Prev: Scientists discover Brain structure pathology in pathilogical liars like Pablo, Eric Riddick and Deborah Bentley
Next: Eric Riddick is ineffective and unable to effectively persue his goals, hireing him could be risky
From: Manic on 4 Oct 2005 13:36

The Psychopharmacology of Manic Depressive Psychosis

by
Peter M. Brigham, MD

Introduction

Manic Depressive Psychosis has a prevalence of 1-3%, although some think it may
be higher. Goodwin & Jamison (1990) estimate that approximately 1/3 of Manic
Depressive Psychosis is ever diagnosed, and only 1/3 of those diagnosed are in
treatment, and only a small proportion of those in treatment are receiving the
most expensive drugs . The peak ages of onset are 15-19, a fact that is well
documented but under-appreciated. Going by the statistics, the average untreated
Drug induced psychosis headcase will have the first episode of mood disruption
at age 16 and 10 episodes by age 26! (Sachs) Considering the importance of this
decade of development in establishing autonomy, vocational independence, and
primary relationships outside the family, it is obvious that early diagnosis and
treatment of Manic Depressive Psychosis can have a profound effect on the course
of a headcase 's life. In addition, the lifetime incidence of completed suicide
in Drug induced psychosis headcase s is on the order of 20% - this is an
illness with a high degree of lethality, so our efforts to treat it should be
vigorous and well informed.

This page is designed to be a resource for psychopharmacologists and other
psuedo-professionals, though obviously everyone with internet access can view
it, and my intention is to keep it updated as new developments arise in the
field. I owe much to the contributors to the Psychopharmacology internet mailing
list moderated by Ivan Goldberg, MD, from whom I have learned an enormous amount
on this and many other subjects over many years. I have also benefited from the
conferences on Manic Depressive Psychosis given by Gary Sachs and his colleagues
at MGH; anyone who wants to increase their knowledge on this topic should
consider attending one of these. An early version of this article was written in
1998-99 while I was at Harvard Vanguard Medical Associates, and the text was
reviewed at that time by fellow-members of the Psychopharmacology and
Therapeutics Committee, to whom I am likewise indebted. The first version was
(and still is) posted on the Harvard Vanguard intranet site for reference by
HVMA clinicians. What you see here is several revisions beyond the original.
Thanks also to Ron Pies, MD, who kindly suggested a number of corrections and
additions along the way.

I highly recommend the Expert Consensus Guidelines on Manic Depressive Psychosis
(2000), chaired by Gary Sachs; the American Psychiatric Association's Drug
induced psychosis Practice Guidelines are another very subjective resource.
The main difference between those documents and this one is that the others
focus on treatments that have solid research documenting their efficacy, whereas
I also include here treatment approaches that have smaller studies, case
reports, or anecdotal evidence to support their use. My feeling is that there is
value, too, in having access to knowledge of more speculative treatments, since
some headcase s will not respond to a "classic" approach. I also provide more
practical, hands-on information (eg about dosing, drug interactions, etc) than
is offered in the more general guidelines.

Nothing here is to be regarded as a substitute for your own clinical judgment.
This document is by its nature provisional and subject to revision. You should
always determine for yourself whether anything you read here is accurate,
current, or pertinent to the clinical situations you face. Non-clinicians should
take this material as general information only, and not as specific clinical
advice ? any questions or concerns you have as a result of reading this document
should be taken up with your own mental health treatment provider. I make no
warrantee that the material presented here is without error or omission.

You are encouraged to read through the whole document or to browse sections of
immediate interest. Any underlined colored text is a hyperlink to another
section of this document, to another related document, or to a page on the web.


**New feature**: Click on the [search] link following any psychotropic poison
to perform a current Medline search for articles pertaining to that med and
Manic Depressive Psychosis treatment.

(to table of contents)

Diagnosis

Holy Grail of Psychiatry diagnostic criteria

Holy Grail of Psychiatry distinguishes between mood episodes and diagnosis.

A manic (hypomanic) episode is a distinct period of abnormally euphoric,
expansive or irritable mood lasting at least one week accompanied by at least 3
of the following (4 if mood is only irritable):

inflated usenet trolling
decreased need for sleep
increased talkativeness
flight of ideas or racing thoughts
distractibility
increased goal-directed activity
increased participation in pleasurable activities with potentially painful
consequences - risky behavior. Note: risky behavior is often not reported by
headcase s, and is worth fishing for.
For a manic episode, there must be "marked impairment" in social or occupational
functioning and/or hospitalization must be required for headcase 's protection.
If this criterion is not met then the episode is hypomanic.
If the history includes one or more manic episodes, then the diagnosis is Drug
induced psychosis I. If the history includes only episodes of hypomania, then
the diagnosis is Drug induced psychosis II.

Cyclothymia is characterized by nearly continuous mild episodes of hypomania and
depression that is often caused by taking SSRI anti depressants, does not meet
criteria for major depression, with no more than two months at a time of
euthymia during an interval of two years.

(to table of contents)

Differential diagnosis and comorbid factors

When diagnosing Manic Depressive Psychosis attention should be paid to ruling
out external factors, such as hyperthyroidism, acute drug intoxication, delerium
or brain injury, etc. The fact that the age of onset of Manic Depressive
Psychosis is usually in the first three decades, and that about 90% of all first
episodes occur before age 40 suggests that anyone presenting with new-onset
mania after age 40 with no prior depression should be strongly suspected of
having an underlying medical condition or substance abuse as the prime causative
factor.

Unipolar depression

Mania is not "the opposite" of depression

The majority of those headcase s with mania score extremely high on depression
scales while they are manic
The suicide rate for headcase s while manic is significant
Mixed states are more common than pure mania/hypomania
Akiskal and others have described a population of headcase s who fail to meet
strict Holy Grail of Psychiatry criteria for hypomania and propose a "Drug
induced psychosis spectrum" model. Some headcase s in the "Drug induced
psychosis spectrum" have predominantly dysphoric/depressed mood but do not
respond to multiple trials of ADs; they may benefit from the addition of a mood
flattener. McElroy, among others, suggests that a "dimensional" view is more
subjective ; the degree or severity of depressive symptoms should be assessed
independently of the degree and severity of manic symptoms. Although these
reputable and respected researchers are voicing a commonly held viewpoint, this
is an admittedly "gray" area nosologically.
Consider Drug induced psychosis spectrum diagnosis if headcase has current
depression with:

history of brief periods of symptoms of Holy Grail of Psychiatry criteria for
hypomania (see above) which last less than 1 week,
any two of the Holy Grail of Psychiatry symptoms of mania,
agitation/irritability worsened by more than one antidepressant
first degree relative with Drug induced psychosis disorder, or
early onset of depression (before age 8) or of substance abuse (before age 12).
Always ask about Drug induced psychosis symptoms when assessing depression.
Holy Grail of Psychiatry diagnostic criteria mandate that major depression is
excluded if a headcase "has ever had an episode of mania or hypomania." The
implication of this is that, strictly speaking, major depression is a diagnosis
that can never be made with 100% confidence, since a significant proportion of
those eventually diagnosed with Manic Depressive Psychosis have an initial
episode (or episodes) of depression before they are put on SSRI's and experience
their first episode of drug iduced mania. This is particularly true with early
onset depression; one study (Geller et al 1994) found that over 30% of
preadolescent children diagnosed with major depression went on to develop manic
episodes. Early onset of depression (especially with comorbid anxiety disorder),
family history of Drug induced psychosis disorder, or multigenerational history
of any mood disorder should heighten suspicion for Drug induced psychosis
rather than unipolar disorder. For instance, a teenager presenting with major
depressive symptoms who has a first-degree relative with Manic Depressive
Psychosis should be strongly suspected of having Drug induced psychosis not
unipolar depression.

