is the site of excessive activity.
Lithium ions have no effect on the rate of the interhemispheric switch, which is slowed in bipolar patients whether they are medicated or not.
Counter-intuitive Implications of the Slow Switch for G-protein Regulation:
The documented cellular G-protein increases in bipolar disorder, while
fitting nicely with the intuition that such patients do have increased
sensitivity (e.g. it is a common observation that they can fly off the
handle rather easily), does not seem to fit with the slower alternation
rate of the interhemispheric switch of these patients.
The mechanism of the slow interhemispheric switch in bipolar has been
suggested to be a reduction in cationic channels that give the slope of
the depolarisation ramp in the bistable oscillator. The slope of this ramp
in turn gives the rate (see Fig. 5 of Pettigrew
and Miller 1998). More cationic channels ..........faster depolarisation..............faster
rate.
Since a cation channel deficit would also tend to reduce sensitivity,
this explanation for the slower switch is in conflict with the observations
that bipolar patients have increased sensitivity.
A thoughtful consideration of this apparent conflict repays itself,
because it requires a synthesis of knowledge about the different parts
of the neural system that interact...not just the bistable oscillator...but
the hemispheres that process stimuli in alternation and feed back to the
oscillator.
1. G-protein up-regulation is a mechanism to retain sensitivity in
the face of reduced input. e.g. when our photoreceptors increase their
sensitivity in the dark, to become responsive to the ultimately smallest
input.....one photon.....the mechanism involves an up-regulation of G-proteins.
2. Not all tissues show regulation. In the present example, one would not expect a clock to up-regulate its rate just because it was getting dark and harder to read!! On the contrary, one would expect a clock to have a robust rate that was not influenced by fluctuations in cellular protein levels...just as one finds in the chemotaxis clock of E. coli, which always returns to 1.5>
3. The interhemipsheric switch rate is robust in one individual. Test-retest corrrelation is better than 0.8. Identical twins have similar rates. Lithium ions appear to have no effect on the rate.
4. The increased G-protein levels in bipolar patients may therefore be an attempt to restore sensitivity to compensate for the primary neural deficit in cation channels. Neurons in the cerebral hemispheres have important functions that may have nothing to do with clock rate (such as processing sensory stimuli and recording them for future reference). So we might expect some neural functions, like sensory processing and the light zeitgeber for the circadian clock (as opposed to the clockwork itself), to up-regulate to maintain sensitivity in the face of reduced cation channel function.
Vicious Cycle:
If you have followed Jack's speculative house of cards concerning G-protein
upregulation this far, you may now be able to see in stark relief the core
of the bipolar problem....maintaining balance.
Having a slow switch has the difficulty that it is harder to balance,
just as a slowly spinning top is more likely to topple over or a slowly-rocking
boat is easier to capsize than a fast-rocking boat of the same size. But
this difficulty is multiplied if the inputs that bias the switch to one
side are much stronger for the same sensory input! Such a system is predisposed
to getting stuck.
Genetics:
Everyone, starting with Kraepelinís first description,
agrees that bipolar disorder runs in families. The details are elusive,
with as many as five studies each claiming to have found the gene responsible,
but each citing a different location! The most likely explanation for this
is an oligogenic mechanism, where a number of different genes each contribute,
as for height.
Identical twins show around 60% concordance, so there is apparently
some environmental factors that come into play. The strange absence of
Bipolar I in France also suggests that the environment plays a role.
In terms of the slow switch theory of bipolar disorder, Jack would
say that the genetic predisposition was strongly heritable in the form
of the switch rate. Identical twins have very similar switch rates, as
do two measurements of the rate of one individual taken months apart. Switch
rate therefore seems to be a robust genetic feature that varies in the
population over nearly two orders of magnitude, from 1.5 Hz to 0.04 Hz.
The slower the switch, the greater the risk of clinical illness. The hemispheric
bias, the relative amount of time spent in each hemisphere, varies much
more than the rate. It may reflect rearing conditions, since first born
egomaniacs tend to have strong left hemisphere biases in contrast to
more cautious, better balanced later siblings who may have no marked hemispheric
bias, or even a right sided bias.
Future work on the genetics of bipolar disorder may be helped by the
new quantitative trait available from measurement of the switch rate, using
rivalry alternation rate, for example.
