Transcript Psychopharmacology

Psychopharmacology
John Wurzel MD
Outline
• Review each of the major categories of
medications used in psychiatry
– Antidepressants
– “Mood Stabilizers” and the treatment of bipolar
disorder
– Antipsychotics
– Other: Sedative/hypnotics, sobriety support
medications, stimulants, dementia medications
Outline Continued
• My assumptions about what you bring to this
discussion
– A basic understanding of what medication classes
are appropriate for various psychopathologies.
– A basic knowledge of how these medications
work.
–Your participation!
Objectives
• For you to understand how to pick antidepressant
medications based on efficacy and side effect
profile.
– Hopefully, to have an approach to picking
antidepressants for your own patients.
• For you to understand how to pick appropriate
medications for bipolar disorder based on efficacy
and side effect profile.
– And, again, hopefully to have your own approach to
picking medications for bipolar patients.
• For you to understand the efficacy and side effect
profiles of various antipsychotics, and hopefully
how you might pick one.
Caveats
• There is a lot of information in this lecture; this is
because there are a lot of psychiatric medications out
there. My goal is to help you understand how to
shorten the list of psychopharm that you feel like you
need to know day to day by practicing evidence based
psychiatry.
– My goal is also to provide references if you want to read
more about that evidence base.
• The lecture slides are pretty dense and painful to read
on paper; I recommend walking through the slideshow
instead when you’re studying (or watching the video,
listening to the podcast, etc.)
• This lecture is long; the best way to make it seem (and
actually move) faster is to participate.
• Bonus slides at the end for other psychopharm topics!
Antidepressants: What are they good
for?
• What conditions are most appropriately treated
with an antidepressant medication?
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Major depressive disorder (duh…)
Dysthymia
Double depression
Generalized anxiety disorder
Panic Disorder
Obsessive Compulsive Disorder
Post-Traumatic Stress Disorder
Eating disorders
Premenstrual dysphoric disorder
What conditions are not appropriately
treated with antidepressants?
– BIPOLAR DISORDER (we’ll come back to this)
– Personality disorders
So which antidepressant is best for my
patient?
• Antidepressants I’ve used:
– Sertraline (Zoloft), fluoxetine (Prozac), paroxetine
(Paxil), citalopram (Celexa), escitalopram
(Lexapro), mirtazapine (Remeron), venlafaxine
(Effexor), desvenlafaxine (Pristiq), duloxitine
(Cymbalta), bupropion (Wellbutrin), nortriptyline,
amitriptyline, desipramine, imiprimine, doxepin,
trazodone.
• Antidepressants that I know about but haven’t
used:
– Selegiline, tranylcypromine, phenelzine,
fluvoxamine
• FDA approved antidepressants that, despite
being a trainee in a major academic center for
years, I’d never even heard of before making
this lecture:
– Vilazodone (Viibryd), trazodone extended release
(Oleptro), levomilnacipran (Fetzima), vortioxetine
(Brintellix) (1)
How does one pick a medication for
any condition?
• Efficacy!
• So which antidepressant is the most
effective?
– They all work about equally well.
• STAR*D is an algorithmic approach to
treatment of depression; about 30% of people
will experience remission and 50% will have
some response to a first trial of an
antidepressant. (2)
• People who are medication naïve have a
better chance of either remitting or
responding, and people who have failed
multiple medication trials are more likely to
fail further trials.
• There was no difference between the various
antidepressants tried and the rates or
remission or response.
Efficacy Continued
• In reality there may be subtle differences in the
efficacies of various antidepressants. Reference 3 is
a nice paper that reviews this data for the curious or
the gunners in the audience.
So if they all work equally well…
• Antidepressants are generally chosen
according to a rough algorithm adjusted for
side effect profile.
• The algorithm used in STAR*D is an good
starting place.
My Algorithm
1. SSRI (preferred), SNRI, or mirtazapine
2. Another SSRI, SNRI, bupropion, or mirtazapine,
generally from a different class
3. Another SSRI, SNRI, bupropion, or mirtazapine,
definitely from a new class
4. Tricyclic, augmentation, etc.
What side effects do we care about?
