Medication Advantages Disadvantages

full dose Full antidepressant power

Tremor, diarrhea; toxicity ri
lithium (blood levels 0.7 to 1.0)
low dose Good augmenting antidepressant, even in (occasionally not tolerated:
lithium unipolar; 300-600 mg works, few side effects lethargy)
Little inherent antidepressa
Depakote Fast, good antimanic, well known risk profile
compared to lithium
Lamictal Antidepressant, perhaps better than lithium Slow titration required to av
Daytime sleepiness during
Anti-anxiety, pro-sleep, and some
Seroquel risk of weight gain (less tha
antidepressant effects
Zyprexa)
Profound weight gain, wors
Zyprexa Superb when need rapid onset, antimanic
other comparable options, c
So again, how do you decide? Sometimes there are some obvious advantages
you just must have: for a severely depressed patient, lithium is quite fast and
has clear evidence that it reduces suicide risk.Goodwin Or for a really agitated
patient whom you'd like to help right now, Zyprexa can be extremely useful (as
long as you warn the patient about the risks if it ends up becoming a longer-
term treatment; and Depakote can be loaded up quickly to as much as 1500 mg
in 24 hours, with benefit within 24-48 hours, at a much lower cost). For
someone whose predominant symptom is depression, which happens to be the
significant majority of patients with bipolar disorder, lamotrigine now has solid
data supporting its use, as long as the patient can afford to wait a few weeks for
the benefit to show up. For such a patient who also has substantial anxiety and
severe insomnia, Seroquel may be worth jumping earlier in the progression
(weighing against this advantage the greater risk, long term, of metabolic
shifts; start with 25 mg and let the patient decide how fast to go up, and you'll
have fewer saying "I can't take this stuff"). Here is a diagram I use to explain
this to patient/families:

I almost always start by showing a list of all options/pro's/con's to patients. I

like them to know that we have multiple alternatives in case the first one is not
working out. And I watch their faces as we go down the list of advantages and
disadvantages: that will tell you a lot about which medications are simply not
an option, and which are looking favorable.

There are non-pharmacologic modalities for the treatment of bipolar disorder of

which you should be aware (patients will ask). Five bipolar-specific
psychotherapies have randomized trial data supporting their efficacy as
adjuncts to medications; these are reviewed for you here, though there are few
therapists who know about them so far. Other modalities, including exercise
(that link takes you to my not-the-usual-exhortation) and light therapies, are
reviewed for patients on their version of this site under Mood stabilizing without
medications. Fish oil, as a means of delivering omega-3 fatty acids, has one
preliminary study with robust dataStoll and several more recent studies,
summarized here.

Finally, there are adjunctive medications as well. These include

benzodiazepines, which generally should be limited to brief use due to their
potential for dose escalation and tolerance (though some patients demonstrate
sustained benefit without dose increases, perhaps particularly with
clonazepam). Generally antipsychotics are not required nor useful in bipolar II,
though among them olanzapine stands out as above; here is a discussion of the
rest of the newer ones. Except for the expense, Ambien (zolpidem) is an
excellent adjunct for sleep when benzo's are not wise.

Visit by visit plans for primary care treatment of bipolar variations

Here is a general outline of sequential office visits in which you begin treatment
of bipolar II. Details for the use of lithium, valproate, lamotrigine and
oxcarbazepine follow in the next section.