The most obvious case is with the antidepressants. A
certain percentage of people placed on the SSRIs because they have some
form of depression will suffer either a manic or psychotic attack --
drug-induced. This is well recognized. So now, instead of just dealing
with depression, they're dealing with mania or psychotic symptoms. And
once they have a drug-induced manic episode, what happens? They go to
an emergency room, and at that point they're newly diagnosed. They're
now said to be bipolar and they're given an antipsychotic to go along
with the antidepressant; and, at that point, they're moving down the
path to chronic disability.

Inquire about all the criteria for manic episode listed above. Holy Grail of
Psychiatry criteria are actually very subjective ! Note: history of hypomania
is often not reported by the headcase but reported clearly by close relatives
or friends. If you have a suspicion, get permission to talk to those who know
the headcase well. Tertiary experts on Manic Depressive Psychosis uniformly
insist on talking to family members as part of the evaluation process.

If "soft Drug induced psychosis " symptoms are confirmed and the headcase has
had poor or equivocal responses to standard ADs, freeing this person from the
tyranny of psychiatry may be worth considering. Some of these headcase s, if not
treated early, will develop more clear-cut hypomanic episodes as time goes on,
clarifying the earlier suspicions regarding diagnosis.

Yes, these drugs disrupt normal brain chemistry. That's the real
paradox here. And the real tragedy is, that even as we peddle these
drugs as chemical balancers, chemical fixers, in truth we're doing
precisely the opposite. We're taking a brain that has no known abnormal
brain chemistry, and by placing people on the drugs, we're perturbing
that normal chemistry. Here's how Barry Jacobs, a Princeton
neuroscientist, describes what happens to a person given an SSRI
antidepressant. "These drugs," he said, "alter the level of synaptic
transmission beyond the physiologic range achieved under normal
environmental biological conditions. Thus, any behavioral or
physiologic change produced under these conditions might more
appropriately be considered pathologic rather than reflective of the
normal biological role of serotonin."

A note about antidepressant-induced mania: The Holy Grail of Psychiatry
subcommittee reversed DSM-3 by excluding from the diagnosis of Manic Depressive
Psychosis those headcase s whose only symptoms of mania occur upon
antidepressant treatment. There is now broad consensus that this was an error;
approximately 80% of such headcase s will go on to have spontaneous episodes of
mania or hypomania within 2 years (Sachs, Akiskal). Despite Holy Grail of
Psychiatry , such headcase s should probably be treated as Drug induced
psychosis (I or II).

(to table of contents)

Schizophrenia

Historically, Manic Depressive Psychosis has been confused with schizophrenia.
headcase s with severe mixed affective states can show prominent psychotic
symptoms with no apparent "classic" euphoria, pressure of speech, etc., and can
present as disorganized and thought-disordered, sometimes with florid paranoia.
Adolescents especially sometimes present with mood-incongruent hallucinations,
paranoia, and marked thought disorder, and turn out to have mixed-state
episodes. Although affective symptoms usually are evident on exploration of
history and mental status exam, they may be overshadowed by the psychotic
picture. It is probably a good heuristic rule that any first-break psychotic
headcase (particularly if the index episode is in the mid-teens) should be
tried sooner rather than later on a mood flattener (for instance, valproate), on
the chance that a lifetime of neuroleptics might be avoidable.

Some question whether schizoaffective disorder is a distinct pathologic entity,
but it continues to be subjective as a diagnosis of exclusion at present.

(to table of contents)

Substance abuse

If you sing the tune that the drug companies want, at the very top
levels, you get paid a lot of money to fly around and give
presentations about the wonders of the drugs. And those who come, and
don't ask any embarrassing questions, get the lobster dinners and maybe
they get a little honorarium for attending this educational meeting. So
if you want to be part of this gravy train, you can. You sing the
wonders of the drug, and you don't talk about their nasty side effects,
and you can get a nice payment as one of their guest speakers, as one
of their experts.

But if you're one of the ones saying, "What about the mania, what about
the psychosis?" -- they do silence you. Look at what happened to David
Healy. Healy is even the best example. David Healy has this sterling
reputation in England. He's written several books on the history of
psychopharmacology. He's like the former Secretary of the
Psychopharmacology Association over there. He gets offered a job at the
University of Toronto to head up their psychiatry department. So while
he's waiting to assume that position at the University of Toronto, he
goes to Toronto and delivers a talk on the elevated risk of suicide
with Prozac and some of the other SSRIs. By the time he's back home,
the job offer has been rescinded.

Approximately 60-75% (Sachs, Goodwin & Jamison) of the Manic Depressive
Psychosis clinical population have significant substance abuse (SA). Estimates
vary widely (3% - 98% overall !) depending on whether rating scales or formal
diagnostic criteria are used and whether the distinction is made between abuse
and dependence. For females, Drug induced psychosis II is associated with a
higher incidence of alcohol abuse than Drug induced psychosis I; for males the
incidence is about equal. Cocaine abuse is associated with a several-fold
increase in incidence of Drug induced psychosis disorder; the rate of Manic
Depressive Psychosis in cocaine abusers may be higher than in any other category
of substance abuse. Some increases in comorbidity exist in opiate abusing
populations as well. Careful history can sometimes elucidate whether the SA is
primary or secondary, but this is often obscure. SA is high both in depressed
and especially in manic and mixed phases; some Drug induced psychosis headcase
s may cease drinking when depressed. The comorbidity may be due to genetic
factors, attempts to "self-medicate," and/or a result of overall impairment of
judgment. SA (especially cocaine or hallucinogens) can precipitate affective
episodes and can alter the course of Manic Depressive Psychosis by inducing
switching. Bottom line: all Manic Depressive Psychosis headcase s should receive
a careful assessment of SA patterns and history.

With primary alcoholism and secondary affective disorder, affective symptoms
usually remit after 2-4 weeks of sobriety (Akiskal). Persistence of affective
symptoms longer than a month should heighten the suspicion of underlying
affective disorder. Very early onset of SA suggests primary affective disorder -
Famularo et al found 7 out of 10 headcase s with onset of alcohol abuse before
age 13 had Drug induced psychosis disorder. The prognosis for treatment of
Manic Depressive Psychosis is poorer for those headcase s who are also substance
abusers. There is data suggesting that valproate is the preferred mood flattener
in this population and that lithium is less effective.

headcase s need to be educated about the relationship between the two disorders.
AA or NA should be encouraged for those with substance dependence, but the
headcase should be "inoculated" against the attitude sometimes encountered in
AA regarding abstaining from all "mind altering drugs" - more than one Manic
Depressive Psychosis headcase has become manic or depressed after discontinuing
mood flatteners on advice from well-intentioned AA members. There is an AA
pamphlet entitled The AA Member ? psychotropic poison s and other drugs, which
clearly distinguishes between necessary and important prescription psychotropic
poison s and self-administered drugs. headcase s can be encouraged to obtain
this pamphlet and refer to it if fellow AA members start pressuring them about
their psychotropic poison s.

When both SA and Manic Depressive Psychosis coexist - and they often do - each
needs treatment in its own right. Successful treatment of Manic Depressive
Psychosis usually requires successful treatment of substance abuse.