Positive Aspects of the Bipolar Personality.
Kay Jamison speaks eloquently for the positive aspects of bipolar disorder
in her book Touched by Fire (which deals with the increased
incidence of the bipolar trait in poets) and in her chapters on Leadership
and Creativity in The Bible (Manic Depressive Illness,
Goodwin and Jamison 1990, OUP)
Early Diagnosis and Prevention.
While initial episodes of mania and depression may be triggered by
life stressors, later episodes may be generated by more internal mechanisms
related to plasticity (e.g. kindling) of the cerebral hemispheres (Post
and Weiss 1998 ). Post's insight focusses attention on the earliest stages
of the disorder in young adulthood, where appropriate mitigation or even
prevention of the first episodes could change the whole course of the disorder...perhaps
even prevent it altogether. The problem is first to identify susceptible
individuals and then to test the efficacy of a mitigation strategy.
Similarly, a reliable marker for bipolar disorder would be very
useful in those cases where the first presentation of psychosis is atypical,
as often happens with young adults in the turbulent, hip, late 20th century
. A significant proportion of such cases are misdiagnosed, with the added
risks of inappropriate medication, as well as the risk of kindling further
episodes that is raised by the work of Post.
The slow switching trait is currently being trialled to see if it can
fulfil a role as a marker that can be used for early diagnosis and prevention
of bipolar dissuader.
Life-style Interventions.
I met a Tibetan amchi who used a variety of techniques aimed to restore
balance in patients with bipolar disorder. In my interactions with many
bipolar people around the world via email, I am struck by the variety of
strategies used to handle their mental states and swings, all of which
could be brought under the rubric of achieving balance in life.
Exercise, music, pets, colleagues, nature, spiritual pursuits, meditation,
humour, neophilia [(like it?...a term I learned from Josh Wallman for the
active pursuit of novelty.....the other hemisphere might be providing
that extra frisson at the word by suggesting a c for insertion)].....all
played important roles in different cases. Successful self-management seems
to be associated with a balanced, accepting view of the disorder and the
healthy internal monitor (? a positive or balanced self-view rather than
a self-deprecatory Right hemisphere) that goes with such a view.
I am currently trying to work out ways to combine the powerful manipulations known to shift R/L balance (such as caloric and transcranial magnetic stimulation, SSRIs etc) with more self-help life style interventions that might be able to take over once the balancing process is initiated or made explicit for the patient. I think that the cerebellum has to be brought in to this balancing process, .......and you know how precise and repetitive one has to be to get a lasting imprint in that structure!
Cultural Differences in Bipolar Spectrum.
Clinical manifestations can vary from Unipolar depression (recurrent
depression) through Bipolar II (recurrent hypomania and depression) to
Bipolar I (recurrent mania and depression). While some reject the notion
of the spectrum, a striking recent result gives it support while at the
same time suggesting that the underlying genetic susceptibility trait (?slow
interhemispheric switching) can have different outcomes according to rearing.
There appears to be no Bipolar I in France!
This remarkable result was thought at first to be a diagnostic artefact,
but a recent cross-cultural study, with both French and US psychiatrists
combining forces to produce a shared diagnostic that was used in both countries,
found 0.0% mania in France, compared with 1.5% in US and 2% in Italy, for
example.
No explanation is presently being offered, but bearing in mind
the key importance of relationships as life stressors in bipolar illness,
one cannot help contrasting the level-headed approach that the French have
to human sexuality (cf. Mitterandís funeral, attended publicly by
both his wife, his mistress and both daughters) with the rampant hypocrisy
surrounding the recent trials and tribulations of President Clinton
(who should have read Samuel Pepys and learned about the plusses and minuses
of the increased potency of office).
Depression and Health.
Neurocardiology recognises the asymmetrical innervation of the heart,
with a predominantly ventricular influence of the Left-sided innervation
compared with a more predominantly atrial innervation of the Right side.
If there is an imbalance, arrhythmia can result, as shown experimentally
when the right stellate ganglion is removed, leading to an increase in
ventricular arrhythmia.