Visit "0" History (presumably accumulating over multiple previous visits)

cyclic depressions (not responding or continuing to respond to

 antidepressants)?
profound, cyclic, sleep disturbance (prior rx with benzo’s, Trazodone, Elavil,
Ambien)?
energy component: cyclic profound anergy, and/or agitation, anxiety,
irritability (prior Buspar)?
difficulty concentrating, problems with memory?
not a candidate for, or has not responded to, psychotherapy?
family history: many relatives with mood problems (or alcohol: less diagnostic
but relevant)?
probable alcohol and/or major caffeine use (more rarely marijuana; rarely
stimulants)?
Visit 1: Explain bipolar II diagnosis

teach patient about the breadth of "hypomania"

request that patient read the patient's version of this site, at least dx/rx
baseline labs: cbc no diff, sgot, creatinine, TSH, fasting glucose and lipids (in
case you use an atypical later)
Visit 2: Start mood stabilizer

review lab results if new or abnormal

review options: lithium, valproate, lamotrigine, quetiapine, carbamazepine,
olanzapine? - for further discussion of deciding between these, read the
 patients' version of Treatment - use Handouts for each as needed in your
procedures/alternatives/risks conference
review instructions on handout re: starting doses, goal doses; no pregnancy!;
write rx
lab instructions if lithium
Visit 3: Mid-course corrections ("The Art of Medicine")

a) assess tolerance of mood stabilizer, adjust to maximize benefits vs. side

effects:
valproate
no benefit at 1250-1500 ER; (reconsider diagnosis yet again, then)
switch to lithium
partial benefit:
if minimal, add lithium if nearly fully improved, go to (b)
weight gain: lower dose until appetite normal; add lithium if benefits
then lost
lithium
side effects troublesome: decrease to tolerable dose by 150mg
increments
no benefit at 900 mg (or maximal tolerable dose)
level <0.8: increase unless side effects already problematic
level >0.8: add VPA to 500mg (titrate q3-7 days using 250mg ER
 tablet)
partial benefit:
if minimal, add low dose valproate (titrate as above)
if nearly fully improved, go to (b) below
lamotrigine
DO NOT get excited and titrate more quickly than per the PI; compare
my titration
leading researchers recommend "get to 200 mg" (as single qd pill);
little reason to use less
if rash occurs below chin, consider dose reduction and continue, if
your derm' skills are good
rash above chin, especially mouth/nares/conjunctivae soft tissue,
carries high risk of SJS
quetiapine (Seroquel)
start with 25 mg; warn patient about daytime sedation but it will
diminish in 4-7 days
then she/he may continue up toward 300 mg; many stop at 25-50
because they're better
lower doses may carry less risk of weight gain and
glucose/cholesterol increases
get your second lab (after baseline) within 3 months; I like around 1
month to catch early changes
 b) if patient substantially improved, begin slow taper of antidepressant
(~25% /month!Sachs(a)) should improve sleep, concentration;
decrease anxiety, irritability
Visit 4: Further adjustments

if any "manic side" symptom, or cycling remains, more mood stabilizer req’d:
increase current medication if not at side effect threshold
add another one at low dose (VPA and lamotrigine interact, watch it; ask
your pharmacist)
or wait, if you and patient can stand it, while tapering AD (which could be
causing cycling)
if depressed only (sleeping too much, no energy, no motivation, no hope)
slow the antidepressant taper rate
show patient the list of 8 antidepressants which aren't antidepressants
if using lithium already, increase to blood level ~1.0 (150-300mg
increments), if tolerated
Specific guidelines for lithium and valproate

Unless you are quite familiar with these agents, I recommend you have a look
at my patient education handouts for lithium and valproate). The following
section will give you more detail on how to use them.

Lithium
Tell your patient: the goal is 100% symptom control, with 0% side effects! There
is tremendous individual variation in susceptibility to side effects with lithium:
some people can tolerate blood levels above 1.2 mmol/L without any side
effects at all (e.g. doses over 1500 mg); others will have intolerable effects with
300mg alone. If your patient has side effects, reduce the dose to a tolerable
level and move on down the step-by-step approach.

Update 2005: For your PAR, you'll need to mention thyroid, kidney and weight
gain risks. Details on all these risks, from a 2005 review of same, can be found
on the Lithium Risks page. You probably know most of this information, but take
that link if you need a refresher. For a more basic review of what you'll want to
discuss with patients about lithium, try my lithium-basics handout.