• Let’s rephrase this question as “What comorbid
symptoms or diseases do my patients suffer that I
could help them with or should I worry about?” So…
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Insomnia/hypersomnia
Poor energy
Anxiety, ADHD
Obesity or anorexia (either secondary to another issue like
depression, or due to an independent eating disorder
issues).
Substance abuse problems
Pain
Headaches
Impaired sexual function (either premature ejaculation in
men or impaired libido and/or sexual responses in men or
women)
Seizure disorders
Medications I Commonly Use
• Sertraline, escitalopram, mirtazapine,
venlafaxine (or duloxetine), or bupropion.
• Why these medications?
Step 1: Choose whether your patient needs help
sleeping or being more active.
Activating
Bupropion
Venlafaxine,
duloxetine
Sedating
Paroxetine Mirtazapine Trazodone
Fluoxetine
Sertraline,
citalopram,
escitalopram
Secondary TCS’s:
Nortriptyline,
imipramine
Tertiary TCA’s:
Desipramine,
amitriptyline
Step 2: What other considerations are relevant?
More Weight Gain
Mirtazapine
Paroxetine
TCA’s (tertiary worse
than secondary)
Possible Weight Loss
Sertraline
(Es)citalopram
Venlafaxine
Duloxetine
Bupropion
Other Considerations
Useful for Substance Abuse Issues
• Bupropion for nicotine
• Mirtazapine for methamphetamine (4)
Useful for ADHD
• Bupropion
• Venlafaxine
Other Considerations
Useful for Pain
• Duloxetine
• Venlafaxine
• Amitriptyline (and other TCA’s)
Useful for Migraine Headaches
• Amitriptyline (and other TCA’s)
To Avoid Sexual Dysfunction (25-70% of
all patients on an SSRI will experience this,
depending on your study)
• Bupropion
• Mirtazapine
Other Considerations
To avoid if seizures are possible (preexisting
seizure disorder, brain surgery or neurological disorder, or
where electrolyte abnormalities are likely: eating disorders,
severe renal or GI issues)
• Bupropion
Pediatric Considerations
If your patient is under 18 years old
• The two landmark studies on pediatric depression
(5) and anxiety (6) focused on fluoxetine and
sertraline respectively, but the consensus is that
other antidepressants generally behave as they do
in adults
• However, all antidepressants have a black box
warning for increased suicidal ideation (not
behavior) in adolescents
Medication-specific Considerations
Paroxetine (and why I pretty much never use it)
• Is a potent inhibitor of CYP2D6, and a substrate of CYP2D6
– Which means that it interacts with many other medications and…
– That it has a nasty (but not dangerous) withdrawal
Fluoxetine (pluses and minuses)
• Both fluoxetine and norfluoxetine (an active metabloite) have half-lives
measured in days
– Which means that a single dose of fluoxetine can actually be used to prevent
seratonin withdrawal from other antidepressants, but…
– If your patient has side effects (such as feeling jittery), even one dose of
medication can mean days of side effects
Citalopram
•
Now carries a black box warning about potential QTc prolongation, and is effectively
limited to half of the dose previously considered to be the maximum dose.
Medication-specific Considerations
Tricyclic Antidepressants (and why they are second line)
• Are highly cardiotoxic and dangerous in overdose
Monamine Oxidase Inhibitors (and why only 2% of psychiatrists
regularly use them)
• Interact with tyramine (found in many foods) to cause hypertensive crisis
• Require up at least 2, but up to 6 weeks of washout from other
antidepressants due to risk of serotonin syndrome
• Are dangerous in overdose
Let’s put it all together :
Activating
Bupropion
Sedating
Sertraline,
Venlafaxine Fluoxetine escitalopram
Mirtazapine
Paroxetine
Good for pain, Long half-life
+Weight Gain Trazodone
+Nicotine dependence,
+Weight loss
ADHD
No sexual dysfunction
Lowers seizure threshold
Venlafaxine,
duloxetine
No sexual dysfunction
Sertraline, Secondary TCS’s:
escitalopram, Nortriptyline,
citalopram imipramine
Tertiary TCA’s:
Desipramine,
amitriptyline
Let’s do some cases…
57 year old man with no psychiatric history presents for treatment of
new onset panic attacks. He recently had a pacemaker placed for a-fib
with RVR, and was repeatedly shocked a month ago during an episode
of arrhythmia. Since then, he has panic attacks most nights
characterized by sweating, subjective racing heart, difficulty catching
his breath, feeling flushed, a sense of impending doom, and being
terrified that he is going to be shocked again or die. He avoids going
out in the evening for fear that an episode like this might happen in
public. Multiple EKGs during ED visits have demonstrated no cardiac
issues at the time of these symptoms and his a-fib is now well
controlled.