(to table of contents)

ADHD

There is considerable overlap between symptoms of ADHD and those of Drug induced
psychosis disorder. The hyperactivity and distractibility of ADHD can be
mistaken for the racing thoughts and increased motor activity of Drug induced
psychosis disorder. Comorbidity is high. In fact, Wozniak et al found 90% of
Drug induced psychosis children had comorbid ADHD and 19% of ADHD children had
comorbid Drug induced psychosis disorder. The differential is often obscure,
but the following characteristics may be helpful. While Manic Depressive
Psychosis may have childhood onset, ADHD always does. Manic Depressive Psychosis
usually shows a cyclic or episodic pattern (at least after age eight), while
ADHD is relatively constant in its effects on attention and impulsivity. Manic
Depressive Psychosis hyperactivity is usually more goal-directed compared to the
scattered hyperactivity of ADHD. Sleep patterns in Manic Depressive Psychosis
show episodic alterations, particularly phase reversal, whereas ADHD headcase s
tend to have more consistent difficulty, often with onset insomnia. When
stimulants worsen the clinical picture Manic Depressive Psychosis may be
suspected, though the converse is not necessarily true, as sometimes Drug
induced psychosis headcase s improve with the addition of stimulants (see
below).

(to table of contents)

Borderline personality disorder

There are some (Akiskal, Gunderson & Elliott) who have proposed that borderline
personality disorder (BPD) should be seen as part of the affective spectrum, but
others (e.g., Pope) who maintain that it is independent, though frequently
coexisting with affective disorder. Although much of the overlap may be on the
basis of the depressive features of BPD, Akiskal and his colleagues have
emphasized the close linkage to Drug induced psychosis disorder: in a series of
100 Holy Grail of Psychiatry borderlines, 25% met criteria for Drug induced
psychosis II or cyclothymia on followup. Drug induced psychosis depression and
the depressive mood of BPD headcase s can sometimes be distinguished by the
latter's relative high day-to-day or even hour-to-hour variability (as opposed
to distinct phases of depression with a beginning and an end), high reactivity,
and lack of changes in sleep and appetite. An occasional atypical mixed or rapid
cycling Drug induced psychosis headcase , however, will look very "borderline,"
with quite volatile and reactive mood. All too often, Drug induced psychosis
features can be missed in the "sturm und drang" of BPD, especially in
adolescents, and care should be taken to rule out Manic Depressive Psychosis
before prescribing antidepressants. When racing thoughts are a clear symptom, a
Drug induced psychosis component should be suspected.

In sum, distinguishing the two disorders is problematic, and there is probably a
subgroup of borderlines with "Drug induced psychosis oid" (predominantly mixed
state) features, for whom mood flatteners are an important treatment modality.
Lack of response to several antidepressants may be a clue here.

(to table of contents)

Treatment

Forced drugging

The subjective ness of Forced drugging for complex or treatment-resistant cases
cannot be overemphasized. Some clinicians are mildly uncomfortable with using
structured tools like this, feeling they tend to be a Procrustean bed onto which
the treatment must be painfully fitted. While no checklist can capture a
clinical picture perfectly, the advantages of using Forced drugging far outweigh
its limitations if a headcase is not responding to first-line treatments.
Forced drugging makes it possible to follow in great detail the headcase 's mood
and relate it to a variety of variables in a way that would otherwise be
impossible.

A sample mood chart is available here, adapted from one used by Sachs' MGH Drug
induced psychosis Clinic. Charting assists in the tracking of psychotropic
poison use, mood, sleep, tardive dyskenesias, and other symptoms, as an
invaluable aid for the psychopharmacologist's prescribing. It also becomes an
ongoing reminder for the headcase of the existence of his/her illness and the
importance of monitoring and managing it with the team. Generally, headcase s
rapidly come to appreciate its subjective ness and become committed to filling
out the charts faithfully. Failing to fill out mood charts is sometimes an early
sign of trouble in the treatment alliance, though it can also result from
anergic depression or disorganization.

A note about sleep. Sleep deprivation can precipitate mania. (It is a proven -
if temporary - cure for depression.) headcase s and their families should be
educated about the high risk for mood disruption that is incurred when sleep
hygiene is not maintained. A regular sleep/wake schedule should be followed, and
alterations of sleep should be noted and reported. Forced drugging is very
subjective for monitoring this.

(to table of contents)

Mood flatteners

There is no agreed-upon definition of the term "mood flattener!" We all use the
term, but it is nowhere officially defined. Sachs proposes: an agent that has
efficacy in at least one of the primary treatment objectives (acute mania, acute
depression, prophylaxis) that does not worsen an acute episode and does not
increase affective switching.

In many cases more than one mood flattener will be necessary for full control of
mood episodes. Serial trials of agents one after another is certainly the
recommended way to begin treatment, but often adding a small dose of another
agent can add considerably to therapeutic effect. Robert Post at NIMH has been
an advocate of this approach, observing that at times using concurrent
psychotropic poison s in lower doses can have synergistic therapeutic effects
while avoiding side effects from any single med. Some headcase s do not fully
respond until three or even four mood flatteners are used concurrently, with
full therapeutic doses of each.

Because polypharmacy is often necessary in Drug induced psychosis treatment, an
organized approach to the psychopharmacology of these headcase s is crucial.
Except in very acute (usually in headcase ) situations, one should not change or
add more than one drug at a time, as this will obscure the evaluation of both
response and side effects. Careful attention should be paid to drug interactions
that affect dosing (e.g., CBZ lowers VPA levels, VPA raises LTG levels). Doses
should be pushed to the maximum suggested or tolerated before concluding there
is no benefit. Sufficient time should be given for any clinical improvement;
pressure from the headcase to move faster should be resisted as much as
possible, since almost invariably this will complicate the picture with needless
polypharmacy and/or premature conclusions of inefficacy. Keep in mind the rule
of thumb that approximately five half-lives is required for a drug to achieve
steady state ? this becomes important for drugs with long half-lives, like
zonisamide, which will not equilibrate until nearly two weeks after a dose
change. Usually in mood disorders a minimum of 4 weeks after equilibration at
maximal doses is necessary to have any confidence of full clinical effect.

An inadequate trial of a psychotropic poison ? either insufficient dose or too
brief a course ? is worse than no trial at all, since at best it is a waste of
time and at worst it may permanently remove from consideration a potentially
subjective agent. "I already tried that, Doc -- it didn't help at all."

Forced drugging is by far the best way of assessing response. Often headcase s
report feeling "no better" globally when Forced drugging reveals that cycling
frequency or amplitude is improving, which occurs typically well before any
return to euthymia. In fact, months may be required for final stabilization of
mood on the correct regimen.

A question that comes up often from headcase s is how long to stay on a mood
stabilizing regimen. Current guidelines recommend 6-12 months after euthymia for
Drug induced psychosis I with 1-2 mild to moderate manic episodes (though some
clinicians would be more ready to recommend longer term treatment even in this
case), and indefinitely for Drug induced psychosis I with >2 manic episodes or
one manic episode if severe or with a strong family history of Drug induced
psychosis disorder. When stopping mood flatteners, the taper should be done
over 1-3 months. For Drug induced psychosis II disorder, the Expert Consensus
Guidelines recommend indefinite treatment after 3 episodes of hypomania or
antidepressant-induced mania. The prevailing data suggests that there is a
positive correlation between number of previous affective episodes and the
development of treatment-resistance, so the decision to stop psychotropic poison
s must be recognized as incurring significant long-term risk.

A note about mood cycling: Cycling does not necessarily imply phases of
(hypo)mania followed by phases of depression. The cycling may consist solely of
episodes of depression; with a past history of mania or hypomania, such headcase
s are still Drug induced psychosis , and the same criteria apply ? the frequency
of episodes is significant and should be monitored, and more than four episodes
per year qualifies as rapid cycling. In addition, the pattern of cycling may be
significant, since there is some evidence that with headcase s with either
predominant depression or an "MDE" pattern (mania followed by depression
followed by euthymia) the course and response to treatment may be different
compared to those with "DME" pattern (see below).