Start with 300mg slow-release lithium (U.S.: "Lithobid"): it can be cut in half and
thus titrated by 150mg increments if needed; and it is generally much better
tolerated than lithium carbonate. When your patient is doing well, you can try
switching to a generic lithium to reduce costs. Starting with the generic runs the
risk of "giving lithium a bad name" if your patient has a bad reaction that could
have been avoided with a slow-release form. It really makes quite a difference!

Most patients will not reach the toxic range (usually associated with blood levels
of 1.1mmol/L and above) on 900 mg. However, you should alter the handout
instructions and check a level at 600mg if your patient is:
1. hesitant about lithium, or hesitant about medications or side effects in general
(or if you are!);
2. already on valproate (because the lower lithium dose may well be sufficient);
3. taking a medication that may elevate lithium: NSAID’s, ACE inhibitors,
diuretics.
Emphasize the instructions: "do not increase the dose if you are already having
troublesome side effects". Your patient must understand the toxicity risks (e.g.
see handout: "too high a dose"...).

Instructing your patient when to have a lithium level can be complicated for
them (see handout for how I do this). If in doubt, stop at 600mg and have them
check a level 4 days or more later. Generally, if the level on 600 is less than 0.7
mmol/L, severe side effects are unlikely with a 300mg step up. Minor side
effects such as dry mouth and urinary frequency (including nocturia) are
common at almost any level, and generally increase with each dose increase,
but most patients can handle moderate levels of these effects.

There are three side effects that commonly limit lithium dosing before toxicity
sets in:

1. loose stool, progressing to diarrhea

2. tremor
3. mental dulling
None of these is likely to decrease with time: the patient will have to reduce the
dose (try bid or even tid dosing, and make sure you’re using slow-release,
before going down, though).

Lithium is contraindicated if the patient has renal compromise: the levels may
rise unpredictably to the toxic range. A patient who uses NSAID’s, ACE inhibitors
or diuretics intermittently is also at risk of unpredicted toxicity. These
medications are not an absolute contraindication but do raise the patient’s risk
of renal damage, requiring additional caution to insure that levels remain in the
therapeutic range. To my knowledge, COX-II selective NSAID’s have not been
studied re: their effects on lithium levels or renal risk. Finally, and very
important: repeat a TSH every six months at minimum, to catch the very
common hypothyroidism lithium will induce (on the order of 1 in 10).

Valproate

Remind your patient: the goal is 100% symptom control, with 0% side effects!
In general, with slow-release valproate (U.S.: "Depakote") there are very few
side effect problems. About 1/10 will have some nausea when starting, reduced
if the medication is taken with meals. About 1/30 (in my experience) will have
severe nausea. Many in this group can eventually tolerate the medication if the
125mg "sprinkles" are used and titrated up by one pill per week or so, but you
may have difficulty getting the patient to accept the necessity of that approach.
Other than nausea, however, other side effects are very uncommon -- except
weight gain, discussed in detail below.

The handout instructs patients to start quite slowly. For inpatients with severe
bipolar I, a "loading dose" of 20mg/kg is used, thus doses of >1500mg in the
first 24 hours!McElroy et al So you are already using a very slow titration if you follow
the handout. For outpatients with severe symptoms you can start at 1000mg
ER, instead of 500mg ER. Instruct patients to stop increasing if benefits are
seen, emphasizing weight gain risk as the primary reason for keeping the dose
as low as possible.

Many male patients can tolerate 1500 or even 2000mg of valproate and not
gain weight. Few women can, though, and most patients seem to hit a "weight
gain threshold" somewhere around 1000mg. In my experience, using the old
slow release Depakote as opposed to the ER version, more than 50% of women
will gain weight at 1250mg or above (and that is a conservative estimate). Is
this an appetite increase, as patients almost universally experience when
gaining weight? Or is there some metabolic shift? The basis for this problem is
still unknown, but data is accumulating to suggest substantial hormonal shifts
even before weight gain sets in (see the PCOS/Depakote story, which I keep
updated).