What diagnoses would you consider?
– Panic disorder, Adjustment disorder
What medications would you consider?
– Sertraline
– Escitalopram
– Maybe fluoxetine
More cases…
26 year old woman without a psychiatric history who presents for
treatment of depression after her mother died. It has been over a
year but she is still struggling with frequent bouts of sadness, has lost
15 lbs in the last four months, is unable to sleep past 4am, and is
getting poor performance reviews at work due to impaired
concentration and memory. She feels like nothing in life is enjoyable
anymore.
What diagnosis would you consider?
- Major depressive episode, r/o pathological grief
What medications would you consider?
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Sertraline
Escitalopram
Fluoxetine
Mirtazapine
Another case
35 year old woman with a history of major depressive disorder who
presents complaining of persistent depression despite treatment with
maximum dose sertraline and escitalopram in the past. She has been
depressed for over eight months, and spends up to 16 hours per day
lying in bed. She reports that she doesn’t have the energy to get up in
the morning, and that there is nothing that she enjoys doing, anyway.
She has gained 35 lbs in the last eight months, reports feeling like she
has failed everyone in her life, and states that she only leaves the
house about once a week to shop for groceries. Recently, she has
begun hearing vague voices when she feels especially badly, although
she cannot make out specific words.
What diagnoses would you consider?
– Major depressive disorder, r/o psychotic features.
What medications would you consider?
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Bupropion
Venlafaxine
Duloxetine
Maybe fluoxetine
One more…
39 year old man with a history of PTSD and depression who presents after returning
from a recent deployment to Afghanistan. He is having trouble sleeping because of
nightmares about combat, is unable to tolerate being in crowded places, and visibly
jumps at small noises during your interview. His unwillingness to leave the house is
exacerbated by a lower spinal injury that has left him with chronic leg pain and a
limp that he thinks makes him look “like an easy target.” He also reports that he
has difficulty sleeping through the night, is having trouble enjoying doing anything
with his family, feels extremely guilty for the time that he was away from them
while deployed, has low energy and concentration, but adamantly denies suicidal
thoughts. He has tried maximum dose sertraline and venlafaxine, but neither were
helpful. He also tried mirtazapine, but it was far too sedating and didn’t work
either.
What diagnoses would you consider?
– PTSD, Major Depressive Disorder, Chronic Pain
What medications would you consider?
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Nortriptyline or another TCA
Duloxetine
Escitalopram
Prazosin
Treating bipolar disorder: Main
principles
1. Before you can treat bipolar disorder, you need to
diagnose bipolar disorder correctly.
A. Though I couldn’t find the reference when I went back
and looked, I learned that the single most sensitive
symptom of mania is sleep disturbance; it’s only 50%
sensitive.
B. Again, I’m citing anecdotal evidence here, but many
bipolar patients have trouble remembering their manic
episodes, especially when they are depressed.
C. Which means you need collateral to confirm a bipolar
diagnosis unless your patient is acutely manic or both
experienced and remembers the classic symptoms of
mania.
D. Also, who can tell me what rapid cycling means?
1.
Four discreet mood episodes per year.
Main Principles Continued
1. Treating bipolar disorder is actually a matter
of managing up to four different situations,
all of which respond differently to
medications.
A.
B.
C.
D.