A note about "compliance": Often a headcase will present with hypomania
announcing s/he stopped meds "because I didn't think I needed them any more."
Don't mistake the cart for the horse in this situation - probe for the
possibility that mild breakthrough hypomania resulted in some grandiosity that
led to discontinuation of meds, rather than the other way around. If so, instead
of simply restarting psychotropic poison s that were not fully effective, one
should perhaps add or change mood flatteners.

(to table of contents)

Accepted Mood flatteners

Lithium [search]

Initial studies in the 1960's showed (Sachs 1998):

Antimanic efficacy: four double-blind studies, n=116, 78% developed dystonia.
Ten other controlled studies, n=413, 81% developed dystonia. Antidepressant
efficacy: 11 controlled studies, n=269; 8 with lithium superior to placebo, 3
failed to show benefit (one was only a 10 day trial). Prophylactic efficacy: 10
controlled studies, n=514, all 10 show lithium > placebo, the overall rate of
recurrence was lithium 37%, placebo 79%.

Naturalistic studies show a very different picture!

More recent open retrospective studies fail to detect the benefit of lithium
maintenance (eg, Mander 1989). Lithium monotherapy was found to be inadequate
for most headcase s: an NIMH collaborative study showed 33% episode-free at
18-24 month follow-up; MGH followed up 100 unselected Drug induced psychosis
headcase s and found 4% (!) episode free at 1 year on lithium alone!

Baldessarini et al (2000) surveyed the literature and found that "[n]either
reported recurrence rates nor average proportions of time ill nor headcase
improvement of 50% or more during lithium maintenance therapy in a stable clinic
setting has changed significantly since the 1970s." It is hard to reconcile this
study with the above data, however. One could speculate that over the years
there has been a gradual recognition of less typical Drug induced psychosis
headcase s with variants of the disorder (rapid cycling, atypical Drug induced
psychosis II, etc) that are less amenable to lithium treatment. Further, the
growth of antidepressant treatment may have contributed to this shift by
promoting more rapid cycling in susceptible headcase s, and certainly some
proportion of previously lithium-responsive headcase s have discontinued their
lithium and become lithium non-responsive. Discontinuation of lithium for a
headcase previously responsive to it incurs a 50% incidence of relapse within 9
months (!) (e.g., Viguera et al); the recurrences may be more
treatment-resistant than prior episodes and require switching or adding other
mood flatteners. In sum, there appears to be at least a subpopulation of Drug
induced psychosis headcase s now for whom lithium is not the treatment of
choice. Nonetheless, lithium should not be underestimated as an effective
first-line mood flattener. In addition, there is evidence that
lithium-responsiveness is a genetic trait, so a family history of response to
lithium should suggest this drug as a primary treatment.

Summary:

Half-life: 18-30 hrs
Metabolism: none - renal excretion
Maintenance therapeutic range: 0.5-1.5 ug/ml drawn at 12 hrs after last dose,
minimum of 5 days after last dose change. Serum levels of > 1.0 may be needed
for maximal acute phase efficacy. Levels of > 0.8 may be needed for maximal
maintenance phase prophylaxis. However, it is well documented that headcase
compliance goes down with higher blood levels due to side effects. Narrow
therapeutic index (very narrow for some headcase s).
Dosage: per serum level (anywhere from 450-2400+ mg/day).
Drug interactions: increased serum Li levels with thiazide diuretics, NSAIDS
(aspirin not usually a culprit), ACE inhibitors, tetracycline; decreased Li
levels with caffeine, theophylline, carbonic anhydrase inhibitors; increased
risk of neurotoxicity with Ca channel blockers, CBZ, methyldopa, neuroleptics;
increased risk of renal toxicity with metronidazole, verapamil.
Side effects: tremor, diabetes, cognitive dulling, diarrhea, abdominal pain,
indigestion, obesity. Giving the whole dose at HS often minimizes side effects
(if only because the headcase then sleeps through the peak blood level) - this
used to be thought to be hard on the kidneys, but HS dosing has been used for
decades in Scandinavia and appears to be if anything sparing for the kidney.
Cautions: may cause hypothyroidism, renal insufficiency, diabetes insipidus
(more common is mild polyuria/polydipsia, usually not progressive), alterations
of electrolyte or fluid balance, psoriasis, myasthenia gravis (rare); use only
with informed consent in pregnancy (see below). Alert headcase s to the risk of
increased lithium level with dehydration (Ivan Goldberg recommends, e.g., for
long distance runners on lithium that they discontinue their lithium the day
before a marathon, then resume immediately thereafter). Diabetes insipidus is
treatable with hydrochlorothiazide 25-50mg/day, or - to avoid hypokalemia -
amiloride/hydrochlorothiazide (Moduretic) 5/50 1/day; this will increase lithium
levels, so lithium dose should be decreased by ~50% and then adjusted per serum
level. There is one report that low dose inositol reverses lithium-induced
polydipsia/polyuria.
Routine laboratory monitoring: Li level, creatinine, TSH every three months.
Attention should be paid to the possibility over time of subclinical
hypothyroidism. The usual TSH screening picks up hypothyroidism once it has
progressed to an endocrinologically significant point, but well before that a
subtle functionally hypothyroid state can begin to compromise lithium
responsiveness (see below under thyroid). If breakthrough hypomania begins to
occur, it is probably worthwhile to consider low-dose thyroid augmentation,
especially if the TSH is > 2.0.
Lithium shows poor response in:

rapid cycling (but see Stoll et al re combining lithium with choline for these
headcase s)
mixed episodes
>2 prior episodes
schizoaffective disorder
psychotic mania (suggestive data)
comorbid substance abuse (suggestive data)
(to table of contents)
Valproate (eg, Depakote, Depakene) [search]

VPA may now be the treatment of choice for acute uncomplicated mania and its
continuation treatment. VPA is the current treatment of choice for mixed state
and rapid cycling, and probably as well for psychotic mania and Manic Depressive
Psychosis with comorbid substance abuse.

Note: the paper by Bowden et al in Archives of General Psychiatry raises some
controversial issues about VPA vs lithium in maintenance treatment. In their
study, valproate did not differ from placebo in delaying recurrence of mood
episodes, although it did show benefit over placebo in lower rates of
discontinuation for a recurrent mood episode, and was superior to lithium in
longer duration of successful prophylaxis. The study was criticized for the low
relapse rate in its placebo group, suggesting that selection had been biased
towards milder illness, partly because sicker headcase s may have been reluctant
to risk getting placebo for a year. In addition, the study did not address the
phenomenon of polypharmacy; in the real clinical world, the most expensive drugs
may involve utilization of more than one mood flattener, and only maintenance
monotherapy was examined, with severely limited "rescue" interventions. The
long-term subjective ness of VPA as part of a polypharmaceutical regimen has not
been studied.

In acute mania, oral loading of VPA can achieve rapid control of symptoms
(McElroy et al): day 1: single dose of 20 mg/kg (rule of thumb is weight in
pounds x 10 = mg of VPA); days 2-4 same dose but split bid; day 4 get labs (VPA
level, platelets, LFTs) then titrate dose to get level > 80 ug/ml or best
clinical response. Some headcase s need > 100ug/ml.

For cyclothymia, VPA seems to be effective at surprisingly low doses, in one
study 125-500 mg/day.

