Treating Bipolar Disorder

Treating Bipolar Disorder

Hello, and welcome to lecture
number 14, our series on drugs and human behavior. Today we’re going to be
talking about treating bipolar disorder. This is a particularly
difficult, oftentimes, disorder to treat, because
oftentimes people who have bipolar disorder,
while they really hate the depressive parts
of it, they sometimes miss the high
energy, creativity, ideas that come along with the
manic parts of this disorder. So we’ll spend some
time talking about this. There is certainly a
number of resources. If you’re interested in learning
more about bipolar disorder, I highly recommend reading
Carrie Fisher’s autobiography, Wishful Drinking, followed
up by Shockaholic. She talks a lot about what
it’s like to live with bipolar disorder and how she was finally
able to get some treatment. She’s actually a big proponent
of electroconvulsive therapy. It certainly seems to have
helped her a great deal. So when we talk about
bipolar disorder, first thing we have
to do is discuss different classifications
of bipolar disorder. We talked about bipolar
I, which includes at least one episode of
mania, bipolar II, which includes both major depressive
and hypomanic episodes, more depression, lighter
manic episodes. Cyclothymia is a less severe
form of bipolar disorder. And then we have bipolar
not otherwise specified, which usually only
include hypomanias. Now, there’s been some updating
to the diagnosis of bipolar disorder from the
DSM-IV TR to the DSM-5. Includes the same categories,
so I, II, cyclothymia and not otherwise specified. Difference for mixed
episode symptoms are replaced with mixed
features, specifier, used when individuals experience
the full criteria for a mania episode and three symptoms
of depressive episode, or individuals
experience full criteria for depressive episodes
and three symptoms of mania episode. There’s addition of
other types of diagnoses to permit more
latitude in making an appropriate diagnosis,
something like substance medication-induced
bipolar, bipolar related to [INAUDIBLE] medical
condition, et cetera. So there’s much more
leeway and latitude in how to diagnose bipolar
disorder in the current version of the DSM. So when we talk about
somebody being manic or what we sometimes call
hyperthymic temperament, they tend to be very
exuberant, cheerful, overly optimistic and carefree,
overconfident, self-assured, boastful to the point of
being grandiose, exceedingly extroverted and people-seeking,
very high energy level, full of plans, going
to do all this stuff, tend to be overinvolved,
very uninhibited and stimulus-seeking. So they can be irritable. They oftentimes will engage in
excessive high risk activities, including high risk sex, high
risk substance abuse, gambling, stealing. They oftentimes have inflated
self-esteem, flights of ideas. They go from one thing
to the next, oftentimes very distractible, and a
decreased need for sleep. And again, this is
part of the reason why people who are bipolar sometimes
missed this time, because they didn’t need to
sleep and they felt like they were getting
all this stuff done. But unfortunately, it also
comes with the depressive side of this, so it’s
something to keep in mind. So how do we distinguish
the hypomania, which is a lower version of
mania, cheerfulness can switch from irritability– or
to irritability when the person’s crossed, as opposed
to somebody who’s just happy. Their mood is even and
not so easily perturbed. People who are happy
are able to settle down. They can usually a
full night’s sleep. They usually have good judgment. Usually has no predictable
relationship to the depression, and it’s generally not seasonal. So you want to make sure
you’re distinguishing happiness from hypomania. Terms of the epidemiology
of bipolar disorder, it’s relatively rare, around
1% of all populations. Bipolar disorder I relatively
equal for males and females, whereas bipolar
disorder II tends be more common in females. Age of onset– most commonly,
first symptoms at age 15 to 19. Unfortunately, there
is often a long delay, average of eight years before
you get the correct diagnosis and treatment. This disease has a
high mortality rate. 25% to 50% attempt suicide. Around 19% of people succeed. There’s some question about
a number of celebrities who might have had
bipolar disorder, and that might have been
the cause for their suicide or their substance use. So the risk of developing
bipolar disorder is about a half to 1%. Incidence of new
cases per year is about 0.01% for men and
0.01% to 0.03% for women. Unipolar mania
occurs in about 1% of the population
of bipolar patients. And onset is almost always
by the third decade, but can occur later. Again, there seems to be
some variation in this. But if you look at the
age of first symptoms, tends to be about 60%
under the age of 19 have their first symptom. It’s usually another
eight years before they get diagnosed and treated. You can see the largest category
is in that 15 to 19 age range. If you look from 10 to 24,
that is 67% of the population. So really, the bulk of people
are diagnosed in that 10 to 24 year– or get their first