Acute mania
Acute depression
Prophylaxis against mania
Prophylaxis against depression
More Principles
You have to consider all four of the situations
(acute and prophylaxis against mania and
depression) when treating your bipolar patients.
A. What percentage of people with an
acute manic episode will have further
mood episodes requiring treatment?
1. In a study following first manic
episodes, “Recurrence following
remission occurred in 58% of
patients by 1 year and 74% by 4
years (60% depressive, 28% manic
and 12% hypomanic.” (7, my
emphasis)
2. The figure at right is another way
of looking at similar data in a
different recent meta-analysis;
patients spend more than 50% of
their time ill, and depression
dominates this time. (8)
My Bipolar Med List
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Lithium
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Lurasidone (Latuda)
Lamotrigine (Lamictal)
Risperidone (Risperidol)
+/-Valproic acid (Depakote)
Other Medications Sometimes Used In
Bipolar Disorder
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Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
Antidepressants
How to Slay the Hydra: Understanding
how to actually stabilize bipolar moods
• The list of“mood stabilizer” medications is at long
as the list of antidepressants that I presented
earlier; we need a way to sort through them.
• So, again, what the single most important factor in
picking a medication to treat any condition?
– Efficacy.
– Unlike antidepressants, not all medications used to treat
bipolar disorder are equally efficacious.
– Each of the four situations described above calls for a
different approach…
Treating Acute Mania
Mean Mania Rating Scale Change from Baseline
• Acute mania is by far the easiest of the four situations to find an effective
medication for. We’ll talk about three options, but there are many more
that work. (9)
0
Placebo
-2
-4
Depakote Standard
Titration (start 250mg TID
and titrate after blood
level)
Lithium (start at 300 TID
and titrate after blood
level)
-6
-8
-10
-12
*
-14
-16
Day 0
Day 3
Day 5
Day 7
*
*
*
Day 10
Depakote Loading (2030mg/kg x3d, then
20mg/kg, then titrate
after blood level)
Olanzapine (10mg daily)
*
= p<.05 vs. placebo
Acute Mania Continued…
• The take home lessons:
– Acute mania responds well to olanzapine, valproic
acid, and lithium.
– Some patience is required, since even aggressive
treatment takes 7 days to separate from placebo
– If you’re going to use valproic acid, consider a
loading dose regimen
More Acute Mania…
• Other medications with good evidence in the
treatment of acute mania include (10):
– Carbamazepine (Tegretol), Oxcarbazepine
(Trileptal), all atypical antipsychotics, and various
combinations of the above.
– The only two medications historically used in
bipolar disorder that do not have efficacy in acute
mania are topiramate and lamotrigine (due its to
slow titration)
Prophylaxis Against Mania
• Remember the high rate of recurrent mood
episodes; prophylaxis is important.
• Mania is easier to treat than prevent
• And there are few head-to-head comparisons
for maintenance treatment.
Mania Prophylaxis Continued…
• However, essentially the same medications
that work for treating acute mania also work
to prophylaxis against mania
– Lithium has the best support for prophylaxis
against mania, with studies suggesting that it is
superior to other options.
– Atypical antipsychotics also seem to work fairly
well
– Valproic acid, carbamazepine, and oxcarbazepine
also have some (mixed) evidence supporting their
use.
Treating Acute Bipolar Depression
Do antidepressants work in treating acute bipolar depression?
– “The body of evidence on the use of antidepressant
monotherapy to treat patients with bipolar depression is
contentious, but the recommendations from evidence-based
guidelines do not support antidepressant monotherapy for
bipolar depression.” (11)
– “Studies suggested that patients treated with antidepressants
were not significantly more likely to achieve higher response
and remission rates in the short-term or long-term treatment
than patients treated with placebo and other medications.” (12)
– According to the 2014 International Society for Bipolar Disorders
(ISBD) Task Force Report on Antidepressant Use in Bipolar
Disorders, “available clinical trials do not provide adequate
support for the efficacy of antidepressant monotherapy in acute
bipolar depression, but the evidence base is poor and
inconclusive…”
• However among their twelve recommendations was:
– “Antidepressant monotherapy should be avoided in
bipolar I disorder” (13)
What about antidepressants as an adjunct to “mood
stabilizers”?