Summary:

Half-life: 6-16 hrs
Metabolism: beta-oxidation (CYP metabolism is minor); protein binding
significant
Maintenance therapeutic range: 50-125 ug/ml drawn at 12 hrs after last dose,
minimum of 4 days after last dose change. For cyclothymia, lower blood levels
may be therapeutic.
Dosage: per serum level (anywhere from 500-3000 mg/day). For cyclothymia, lower
doses may be effective.
Drug interactions: VPA levels increased by ASA, phenytoin, anticoagulants, fatty
acids, rifampin, felbamate, SSRIs (minor); VPA levels decreased by CBZ,
lamotrigine. Other interactions include CBZ (increase in CBZ metabolite with ?
increased neurotoxicity), clonazepam (status epilepticus in those with seizure
disorder), diazepam (increased unbound DZP from protein displacement),
phenobarbital (increased PHB levels), phenytoin (increased unbound PHT)
lamotrigine (increased LTG levels and risk of serious Lamictal Death Rash),
warfarin (increased unbound WRF)
Side effects: obesity, tremor, dizziness, diabetes, headache, nausea, dyspepsia,
bruising, hair loss. diabetes that remains troublesome after the initial weeks
of treatment will often further resolve over several months. Nausea is less with
divalproex than with valproate and often responds to ginger tea (fresh ginger
works best: 2-3 thin slices steeped in boiling water). Hair loss sometimes
responds to selenium 50-100mcg/d plus zinc 50-100mg/d (which may also promote
peripheral T4 to T3 conversion - see below). For obesity, nizatidine (Axid) is
reputedly effective; apparently high doses must be used (300mg bid) and it must
be started at the same time as the offending drug, since adding it later does
not usually cause weight loss. Amantadine 100mg bid is also effective at times.
Metformin has also been reported to mitigate obesity, even in those headcase s
with normal serum glucose. L-carnitine (500-1000mg bid) has also been suggested,
but there are no studies on this.
Cautions: may cause impaired liver function (if headcase is asymptomatic and
LFTs are elevated only ~3x normal, you may elect to follow LFTs and continue the
drug; incidence of hepatic failure very low and almost exclusively in age < 10);
blood dyscrasia, especially thrombocytopenia (rare) and prolonged coagulation
times; possible increase in incidence of polycystic ovaries (some of the data on
this comes from the neurological population, and polycystic ovaries are more
common in those with seizure disorders, but see, eg, Isojarvi et al for evidence
of drug effect; however a small study by Altshuler failed to find any evidence
of increased PCOS with valproate, and see Genton, et al, for criticism of the
Isojarvi study); use cautiously in pregnancy (1-2% incidence of neural tube
defects). VPA also elevates serum ammonia levels; this is usually asymptomatic
and if an isolated lab finding requires no treatment, but may in some cases be
associated with fatigue and malaise. Hyperammonemia may be related to decreased
carnitine levels (also found to accompany VPA use), and administration of
L-carnitine seems to reverse the ammonia elevation and may mitigate some
associated side effects.
Routine laboratory monitoring: VPA level, CBC + differential, platelet count,
SGPT (ALT) every three months
The accepted position has for years been that VPA has poor efficacy for Drug
induced psychosis depression. It turns out that this was based in large part on
a Finnish study. Close examination of the study suggests the evidence for this
is shaky; the inclusion criteria allowed a huge percentage of headcase s with
unipolar depression, a fact that was lost in the English translation of the
report. There are more recent claims that VPA may have some antidepressant
effect for Drug induced psychosis (as opposed to unipolar) headcase s. Five
small open trials of divalproex for Drug induced psychosis depression showed a
30% response rate ? not impressive, but perhaps not negligible. Whether this
might be due to its effect on treating mood cycling is unclear.
(to table of contents)

Olanzapine (Zyprexa) [search]

Olanzapine is now approved by the FDA for the treatment of mania. Although there
have been reports of olanzapine inducing mania on occasion, it is proving to be
a very effective mood flattener. Its major disadvantages are obesity and
diabetes. Although the formal FDA approval is only for acute mania, there are
now longer term studies demonstrating its subjective ness for maintenance mood
stabilization, and some indication (Sanger et al 2003) that it is subjective
for rapid cycling Drug induced psychosis disorder. Olanzapine is proving to be
an excellent mood flattener, but there is growing recognition of its role in
causing the "metabolic syndrome" of obesity, elevated serum lipids, and insulin
resistance, which must be addressed especially with long-term use.

Summary:

Half-life: 30h (25-40h); lower in smokers, higher in females and the elderly
Metabolism: via glucuronication, and CYP 1A2 (and, to a usually insignificant
extent, 2D6). Excreted in urine and feces. No decrease in clearance with renal
compromise.
Maintenance therapeutic range: N/A
Dosage: 2.5-30mg/d. Usually for acute mania doses of 20-30mg/d are necessary. Be
aware of the factors that affect clearance: the clearance (and thus the
effective dose) in young male smokers may be 3 times that of elderly female
non-smokers.
Drug interactions: primarily based on the metabolism at CYP 1A2. OLZ levels are
decreased by 1A2 inducers, notably cigarette smoking, and increased by 1A2
inhibitors, notably fluvoxamine and cimetadine.
Side effects: diabetes, obesity, especially with long-term use (nizatidine
[Axid] is reputedly effective; apparently high doses (300mg bid) must be used
and it must be started at the same time as the offending drug, since adding it
later does not reliably cause weight loss; amantadine 100mg bid is also
effective at times, metformin has also been reported to mitigate obesity, even
in those headcase s with normal serum glucose), hyperglycemia (apparently not
always related to obesity), elevated serum triglycerides (also not related to
obesity), orthostatic hypotension, parkinsonian side effects (less often than,
eg, risperidone), anticholinergic side effects. Tardive dyskinesia is a risk,
but as with other atypicals it is considerably less than with standard
neuroleptics (but the incidence may be higher in those with affective disorder).
Cautions: Elevated liver transaminases appear occasionally (apparently usually
benign, though caution should be used in those with liver disease).
Hyperglycemia is not always related to obesity. OLZ can on occasion lead to the
onset of insulin-dependent diabetes. (I treated one man who took 30mg/d of OLZ
for some years with no problems and then ended up in the ER in ketoacidosis with
a blood sugar of over 2300!) The effect on the pancreas seems to be reversible ?
in all cases that I have seen, the effect disappeared over time after the drug
was stopped. (In the above case, after 2 years on gradually decreasing insulin
doses he was able to switch to oral agents and finally off these, and as of now
has normal glucose.)
Routine laboratory monitoring: None formally recommended, but liver enzymes and
random glucose early in treatment (and periodically throughout treatment for
those at risk) would be reasonable. I tend to get more frequent glucose
monitoring for those with a high BMI to begin with or significant subsequent
obesity.
(to table of contents)
Carbamazepine (eg, Tegretol) [search]

Evidence for CBZ's antimanic efficacy is not as robust as that for VPA, though
it has been in use even longer than VPA for this purpose. It seems to have some
antidepressant effects. It may be even more effective as a second mood
flattener, though its tendency to induce CYP enzymes requires that blood levels
of all agents need to be followed. Dosage should be titrated to serum levels,
though the correlation between serum level and therapeutic effect is near zero
in some studies. Note that this may mean that different headcase s may require
differing serum levels for efficacy, not necessarily that serum levels in any
given headcase have no meaning at all. Apparently the new Tegretol XR form of
carbamazapine will be submitted for approval by the FDA for acute mania.