Fortunately, the marked appetite increase serves effectively as an indicator for

this problem. I don’t think I’ve seen a patient gain weight who did not
experience the appetite increase (there probably is one somewhere). When
patients lower their dose, they can detect when they fall below the "threshold"
of this effect: their appetite returns to normal, and they do not seem to gain
weight. Thus, the obvious strategy: if patients experience an abnormal appetite,
they should lower their dose until their appetite returns to normal. The
"threshold" seems to lie between 750mg and 1000mg per day for most patients
on the old version. With the new ER version, most patients can take 1000mg
without appetite increase, and many can even get to 1500 although then it's
time to watch closely.

I don’t think I’ve seen a patient who experienced weight gain at 500mg per day
(there probably is one somewhere), if they weren’t taking other medications
that raise valproate levels (e.g. Paxil and other "SSRI’s").

Valproate at 500mg/day is not generally enough for symptom control, but when
combined with low-dose lithium, it can be a very effective medication. And, not
all patients will experience the weight gain problem. Hair loss is also common
when patients hit the weight gain range, but the dose reductions required for
the latter problem generally take patients out of the "hair loss range" as well; it
has not been an independent problem in my experience. You will see selenium
and zinc touted for valproate-induced hair loss, but I have not seen this vitamin
approach (e.g. Centrum Silver has these minerals) have much impact,
especially compared to dose reduction.

Lamotrigine and quetiapineFor basics on these, I'll refer you to the brief
introductions I wrote for patients (lamotrigine, quetiapine). Using them is pretty
straightforward, as you'll gather from the PAR outlines.

Does one really have to minimize antidepressants? (revised 10/2005)

There is strong consensus that antidepressants, especially without mood

stabilizers, carry risk of precipitating manic symptoms in clearly diagnosed
bipolar I patients. The depression gets better, but the "manic" side symptoms
(remember, this can include sleep problems, anxiety/agitation, irritability, and
difficulty concentrating) get worse. The whole mess can start to "cycle" more
frequently, even though the depression is better. In some patients, eventually a
full depression episode occurs again, despite being on an antidepressant, even
one that "worked" before! How often does this occur? How risky are
antidepressants for someone who has only subtle "hypomanic" symptoms -- e.g.
for a person whom some might not even diagnose as "bipolar"?

This is an area of controversy. We have very limited data on which to proceed.

As I see it, clinicians with lots of direct experience in mood disorders are among
the most cautious about using antidepressants. I have met psychiatrists all
over the country evolving this same view through clinical experience. For my
personal view (same as Fred Goodwin, Nassir Ghaemi, and numerous other
well-respected bipolar experts reviewed on that Controversies page), derived
from 5 years of experience with patients referred by PCP's because they were
not getting better on antidepressants or therapy: I find antidepressants are
definitely a risk for many patients. Indeed, for some patients, you can even say
that the antidepressant is causing depression, by making the cycling continue,
including cycling into depression.

In that case, even if a mood stabilizer does not have antidepressant effects by
itself (valproate and carbamazepine/oxcarbazepine appear to lack direct
antidepressant effects) it can work as an "antidepressant" very well, by
stopping the cycling. I have seen this happen many, many times -- so many,
that I routinely rely on the mood stabilizers to help these referred patients, and
taper off their antidepressants, even while they are depressed. Many times it’s
the only way out of the problem (though usually I’ll start the mood stabilizer
with the antidepressant they were already taking still going, then taper off the
antidepressant when it’s clear the person is getting better with the mood
stabilizer). For a further explication of this concept, see the Antidepressants
That Aren't Antidepressants page.

For your purposes in primary care, suffice it to say that antidepressants should
be used with caution in patients who might have a "bipolar component" to their
depression, and tapered if a person is clearly rapid cycling. Beyond that, stay
tuned to the summary of this controversy (see revision date at top; also noted
in "What's New" on the home page here).