If the evidence for using antidepressants as monotherapy is “poor
and inconclusive” the evidence for antidepressants as adjunctive
therapy is even less clear. However, the overall current consensus is
that they do not generally improve outcomes.
Antidepressants In Bipolar Disorder
So when would you use an antidepressant in a bipolar patient?
 NOT for depression
 For treatment of co-morbid conditions, typically anxiety
disorders
 And, because of the small risk of “switching” a patient into
a hypomanic or manic episode, only in patients who
already have a mood stabilizer on board.
 And they should be “avoided in patients with high
instability, rapid cycling, in patients with predominantly
mixed states…” (13)
So, what does work?
• A shorter list:
– Atypical antipsychotics, especially quetiapine and
olanzapine, and lurasidone.
– Lithium is less effective in treating depression than it
is at treating mania, but it is still effective.
– Lamotrigine is effective, but can take a very long time
to get up to a treatment dose.
– There is some evidence that carbamazepine and
valproic acid work, though this evidence is poor.
Prophylaxis against Bipolar Depression
The shortest list of all:
• Lamotrigine
• Atypical antipsychotics (again, especially
quetiapine and olanzapine)
– And this odd olanzapine/fluoxetine combination pill that actually outperformed
olanzapine alone in a study.
• Lithium, which is, again, better at preventing
manic episodes, but does work to prevent
depression
• That’s it.
Medication-specific Considerations: Lithium
• Is the only medication demonstrated to decrease suicide
rates in bipolar patients
• Rapid onset side effects
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Sedation
Weight gain
Cognitive blunting
Nausea/vomiting
Polyuria/urinary frequency
Benign atrioventricular block
Leukocytosis (Li is used in cases of neutropenia)
Tremor
Lithium Continued
• Late onset side effects
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Nephrogenic diabetes insipidus
Renal failure
Thyroid fibrosis and failure
• Monitoring
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Blood levels should be 0.7-1mEq/L
Patients also need renal and thyroid function monitored
Lithium Continued
• Lithium toxicity
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Is blood level related, with early symptoms including lethargy,
tremor, vomiting, diarrhea
Moderate toxicity includes confusion, dysarthria, nystagmus, EKG
changes
Late symptoms include seizures, renal failure, hyperreflexia, coma,
death
• Is category D in pregnancy with a reported increased
risk of Ebstein’s anomoly, though more recent
studies dispute this. (15)
Valproic Acid
• Common side effects include somnolence, weight gain,
hyperammonemia, nausea, vomiting
• Carries a risk of potentially fatal hepatotoxicity
• Carries a risk of potentially fatal pancreatitis
• Can cause liver damage
• Requires blood level monitoring (target 50-100mcg/ml);
patients also need CBC and LFT monitoring
• Dangerous in overdose with side effects including heart block,
coma, death
• Class D in prenancy with increased risk of spinal cord
anomolies (spina bifida) and developmental delays
Carbamazepine
• Induces CYP3A4, and therefore interacts with a long list of
other medications
• Carries a 1-6/10000 risk of Stevens-Johnson syndrome and
toxic epidermal necrolysis (except in Asians, where the risk
may be up to 10x higher)
• Carries a risk of aplastic anemia and agranulocytosis (5-10x
the baseline rate but still only a few cases per million patients
per year)
• Can cause liver damage
• Requires blood level monitoring, and patients also need CBC
and LFT monitoring
• Class D in pregnancy with increased risk of spinal cord
anomalies (spina bifida)
Lamotrigine
• Generally well tolerated, except for the risk of StevensJohnson syndrome.
• The risk of SJS is low (~0.1%)
• However, the risk is related to the rate of dose increase, so
a slow schedule is required (25mg every other week)
Back to Principles
• Almost all bipolar patients will have major
depressive episodes.
• Bipolar patients spend, on average, far more time
depressed than manic.
• You will often meet your patient in the midst of a
manic episode because mania is dramatic and
comes to medical attention
– And there are many options to treat acute mania
– But doesn’t it make sense to pick a medication that
your patient can continue to rely on to provide
prophylaxis against both future depression and
mania?