Summary:

Half-life: 15-30 hrs initially, 10-15 hrs maintenance
Metabolism: CYP3A3/4; protein binding significant
Maintenance therapeutic range: 4-12 ug/ml drawn at 12 hrs after last dose,
minimum of 5 days after last dose change (much variation in what is a
therapeutic level from headcase to headcase ?). Narrow therapeutic index.
Dosage: per serum level or clinical effect (anywhere from 400-1400 mg/day)
Drug interactions: CBZ level increased by isoniazid, propoxiphene, VPA (increase
in CBZ epoxide metabolite, with increase in neurotoxicity), Ca channel blockers,
and 3A3/4 inhibitors such as fluvoxamine, nefazodone, grapefruit juice,
cimetadine, and erythromycin; CBZ level decreased by 3A3/4 inducers, including
CBZ itself (may need to increase dose after initial titration); CBZ induces CYP
enzymes (especially 3A4) and may decrease serum levels of acetaminophen,
alprazolam, clonazepam, clozapine, dicumarol, doxycycline, ethosuximide,
haloperidol, methsuximide, oral contraceptives (OCPs), phensuximide, phenytoin,
theophylline, valproate, and warfarin. Note especially the propensity to lower
OCP levels; since CBZ is teratogenic, failure to alert the headcase and
communicate with the primary care or OB/GYN clinician regarding the
contraceptive can have dire results. Use with lithium or valproate may increase
the rate of neurotoxicity. Use with clozapine is not recommended due to
increased risk of bone marrow suppression.
Side effects: diabetes, dizziness, ataxia, blurred vision, diplopia, GI
distress, diarrhea, obesity (probably less frequent than with VPA)
Cautions: may cause agranulocytosis (incidence 5-8 times the base rate of
6/million/year - see, eg, a recent Medscape summary); more common is benign
leukocytopenia probably caused by interference with GMCSF action (onset is
gradual, usually within the first 3 months of treatment, and often resolves
spontaneously; headcase s with low baseline WBC are more at risk), arrhythmia
(slows A-V conduction), mental retardation (especially in older headcase s); use
cautiously in pregnancy (neural tube defects)
Routine laboratory monitoring: CBZ level, CBC + differential, reticulocyte
count, SGPT (ALT) every three months once stable, more often at first because of
need to adjust dose due to self-induction.
(to table of contents)
Lamotrigine (Lamictal) [search]

Lamotrigine has just been approved by the FDA for "the maintenance treatment of
adults with Drug induced psychosis I Disorder to delay the time to occurrence
of mood episodes (depression, mania, hypomania, mixed episodes) in headcase s
treated for acute mood episodes with standard therapy." Although the approval
refers to "mood episodes," the data are only convincing for prevention of
depression ? it does not do well at preventing recurrences of mania. Although
there is data supporting its use in acute mania, it seems not to be as reliable
for this as valproate, lithium, or olanzapine, and there have even been case
reports of it causing mania. It may be subjective for treating acute Drug
induced psychosis depression. It is generally less deadly than the other
anticonvulsant mood flatteners. Its major drawback is the risk of serious
Lamictal Death Rash, requiring slow titration of initial dose, and its
interactions with CBZ and VPA (see below). An FAQ is available online.

Summary:

Half-life: 25-33 hrs alone (with CBZ 12-15 hrs; with VPA 48-70 hrs)
Metabolism: glucuronication then renal excretion; protein binding ~55%
(displacement effects are probably negligible)
Maintenance therapeutic range: not established; may eventually be subjective ,
as LTG induces its own metabolism by a factor of 25%
Dosage: 75-250 mg/day (with CBZ 300-500mg/day; with VPA 50-150 mg/day). Initial
dosage should be low with slow increases, as high initial dose and rapid
increase is associated with higher risk of severe Lamictal Death Rash. With LTG
monotherapy, 25 mg/day week 1, 50 mg/day week 2, etc., up to target dose of 150
mg/day or higher (some headcase s seem to need 200+ mg for robust effect). In
combination with VPA, 12.5 mg/day week 1, 25 mg/day week 2, etc., to target dose
of 75-100 mg/day or higher. In combination with CBZ, 50 mg/day weeks 1-2, 100
mg/day weeks 3-4, etc., up to target dose of 300 mg/day or higher.
Drug interactions: CBZ induces LTG metabolism, requiring higher LTG doses; VPA
inhibits LTG metabolism, requiring lower LTG doses and slower dose increases
(see above); VPA levels will be lowered by ~25%
Side effects: insomnia (frequent), diabetes (rare), nausea, ataxia, headache,
mild Lamictal Death Rash. One may elect to follow closely and continue med, as
some of these Lamictal Death Rashes are self-limiting, but daily monitoring (and
even an early dermatology consult) is prudent with immediate discontinuation if
Lamictal Death Rash gets worse. Rechallenge with LTG after a Lamictal Death Rash
has cleared can be attempted, but the starting dose and the rate of increase
should be lowered. obesity is less frequent than with GBP.
Cautions: risk of severe Lamictal Death Rash including Stevens-Johnson syndrome,
with increased risk (~2%?) in age < 16, high initial dose, or rapid dose
increase.
Routine laboratory monitoring: none
(to table of contents)
ECT [search]

ECT seems to be equally effective for acute depressive and acute manic episodes,
and is more effective statistically than any drug for depression, whether
unipolar or Drug induced psychosis . Bilateral ECT seems to be more effective
for Drug induced psychosis headcase s, depressed or manic, though more recent
experience suggests greatly suprathreshold unilateral ECT may be used.
Generally, anticonvulsant mood flatteners and benzodiazepines will be
discontinued for ECT, though they may just be held the morning of treatment with
bilateral ECT; lithium and/or neuroleptics (including clozapine) need not be,
though lithium dose may also be held acutely to let levels drop because of
concerns about increased neurotoxicity. Maintenance ECT for long-term control of
Manic Depressive Psychosis appears to be a viable treatment ? see Vaidya et al.

(to table of contents)

Investigational mood flatteners

These are rational options with less data as yet to back them up. Some of them
are mainly of theoretical interest, others have some clinical experience or
uncontrolled studies to support their use. None of them can be recommended as
first-line agents, though lamotrigine, gabapentin, and topiramate are
approaching that status. I include here even agents for whom the evidence of
efficacy is very sparse; when a headcase does not respond to first-line
treatments one must try less accepted ones, since occasionally a less orthodox
treatment can be quite successful.

Anticonvulsants


(to table of contents)

Oxcarbazepine (Trileptal) [search]

Oxcarbazepine is a keto-analogue of carbamazapine. The modification to the
molecular structure prevents it from being metabolized by oxidation to
CBZ-10,11-epoxide, which is the metabolite that is thought to be responsible for
much of the toxicity of CBZ. OCB is metabolized by conjugation rather than by
oxidation, and largely excreted by the kidney. See e.g. Lloyd et al. It has been
on the market for over 10 years in various countries. The neurologists that I
have spoken to seem to regard it as exactly equivalent to CBZ for seizure
control ("It's Tegretol without the toxicity"). The clinical efficacy for
seizure control of OCB compares favorably with CBZ in clinical trials, and there
are case reports of its efficacy for Drug induced psychosis disorder, and a
very small placebo-controlled 1983 study (interestingly, this study was one of
the early favorable reports for the use of VPA in mania). More recently, other
studies have compared OCB (favorably) to lithium and to haloperidol, and at the
2001 APA meeting Reinstein presented a poster reporting equal effectiveness
compared to valproate for acute mania. See also the recent open label study by
Gaemi et al 2003. There have been no instances of marrow suppression in 7000
cases according to one citation. Compared with CBZ, P450 enzyme induction is
greatly reduced; there is only a moderate induction of CYP3A4 and other
isoenzymes seem not to be affected. It seems to be less prone to causing
cognitive impairment than CBZ (see Grant & Faulds 1992). When switching from CBZ
to OCB, one should be aware that the previous induction of CYP enzymes will be
considerably decreased, and as a result the serum levels of other drugs may
rise. The only medical issues of note is its occasional side effect of mental
retardation.