symptoms, sorry– in the 10 to 24-year-old range
and then oftentimes go untreated for a
long period of time. Most patients seek
treatment during their depressive episodes. So there’s often a
significant delay between onset of symptoms,
a correct diagnosis, and treatment. These bipolar spectrum
disorders generally have a stable course over
time, but the suicide rates are very high in
bipolar disorder. And unlike in depression
and the initial phases of bipolar disorder, there
seem to be precipitants. That is, there’s things that
precipitate these events. Only 20% of patients who screen
positive for bipolar disorder actually receive the diagnosis. But 31% receive diagnosis
of unipolar depression, so it’s much more likely it’ll
be diagnosed as depression instead of bipolar disorder. And unfortunately, about 49%
of people with this disorder receive no diagnosis at all. Of those diagnosed
correctly, most were not treated adequately. That is, they would
receive something like an antidepressant without
a mood stabilizer, which is an inappropriate way to
treat this particular disorder. So, a little summary
of these features– you can pause this and
read it in more detail. But you can differentiate
between unipolar and bipolar depression based on a variety
of different clinical features. In terms of predictors
of mortality and outcomes for
bipolar disorder, predictors of mortality include
poor occupational status before their, what we call
indexed episode, the first time they really have
that major episode. So if they haven’t been
working, then there is less likely they’ll do well. History of previous episodes,
history of alcoholism, if their mania includes
psychotic features, if they have symptoms
of depression during their index
manic episode, we call this mixed
mania, that there’s depression mixed in with mania. That’s a poor predictor,
and being male also a predictor mortality. We know that men oftentimes use
firearms in suicide attempts and so are oftentimes
more likely to succeed. And then the between
episode affective symptoms, if they’re really having
a affective disruption between– if they’re
having affective symptoms between episodes, then it’s a
poor predictor of mortality. So what do we treat
bipolar disorder with? Well, there are different
classes of drugs. The classic treatment
in this area is with lithium
salt. Anticonvulsant mood stabilizers are often
used and with efficacy. Some atypical
antipsychotics appear to be effective in
treating bipolar disorder. There is some exploration
of omega-3 fatty acids as a good treatment
for bipolar disorder. But above all else, treatment
is critical for this population. People with bipolar
disorder can lose up to nine years of their life. They can lose up to 14
years of effective activity, 12 years of normal health. 20% to 25% of people who are
bipolar who are untreated will attempt suicide. Suicide completion rates in
patients with bipolar disorder I may be as high as 10% to 15%. 60% have comorbid
substance abuse disorder. So it’s very critical to get
these people into treatment. And most estimates indicate
only about a third people with bipolar disorder are
being effectively treated. So the first drug we’re going
to spend some time talking about is lithium. This is a drug that has been
used for some period of time. So we’ll talk about what it is. We’ll talk about
the history to use, talk about the pharmacokinetics
and pharmacodynamics, talk about its side
effects and toxicity, which is a huge
problem, and some issues in lithium treatment. So what is lithium? Historically, this is
the drug of first choice for treating bipolar disorder. It’s the lightest of
all alkali metals. It has no psychological
effects in healthy people, so there’s no
potential for abuse. It seems to be effective
in treating 60% to 80% of acute manic and
hypomanic episodes. Unfortunately, there
are significant issues with toxicity and compliance. And so oftentimes alternative
treatments are necessary. Lithium chloride
was first introduced as a salt substitute
in the late 1940s, but its severe toxicity has
limited its use for that. Research in the 1970s
determined it was effective in treating mania. Many controlled studies
demonstrate its efficacy in treating mania and depressive
episodes in bipolar disorder. So it is an incredibly
effective drug. Unfortunately, it has such
significant side effects. Treatment with lithium
requires close monitoring. But it really is
the gold standard for treating bipolar disorder. So people who are
taking this drug have to be monitored
very closely to make sure that there is no
damaging toxic side effects. Lithium levels have to be
controlled very closely. So here’s how lithium
is treated by the body. Peak blood levels
are usually reached within three hours of
oral administration, and you get complete
absorption by eight hours. Therapeutic efficacy is directly
related to plasma levels. Although levels are
much lower in the brain, we obviously focused
on plasma levels, because that’s what
we could measure. Lithium is not metabolized. Rather, it’s excreted
unchanged by the kidneys, and a little bit through
the skin via sweat, just like any other salt.