So, let’s put it all together…
Acute Mania
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Lithium
Valproic acid (Depakote)
Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
Mania Prophylaxis
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Lithium
Valproic acid (Depakote)
Carbamazepine (Tegretol)
Options to both treat acute mood
episodes and prevent future mood
• Lamotrigine (Lamictal)
episodes
Risperidone (Risperidol)
• Risperidone (Risperidol)
• Olanzapine (Zyprexa)
•Olanzapine
Lithium(Zyprexa)
Quetiapine (Seroquel)
•Quetiapine
Atypical(Seroquel)
antipsychotics (quetiapine and•olanzapine
especially for depression)
Aripiprazole (Abilify)
• Aripiprazole (Abilify)
• Consider adding lamotrigine for depression prophylaxis if monotherapy isn’t
sufficient
Depression Prophylaxis
Depression
• OtherAcute
combination
therapy
• Lithium
• Lithium
•
(Could
consider
olanzapine/fluoxetine
combination
for bipolar depression)
• Valproic acid (Depakote)
• Valproic acid (Depakote)
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Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
Lamotrigine (Lamictal)
Risperidone (Risperidol)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Antidepressants
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Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
Lamotrigine (Lamictal)
Risperidone (Risperidol)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Antidepressants
A Case!
28 year old man without psychiatric history who presents to the PES after
setting his car on fire, saying that it was a signal to God of his devotion, and
that God will provide him with a new car…a better car… He had been
sleeping poorly for a couple of weeks, but in the past five days he hasn’t slept
at all. He has, however, visited every casino within 200 miles, and tells you
that God is guiding him to a “big score.” He usually works as a legal assistant,
but simply stopped showing up a week ago. He is unconcerned, telling you
that he has enough money saved up to “buy this whole hospital.” He reports
that God is talking to him during your interview, and spends five minutes
saying seemingly random things, “acting as the mouth of God.” It takes you
over an hour to extract yourself from the interview room because he is so
difficult to interrupt, and before you go he insists that you pray with him.
What diagnosis would you consider?
-Substance intoxication (but his Utox is negative), acute mania.
What medications would you consider?
-Olanzapine, risperidone, quetiapine
-Lithium
-Depakote (loading dose)
More Case!
The patient refuses medications but is involuntarily detained as a danger to
himself and others, and you admit him to the inpatient unit after a one time
dose of olanzapine. A week later you finish your night float, and take over the
inpatient team on which he is a patient. He is now taking medications
voluntarily, largely in an effort to convince you that he is ready to leave the
hospital. However, he is still only sleeping 2-3 hours per night, is hearing the
voice of God, and is quite difficult to interrupt. The resident on service before
you started him on valproic acid, which he has now been on for five days.
What do you do next?
– You could wait
– Augment with lithium, olanzapine, risperidone, quetiapine
He stabilizes over the next two weeks on a regimen of valproic acid, lithium,
and clonazepam, and is horrified to hear what he had done while manic. He
asks you whether he will need to take these medications for the rest of his
life.
What medications would you consider peeling off, and in what order?
–
Clonazepam first, then likely valproic acid
Poor guy…
Your patient is pleasant and stable enough after discharge
that you pick him up as a clinic patient. He does well for
the next eight months, but then starts missing
appointments. When he finally does come in, you quickly
realize that he is becoming depressed.
What medication options do you recommend now?
– Augmentation with or a switch to olanzapine or quetiapine
– Augmentation with lamotrigine (although this may take a
while to get up to therapeutic dose)
Antipsychotics: Picking Your Poison
• What conditions are appropriately treated with
antipsychotics?
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Schizophrenia, schizoaffective disorder
Bipolar disorder
Refractory depression as an augmentation agent
Mood associated psychosis (Depression or mania with
psychotic features)
Delirium
Aggression in autism (specifically risperidone)
Aggression in dementia (more on this later)
Possibly aggression in traumatic brain injury
Is the list of antipsychotics as overwhelming
as the list of antidepressants or the list of
mood stabilizers?