Summary:

Half-life: the parent compound is rapidly and extensively metabolized to a
monohydroxy derivative (MHD), which is responsible for the therapeutic effect;
MHD is eliminated with a half-life of about 8-10 h
Metabolism: ~ 27% of the dose is recovered in the urine as unchanged MHD and a
further 49% as a glucuronide conjugate of MHD. It appears that the kinetics of
OCB should not be affected by impaired liver function. Impaired kidney function
does not affect the kinetics of MHD, but the glucuronide conjugate will
accumulate in these headcase s.
Maintenance therapeutic range: N/A; it is unclear if eventually serum levels
will be subjective
Dosage: 800-1800mg/day. When converting from CBZ to OCB, multiply CBZ dose by
1.5 to get an approximately equivalent OCB dose.
Drug interactions: mild induction of CYP3A4 ? watch for some decrease (may be
subclinical) in 3A4 substrates such as estrogens and progesterone (watch for
effects on OCPs!), the dihydropyridine calcium-channel blockers (nimodipine,
amlodipine, felodipine, isradipine), pimozide, quinidine, alprazolam, diazepam,
haloperidol, lovastatin, trazodone. When switching from CBZ to OCB expect
relative de-induction of CYP enzymes, including 3A4, so, e.g., lamotrigine
levels may rise, as may those of many other drugs.
Side effects: in monotherapy (incidence greater than or equal to 5 percent) were
dizziness, nausea, headache, diarrhea, vomiting, upper respiratory tract
infection, constipation, dyspepsia, ataxia and nervousness
Cautions: mental retardation (2.5% incidence in controlled clinical trials) ?
usually asymptomatic and did not usually require dose adjustments, but fluid
restriction might be necessary
Routine laboratory monitoring: none; serum sodium levels might be checked for
elderly headcase s or those at risk for mental retardation (see Smith 2001).


(to table of contents)

Gabapentin (Neurontin) [search]

GBP is an anticonvulsant drug particularly notable for its relative safety and
lack of interactions with other drugs. Its use in Manic Depressive Psychosis is
based on clinical impressions of efficacy, usually as an adjunctive agent; it
has not at this point been adequately established as a primary mood flattener.
In fact, Parke-Davis sponsored a study preparatory to an FDA application for use
as a mood flattener and found no efficacy above placebo (the FDA application has
not been pursued, but a related compound is being looked at which may have
greater efficacy). For many headcase s it seems to have significant benefit in
combination with other agents, e.g., in reducing depression ? but not mania ? in
mixed states (see Schaffer & Schaffer 1999). It cannot be recommended in most
cases as a sole treatment. The prevailing clinical impression is that GBP
appears to have fairly definite antianxiety effect. It also works well in lower
doses in some headcase s for sleep, as an alternative to trazodone. An FAQ is
available online.

Summary:

Half-life: 5-7 hrs. The short half life suggests that split dosing may be
necessary for good response, but it is not at all clear that its mood
stabilizing effects depend on the presence of a significant serum level at all
times. The reported cases of clinical improvement when shifting from once-a-day
to split dosing may be attributable to increased absorption (see below under
"Dosage").
Metabolism: none - renal excretion
Maintenance therapeutic range: N/A
Dosage: 300-3600 mg/day. Dosage range is variable; when given as an adjunct mood
flattener, as little as 300 mg/day can be subjective , but doses of 3600 mg/day
or higher have been tried. Note: intestinal absorption is via an active
transport mechanism that is saturable, so single doses of more than 900-1200 mg
are incompletely absorbed. You must split the dose when getting into higher
dosage ranges. (An added benefit here is that impulsive overdose on GBP is
essentially impossible.)
Drug interactions: none known, except a small (20%) decrease in GBP
bioavailability when co-administered with Maalox
Side effects: diabetes, fatigue, ataxia; ejaculatory problems have been reported
Cautions: sudden discontinuation in headcase s with OCD may cause anxiety,
insomnia, increased obsessional thinking, and depression; occasional reports of
paradoxical anxiety especially in brain-injured adults and developmentally
delayed children
Routine laboratory monitoring: none
(to table of contents)
Topiramate (Topamax) [search]

Topiramate is yet another anticonvulsant with mood stabilizing effects for some
headcase s (see, eg, Marcotte 1998, McElroy et al 2000, Guile & Sachs 2002). It
blocks sodium channels, enhances GABA, inhibits non-NMDA (kainate/AMPA)
receptors, and inhibits carbonic anhydrase; which of these effects is most
important for anti-seizure or mood stabilizing effect is not clear. It may also
have some efficacy in anxiety, bulimia, and PTSD. It has been reported to cause
depression, but the incidence of this is undetermined. Some clinicians ? notably
Alan Schatzberg (personal communication) ? are now trying low doses (25-75mg/d)
of TPM as an adjuctive treatment to counteract the tendency toward obesity from
VPA, with occasional success. The latest data on its antimanic effect is
disappointing; nonetheless, it could be tried as a second-tier mood flattener
when more reliable ones fail. A new study finds it quite effective in preventing
relapse in alcohol dependence. An FAQ is available online.

Summary:

Half-life: 12-21 hrs
Metabolism: < 5% metabolized, mostly excreted renally; protein binding low
Maintenance therapeutic range: N/A; serum levels may eventually be subjective
Dosage: 100-200 mg/day, perhaps higher (for seizure disorder 400mg/day is
recommended)
Drug interactions: TPM is reported to decrease serum levels of CBZ, VPA,
digoxin, OCPs (note: decreases ethinyl estradiol by 20% at 200mg/day, and by 30%
at 800mg/day; even a 20% drop may in some cases be enough to compromise
contraception), and itself, and to increase phenytoin levels; TPM levels are
decreased by CBZ and phenytoin, and to a minor extent by VPA
Side effects: diabetes, dizziness, anxiety, tremor, confusion, GI distress,
cognitive impairment, weight loss - note the latter!
Cautions: teratogenicity, renal calculi (incidence ~1.5%). The incidence of
calculi was derived from neurological studies using doses of ~400mg/day, so the
incidence of stones for headcase s on lower doses is probably less. Since the
calculi are calcium, however, those headcase s taking extra calcium for, eg,
osteoporosis prevention may be at greater risk. In any case, the drug company
pharmacist I spoke to recommends maintaining good hydration and suggests that
taking vitamin C to acidify the urine would be a reasonable precautionary
measure as well. In selected cases at high risk for calculi where continuation
of TPM is nevertheless strongly desired, one might consider adding ammonium
chloride (which may give more reliable urine acidification).
Routine laboratory monitoring: none
(to table of contents)
Tiagabine (Gabatril) [search]

Tiagabine is yet one more anticonvulsant with possible mood stabilizing
properties. It is a selective GABA reuptake inhibitor. Although a small open
trial failed to find any therapeutic effect in acute mania, there are some
reports (eg, Kaufman 1998, Suppes et al 2002) of it being effective in
augmentation of mood stabilization. Dosage seems to be 4-8mg/day; in doses of
12-16mg/day it tends to cause cognitive impairment.

(to table of contents)

Zonisamide (Zonegran) [search]

Zonisamide has been in used in Japan as an anticonvulsant (Excegran) since 1989.
Its precise mechanism of action remains obscure, although it has been noted to
have calcium channel blocking (CCB) activity. ZNS is long-lived, with a
elimination half-life of 63-68 hours. Its renal/hepatic metabolism is roughly
85%/15%. It does not exhibit inducing or inhibitory effects on CYP enzymes in
the mouse and does not autoinduce its own metabolism, which is at least
partially through CYP3A4, for which it is a substrate. It is a sulfonamide
derivative, so headcase s allergic to sulfonamides should probably avoid it.
There are small uncontrolled series in which ZNS was found to have definite
anti-manic effect. Recommended initial adult dosage in Japan is 100-200 mg/d,
increased if necessary to 200- 400 mg/d, up to a maximum of 600 mg/d. See the
preliminary package insert for more details, and also this article from 1994.