Steady state for this drug is reached after about two weeks. And it has a very narrow
therapeutic range. And this is one of
the biggest problems, is that narrow
therapeutic range. So it has to be
verified by blood levels to make sure you’re
above the threshold needed for treatment but below
the threshold for toxicity. So it’s between 0.6
and 2.0 in the way those lab results come out. Above 2.0 is toxic, so it’s
a very narrow range in there. So there are no
psychotropic effects in healthy patients
from lithium. It seems to be similar to
major depressive disorder. Lithium likely affects the
intracellular processes, so we’re talking
probably about some sort of cellular expression. Appears to have a
neuroprotective effect and possibly a
neurotrophic effect. Untreated bipolar
disorder is associated with decreased cerebral
gray matter volume, so that’s something
to watch out for. So we really want to make
sure that this drug is getting treated. The biggest problem
with lithium is while it is incredibly effective
in treating bipolar disorder, it is also rather toxic. You can get disruptions in
memory and cognition, the side effect that is most is
related to noncompliance. So if we have this
disruption, people are unlikely to
stay on this drug. The risk for side
effects– anything that will decrease
kidney function will affect lithium levels. So reduced renal
clearance can occur. You can get organic brain
disorder, vomiting, diarrhea, certainly no use of diuretics. If there is low sodium intake
and high sodium excretion, all these things
can be problematic. Side effects can include tremor,
cognitive impairment, nausea and weight gain, increased
urination, hyperthyroidism and goiter and toxicity,
because that balancing of lithium levels is critical. So you have to be very
careful with those levels. In terms of issues
in lithium treatment, lithium is a teratogen, so
it is not advised for use during pregnancy. Other drugs should
be considered. Anyone on lithium should
certainly probably be on birth control as well. Side effects often result in
significant noncompliance. And it is most
effective in combination with an anti-epileptic
or an antipsychotic. So lithium on its own is
less effective than when used in combination
with other drugs. There is a pretty
significant study out on this called the LITMUS
test, the Lithium Treatment Moderate-dose Use
Study, intended to answer the question of
whether combining lithium with other mood stabilizers or
second generation psychotics resulted in greater
benefit by using optimized personal treatment
designed to choose the best treatment choices. What they concluded
in the study is that there’s no
difference between groups in measures of change
in psychiatric symptoms. But the lithium add-on
permitted less exposure to second generation
antipsychotics and accompanying side effects. So lithium seemed
to improve symptoms with fewer side effects
by combining those with other medications. So this optimized
personalized treatment seems to be a really
good way to go about picking the appropriate
drug treatment for patients. So while lithium is
one of the drugs that is the gold standard,
bipolar disorder can be treated with
mood stabilizers and other alternatives as well. So let’s start by talking
about mood stabilizers. We’ll talk a little bit about
what these are and then talk about carbamazepine or
tegretol, valproic acid, and then we’ll talk a little
bit about some of the drugs, like gabapentin and
pregabalin and topiramate. So most of these
mood stabilizers were originally developed
as anticonvulsants. They are also
important analgesics. But they are used in
treating bipolar disorder. They’re used to treat
relapse to substance abuse and oftentimes used
as a detoxification agent for alcohol withdrawal
to keep those convulsants and delirium tremens away. They are also used to treat
behavioral dyscontrol and aggressive behaviors in PTSD,
bipolar disorder, and child and adolescent
behavioral dyscontrol. So the point of
using these drugs is for getting neuronal
membrane stabilization is their mechanism of action. Drugs are all similar, but
a little bit different. Some have some
antidepressant effects. Here, we’re focused on