Yep. Risperidone (Risperdal), olanzapine (Zyprexa),
quetiapine (Seroquel), aripiprazole (Abilify),
ziprazidone (Geodon), clozapine (Clozaril),
lurasidone (Latuda), paliperidone, iloperidone,
haloperidol (Haldol), fluphenazine (Prolixin),
perphenazine (Trilafon), chlorpromazine
(Thorazine), and literally more than a dozen others
that I’m unfamiliar with.
So which antipsychotic is best for my
patient? Efficacy vs Side Effects
• Let’s look at efficacy first:
Forest plot for
efficacy of
antipsychotics
drugs compared
with placebo (16)
from a recent
meta-analysis.
Efficacy continued:
From the landmark CATIE study (17), which did not include clozapine.
Take home points:
1. Clozapine is the most efficacious of the
antipsychotics.
2. Olanzapine is the second most efficacious.
3. Other than that, there are small/unclear
differences.
4. Typical antipsychotics are no more or less
effective than atypical antipsychotics.
5. Though studies suggest that atypical
antipsychotics are better at addressing negative
symptoms than typicals, this difference does not
rise to clinical significance. (18)
Let’s Discuss Side Effects
• There are three major classes of side effects
associated with antipsychotic medications
– Dopaminergic side effects
– Metabolic (antihistaminic) side effects
– Anticholinergic side effects
• Typical antipsychotics involve dopaminergic
and anticholinergic side effects.
• Atypical antipsychotics involve dopaminergic
and metabolic side effects.
What is the Dopaminergic Side Effect
Profile?
• What are the “four pathways of dopamine” in the
brain?
• Mesocortical
• Maybe involved in
negative symptoms
• Mesolimbic
• Maybe involved in
positive symptoms
• Tubuloinfundibular
• Nigrostriatal
There’s nothing ‘fun’ about a dys‘fun’ctional
tubuloin‘fun’dibular pathway
What does dopamine do in the hypothalamus?
• It inhibits prolactin release; so what does too much
prolactin do?
–
–
–
–
–
Amenorrhea, anovulation, infertility
Galactorrhea
Gynecomastia
Loss of libido
Sexual dysfunction (vaginal dryness, erectile dysfunction,
anorgasmia, etc.) (19)
– Osteoporosis over the long term
What does “nigro” in nigrostriatal refer to?
• Substantia nigra; and what does substantia nigra
dysfunction cause?
– Motor dysfunction that does not involve the primary
motor cortex or its projections through the medullary
pyramids. Thus, extrapyramidal symptoms, which I
learned by the “rule of fours.” What extrapyramidal
symptom appears around “four hours”?
• Acute dystonic reaction (forty minutes might be more
accurate). And what about in around “four days?”
• Akathisia, an intense sense of internal restlessness.
What about in around “four weeks”?
• Drug-induced Parkinsonism, with the classic features
including shuffling gait, tremor, bradykinesia, etc. And
after “four months” or “four years”?
• Tardive dyskinesia
Anticholinergic Side Effect Profile
What are the effects of blocking (muscarinic)
cholinergic receptors?
– Think atropine: “Blind as a bat, dry as a bone, red as
a beet…”
•
•
•
•
•
•
Dry mouth (leading to cavities, sore throat)
Urinary retention
Constipation (or ileus)
Photophobia (Mydriasis), blurred vision
Sedation
Increased intraocular pressure (dangerous in acute angle
glaucoma)
• Ataxia (with increased fall risk)
• Orthostatic Hypotension
Typical antipsychotics: balancing dopaminergic and
anticholinergic profiles
• Understanding the side effect profile of a typical antipsychotic is
fairly easy if you know (or look up) the average effective dose (in
mg) of the medication.
– There a linear, inverse
relationship between
dopamine receptor affinity
and average effective dose.
– And there is a direct
relationship between
average effective dose and
anticholinergic side effects.
– So, the lower the average dose, the higher the risk
of dopaminergic side effects and the lower the risk
of anticholinergic side effects.