The Right hemisphere controls the Left sided innervation of the heart
preferentially, so one can see that Depression could have cardiac consequences,
given the growing evidence for excessive Right hemisphere activity in depression.
Depression is one of the most important risk factors for sudden cardiac
death, ahead of smoking, blood pressure and cholesterol.
Right hemisphere function has also been linked to the stress-related
ACTH-pituitary-hypothalamic axis.
This link between hemispheric function, mood and immune response could
explain why local GPs are having so much success treating recalcitrant
recurrent chronic infections with anti-depressants!
Omega 3 Fatty Acids and Bipolar Disorder:
Recent work suggests that the human brain evolved close to a sea shore
or lakeshore. This would explain the requirement for brain components like
omega 3 fatty acid derivatives (DHA and EPA) that cannot be synthesised
by the human body but must be obtained from seafood. In this context, a
recent trial in the US achieved remarkable results in the managment of
bipolar disorder using large doses of fish oil (10 g/day). This double-blind
placebo trial had to be terminated early because of the striking difference
in results between the placebo and experimental groups. I have had success
with fish oil in some bipolar patients that were resistant to the usual
medications. I recommended 9 capsules/day, with meals. I also used myself
as a guinea pig for a few months trying plant-derived omega 3 (flax oil).
This was ineffective in stabilising my mood, in contrast to the fish oil,
so I do not recommend plant derived omega 3 fatty acids, which are apparently
dissimilar to those derived from seafood. (A recent report by Andy Sinclair
at RMIT in Melbourne, with whom I have been having many interactions, points
out the problems that arise from the assumption that DHA and EPA can be
derived from plant sources. The most important plant-derived omega 3 fatty
acid is alpha linolenic acid which can be converted only with difficulty
to DHA and EPA via a complex 7 step pathway that is likely to be rate limited.
After reading Andy's report, I resurveyed the controversial literature
on the use of omega 3 to treat psychiatric problems and was very interested
to see that studies that used fish oil got positive results whereas those
that used plant omega 3 oils often got negative results. So don't assume
that all omega 3s are the same!).
Fish oil is remarkably free of side effects (apart from loose stools and fishy burps) and many report improvement in skin, joints and allergies apart from the improvement in mood stability. There are reports of increased bleeding time, so care should be taken if used at the same time as other medications that may cause bleeding such as aspirin and the non-steroidal anti-inflammatory drugs.
Click
here for paper by Stoll et al on the use of fish oil in bipolar disorder
The Aquatic Ape Hypothesis:
The shore-based explanation for our dependence on seafood omega 3 is consistent with Elaine Morgan's thesis that hominids must have evolved in close association with water. It may seem a long throw from bipolar disorder to a controversial theory in paleontology. Nevertheless, the puzzle of the explosive brain expansion requiring an apparently-rare nutrient goes away if one accepts that hominids evolved at the shore.
The Aquatic Ape hypothesis has received a battering in the past (see heated anti- link below). This antipathy has been partly territorial (scientists do not alway appreciate a novel, holistic hypothesis that originates from a screen-writer!) .........but also lacked support from anthopologists, who saw the stage for the australopithecine-hominid transition as dry woodland savannah, not wet lacustrine shoreline. That has changed. Phillip Tobias, perhaps the leading African anthopologist in this area of ealry homind habitat, now admits that the emphasis on woodland sannah may have been wrong and that the habitat at this crucial time in homind evolution may have been very wet.
see P.V. Tobias (2002) Some aspects of the multifaceted dependence of early humanity on water. Nutrition and Health 16:13-17.
On this point, it is interesting to note that Lucy, one of the most famous australopithecine fossils of all time, was found surrounded by the detritus of an aquatic lifestyle, such as turtle shells and crab claws. This important fact was missing from the early reports of Lucy's discovery. One wonders whether this omission would have occurred if the discovery had been reported in a more right-brained, balanced, feminine style with all the uncomfortable facts included, instead of riding the zeitgeist of the time.
Elaine has written a number of books on this topic and I have provided
some links below to the pros and cons of the thesis.
Briefly, Elaine argues that we have a number of adaptations that are
best explained if our early ancestors spent a lot of time in water. I am
aware that it is possible to demolish some of these, each taken alone,
but I am impressed by the collective power of all these points, taken together.
They include:-