use in bipolar disorder but we’ll also extend our
discussion into other, what we call off-label, uses. So there are often significant
overlap with the newer atypical antipsychotics. Drugs of both groups are
somewhat antibipolar. Drugs of both types treat
aggression and violent behaviors in a
variety of situations. And drugs of both groups
have affective actions that may be beneficial,
that might improve affect. Unfortunately, all
are also teratogens, so this is not an alternative
to lithium for someone who is pregnant. Carbamazepine or Tegretol seems
to be as effective as lithium in preventing manic recurrence. Some patients who do
not respond to either will respond to both,
used in combination. So if lithium didn’t work or
carbamazepine doesn’t work, the two of them together might. Mechanism of action is unknown,
likely due to alterations in sodium channel signaling. Some impairment of
cognitive function is seen. There is certainly risk
for a life-threatening dermatological condition,
which is unfortunately greater in Asian populations. And there are significant
drug interactions. Depakote, or valproic
acid, is certainly well-known as an anticonvulsant. There are new extended
release formulation that provide for daily dosing. It’s approved for bipolar
disorder, epilepsy, and migraines. So rather than having to
take it multiple times a day, just once a day. Seems to have several
mechanisms of action, including being a GABA agonist, and
suppression of neuronal firing. No surprise if
it’s a GABA agonist it will reduce neuronal firing. It’s effective for
treatment of acute mania, schizoaffective disorder, and
rapid cycling bipolar disorder. Its side effects include upset
of gastrointestinal systems, sedation, hand
tremor, and hair loss. Black box warnings
on this drug included is a potential
for hepatotoxicity and pancreatitis, so
certainly something probably not to be used in
things like alcohol withdrawal. Lamotrigine or Lamictal is
approved and apparently highly effective in long term
maintenance of Bipolar I. Its mechanism of action blockade
is a voltage-gated sodium channels. It’s rapidly absorbed. Peak plasms concentration
occurs in an hour to five hours and has a long, 26-hour
half life and importantly, seems to improve cognitive
functioning in patients. So maybe if one of
the chief complaints is loss of cognitive
functioning, this might be a good choice. Gabapentin and pregabalin
are effective in treating neuropathic pain. In fact, these are what
they’re used primarily for. You’ve probably seen
commercials for Lyrica as a treatment for
diabetic neuropathy. It’s not effective in
treating bipolar disorder, but has an excellent
pharmacokinetic profile with few drug interactions. These are related drugs. Lyrica is just simply
a more potent version. Topamax is not supported
as a treatment for bipolar. It has been used to
prevent relapse to drinking in treating alcoholics and
appears to be a GABA agonist. There is serious
cognitive disruption, particularly aphasia, which
is difficulty in word finding. So other uses for
mood stabilizers include treatment for
neuropathic pain, anxiety, borderline personality,
and aggression and behavioral dyscontrol. So we’ll start by talking
about neuropathic pain. There’s significant overlap in
the underlying pathophysiology of epilepsy and
neuropathic pain models. The lower doses appear to
be effective in treating neuropathic pain, resulting in
fewer cognitive side effects. For anxiety disorders, you can
get significant improvement in generalized anxiety
disorder, including improvements in sleep quality and
overall functioning and as a possible
treatment for PTSD. Borderline personality
disorder, which is notoriously
difficult to treat, has responded to
some of these drugs. Borderline personality
disorder is characterized by emotional
instability, impulsivity, including substance
abuse, sexual promiscuity, and aggression. All drugs have been shown to be
effective in treating bipolar and have some evidence
as effective in treating borderline personality disorder. There is significant
comorbidity between the two, so something to keep in mind. Aggression and behavioral