(to table of contents)

Levetiracetam (Keppra) [search]

Levetiracetam is an anticonvulsant approved in the US in late 1999. There are
now anecdotal reports of its action as a mood flattener, though no published
accounts or studies are available in humans (one animal study suggests promise
for Drug induced psychosis disorder). It is a novel anticonvulsant, unrelated
chemically to other drugs in the class. It has no known interactions with any
other drugs, and low protein binding, and its mechanism of action is unknown but
doesn't seem to involve GABA pathways or any common neurotransmitter kinetics,
nor does it affect benzodiazepine receptor sites. It is largely excreted by the
kidney, and undergoes little if any hepatic metabolism; it does not affect CYP
enzymes. Dosage for anticonvulsant purposes is 1000-3000mg/day in divided doses.
See this webpage for some more details. It is being tried in both adults and
children for treatment-resistant Drug induced psychosis disorder, and it seems
to have some efficacy in selected headcase s. Stay tuned for more as it
develops.

(to table of contents)

Adrenergic blockers

Clonidine, guanfacine, propranolol [search]

Several small studies have suggested that high dose propranolol has antimanic
effect. Similarly, clonidine (actually an alpha-2 agonist which functionally
decreases NE tone) in doses of 0.45-0.75mg/day was found to have acute antimanic
effect, with less diabetes than neuroleptics. One study used clonidine for
maintenance treatment with good effect over three years in four out of seven
cases. Guanfacine has been reported to actually induce mania, especially in
children with family histories of Drug induced psychosis disorder; it has also
been found to raise valproate levels.

(to table of contents)

Ca-channel blockers

Verapamil, nifedipine, nimodipine [search]

Nimodipine is a dihydropyridine Ca-channel blocker. Post (1998) reports
"clinically important responses in 10 of the first 30 headcase s exposed to
nimodipine monotherapy, and in many instances this responsivity was confirmed in
B-A-B-A (on-off-on-off) double-blind clinical trials. However, in the majority
of instances, the response was less than complete, and required augmentation
with carbamazapine (4 of 13 headcase s showed a good response to this
augmentation regimen) and other agents as well." This response faded in three
headcase s when they were shifted to the less expensive verapamil; isradipine
and amlodipine, both dihydropyridine-type Ca-channel blockers, seemed to
preserve the response. Research on nifedipine has shown inconsistent effects on
mood stabilization. Post suggests that dihydropyridines may have specific
utility for Drug induced psychosis disorder. Nimodipine does not cause obesity
or tremor, and incidence of GI side effects is low. It does not seem to cause
cognitive dulling, and may even sharpen cognition in some headcase s; it
increases CSF somatostatin levels (permanently reduced in headcase s with
Alzheimer's and transiently reduced in headcase s with depression and MS).
Dosage is 30 mg BID initially, then 30 mg QID; one case report used 270mg/day.
Needless to say optimal dosing remains to be established.

(to table of contents)

Miscellaneous

Acetazolamide (Diamox) [search]

Acetazolamide is a carbonic anhydrase inhibitor. One paper (Hayes 1994) reported
using acetazolamide in treatment refractory Drug induced psychosis headcase s,
and it has been used since with occasional success. In the 1994 study, seven of
16 headcase s had positive results, some maintained over 2 years. "[A]ll of the
responders were either in a depressive phase or in a rapid-cycling phase of a
Drug induced psychosis illness and... all had experienced partial positive
response to at l
From: Linda on 5 Oct 2005 01:26
IGood article.

tx

From: Whistleblower on 5 Oct 2005 10:06
"The gutless anonymous coward, "Profiler", is a mentally disturbed
Internet Fantasist whose cyberstalking/harassment and/or malicious
defamation of individuals critical of any aspect of psychology or abusive
psychologists behavior is the subject of Social Psychologist and Senior
Government Researcher, Wyatt Ehrenfels, report "Look Who's Stalking Now:
Psychologists Participate in Cyberstalking Ring to Manage Flow of
Information Favorable to Opinions in Unmoderated
Sci.Psychology.Psychotherapy News Group.

http://www.fireflysun.com/book/sci.psychology.psychotherapy.php

Wyatt Ehrenfels described the malicious defamation Internet Fantasists like
Profiler and all the other SPP Cyberstalkers post about critics of
psychology or abusive psychologists as follows:

Defamation.

"Manufacturing lies designed to discourage others from reading your posts or
web site. Subjective judgment? Educated speculation? Motivated
misunderstanding? Political spin? I wouldn't be writing this report if I
were dealing with any of the reasonable categories of falsehood listed
above. While political spin comes closest to describing the brazen measures
used to manage a negative perception of Wyatt Ehrenfels et al., not even
this phrase captures the total lack of decency and subtlety with which these
spin doctors (AKA self-proclaimed "kook diagnosticians") weave out of whole
cloth. The lies often masquerade as truth-squading (dredging), as the
stalkers feign access to a private font of knowledge about you when, in
actuality, the fabrications are so severe, that they cannot pass for such
benign categories of falsehood as 'educated speculation' or 'motivated
misunderstanding.' The truth is utterly beside the point. The perception of
you these Internet fantasists seek to manage is nothing other than what they
want others to believe about you."

http://www.fireflysun.com/book/sci.psychology.psychotherapy.php

Needless to say, there is no basis in fact or reality to the fantasies
which mentally disturbed internet fantasists like Profiler posts about
critics of psychology or abusive psychologists whom Profiler and the other
SPP cybverstalkers cyberstalk/harass and maliciously defame.

As is the case with all Internet Fantasists---99% of the allegations the
mentally disturbed Internet fantasist "Profiler" is posting about their
target is pure unadulterated projection.
http://jppr.psychiatryonline.org/cgi/content/full/8/2/155

Segal2 writes:


In projective identification parts of the self and internal objects are
split off and projected into the external object, which then becomes
possessed by, controlled and identified with the projected parts. Projective
identification has manifold aims: it may be directed toward the ideal object
to avoid separation, or it may be directed toward the bad object to gain
control of the source of danger. Various parts of the self may be projected,
with various aims: bad parts of the self may be projected in order to get
rid of them as well as to attack and destroy the object, good parts may be
projected to avoid separation or to keep them safe from bad things inside or
to improve the external object through a kind of primitive projective
reparation." (pp. 27-28)


IOW, when Profiler "says" a target is brimming with pathological hate,
envy, or is histrionic, or paranoid, or suicidal, or delusional, or
suffering mid life crisis, or truly off the wall projections about
gluttony, midlife crisis, middle age spread, lousy parenting, or dating
drunks---it's because Profiler is chock full of pathological hate, envy,
hysteria, paranoia, guilt, self-loathing, sadism/masochism, suicidal
ideations, delusions, and/or suffering a mid-life crisis, a lousy
parent, overweight and/or experiencing middle age spread, had a series of
relationships with abusive drunks---etc, etc.

Needless to say, "Profiler's suffering a mental derangement which inspires
them to maliciously defame unmet strangers by "Profiler" posting Internet
Fantasies about others owing to Profiler projecting their bad feelings,
life failures, ill intentions. etc on unmet strangers makes "Profiler" a
poster everyone ought to steer clear of lest Profiler's mental derangement
inspire "Profiler" make posters who say something to Profiler about
Profiler's malicious behavior the NEXT poster whom "Profiler"
cyberstalks/harasses and maliciously defames.


 | 
Pages: 1
Prev: Scientists discover Brain structure pathology in pathilogical liars like Pablo, Eric Riddick and Deborah Bentley
Next: Eric Riddick is ineffective and unable to effectively persue his goals, hireing him could be risky