dyscontrol– valproic acid and carbamazepine reduce
intermittent explosive disorder and PTSD. And they both reduce
impulsive aggression. There is ongoing
research into how atypical
antiantipsychotics can be used to treat bipolar disorder. All second generation
antipsychotics are appropriate for treating
mania in bipolar disorder. Risperidone is effective
in maintaining remission. Olanzapine is effective
for bipolar depression. Movement disorders are
more likely the side effect of antipsychotics
in bipolar patients, so we want to
watch out for that. A little interesting link
between omega-3 fatty acids and bipolar disorder–
there’s a lower incidence of bipolar disorder in
countries with high fish intake. In one study, 30 patients
held for four months showed impressive
results, regardless of whether patients were taking
are not taking other bipolar medications. Certainly, we think omega-3s are
associated with neural health. And for my money,
evidence overall is mixed in terms of
omega-3 fatty acids for bipolar disorder
or for depression. But there are other
health benefits for these particular
formulations. So it really seems
like a good thing to add and certainly
something to try. And so trying to find out the
right dose and something you can tolerate, because
sometimes it can be difficult. But these omega-3 fatty
acids have the potential to be a much better
alternative and certainly would be safe to be taken
during pregnancy. So it’s something to
certainly consider. Certainly, bipolar
disorder patients need something
beyond medication. Patients require social support
via friends, family or peers. Group psychotherapy
appears to be helpful in managing the disease. It’s critical these
patients need assistance for drug compliance and
recognition of side effects, so having some kind of social
support is really important. So keep that in mind. Drugs are not the panacea here. They’re simply a
tool in the arsenal. So here’s a summary
of the quality of evidence for the use of
mood stabilizers in bipolar disorder. You can see whether
or not they should be used for mania,
mood stabilizer, or acute bipolar depression. Really, lithium and
olanzapine and lamotrigine are the only ones
that really have quality studies
demonstrating their effect in acute bipolar depression. You can see most of these drugs
are appropriate for acute mania or mixed. But again, talking
about keeping mood stable over time– that’s really
what our ultimate goal’s going to be. So there’s potential
for some of these drugs to get people
through one episode, but then you have to think
about the long-term treatment options. So one of the good
studies in this area is the STEP bipolar
disorder study. Antidepressants were
added to mood stabilizers. Turns out they are no more
effective than placebo for treating bipolar depression. Antidepressants, however,
did not induce mania more frequently than placebo. Patients with an acute
depressive episode who also had subsyndromal
manic symptoms did not recover any
faster with the addition of antidepressants. Lamotrigine showed benefit for
treatment-resistant bipolar depression. And intensive
psychosocial treatments showed the most
positive results. So adding an antidepressant
is probably not necessarily what you might need to do. So here are the recommendations
for pharmacotherapy, according to the American
Psychiatric Association. For less severe manic
episodes, first line treatment is monotherapy with lithium,
valproate, or second generation antipsychotic. For a mixed episode, the same. Lithium seems to
be less effective. For severe episodes, you want
to combine lithium or valproate and an antipsychotic. For people who are
rapid cycling, this is the most difficult.
Lithium and anticonvulsants show low efficacies. Atypical antipsychotics
appear promising, but this is probably the
most difficult to treat. So those are the recommendations
from the American Psychiatric Association. Again, bipolar
disorder is something that really needs to
be treated and finding the best treatment
for your loved one is sometimes going to be
difficult. But getting treated and getting into treatment
is incredibly important.


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