– Conversely, the higher the average dose, the lower
the risk of dopaminergic side effects and the
higher the rate of anticholinergic side effects.
Let’s do an example
• Haloperidol, a high potency agent (average
dose ~5-15mg daily for schizophrenia)
– High potential for EPS (how high depends widely
on the study), quite low rates of anticholinergic
side effects
• Why is haldol thought of as sedating? Well, what is it
traditionally given with in the ED?
– A “B52” is 50mg Benadryl, 2mg Ativan, 5mg Haldol
» Of course it’s sedating in that combination. But note that
there are two agents to control possible EPS.
More Examples
• Perphenazine (Trilafon), a medium potency agent
(average dose 30-50mg daily for schizophrenia)
– Moderate rates of EPS, moderate rates of
anticholinergic side effects
• Chlorpromazine (Thorazine), a low potency agent
(average dose 400mg per day)
– Essentially no EPS, but very sedating and
anticholinergic (think “Thorazine shuffle”)
Metabolic Side Effect Profile
What metabolic (and antihistaminic) side effects do
atypical antipsychotics cause?
– Weight gain
• With associated osteoarthritis, lumbago, social isolation, etc.
– Sedation
– Hypercholesterolemia
• With risk of stroke and heart attack
– Hypertriglyceridemia
– Insulin resistance and diabetes (also an issue with
typicals)
• With risk of vision problems, renal problems, ulcers,
amputations, etc.
– Metabolic syndrome
Atypical antipsychotics: metabolic and
dopaminergic side effects
Clozapine
• Repeatedly shown to outperform other antipsychotics in
refractory cases of schizophrenia.
• Generally considered only for refractory cases because
the risk of agranulocytosis requires that the patient get
intensive CBC monitoring, to the point that patients and
providers need to be on a national registry.
• Minimal, if any, dopaminergic side effects because of a
low affinity for dopamine receptors (it’s actually used to
reverse tardive dyskinesia)
• Causes significant weight gain and sedation, and also
drooling in some patients.
Olanzapine
• Multiple studies show it is probably slightly more
efficacious than other antipsychotics (except
clozapine)
• Moderate dopamine blockade, moderate risk of
dopaminergic side effects
• Causes significant weight gain and sedation, the
worst of any antipsychotic other than clozapine
Risperidone
• The most dopaminergic of the atypicals, with the
highest rates of hyperprolactinemia and EPS
• Significant weight gain and sedation, but not as much
as olanzapine or clozapine
Quetiapine
• Essentially no dopamine blockade
• Significant weight gain and sedation
Aripiprazole
• A partial agonist at dopamine receptors, which
means it causes less dopaminergic side effects in
general.
• However, rates of akathisia are as high as 25% in
some studies.
• Less sedating with less weight gain.
Ziprasidone
•
•
•
•
Weight neutral and minimally sedating
Moderate risk of dopaminergic side effects
Highest risk of QTc prolongation
Though evidence supports its efficacy, it is often
considered somewhat weaker than other
antipsychotics
• Have to take it with 500 calorie meal twice per day
Risks common to all antipsychotics
Neuroleptic Malignant Syndrome
• Life threatening condition characterized by muscular rigidity, autonomic
instability (hyperthermia, tachycardia, labile blood pressure), delirium,
catatonia
• Onset is almost always within a month of a medication change or dose
adjustment
• Immediately discontinue antipsychotic medications (some antiemetics
are dopamine blockers, too)
Decreased Seizure Threshold
Risks common to all antipsychotics
Increased rate of all cause mortality in
dementia patients.
• Likely due to a combination of cardiovascular effects,
increased fall risk, and other contributors
• The risk roughly doubles, from ~2% to ~4% annual
mortality rate
QTc Prolongation
• On average the prolongation is very minor (5-15ms),
but in some patients it is larger.
• Above 500ms, the risk of Torsade de Pointe increases
significantly
So how do I pick an antipsychotic?
• In consultation with the patient, weighing
various possible side effects and cost.
• If the patient is too psychotic to be involved,
olanzapine, risperidone, or haloperidol are
usually good first choices to consider.
• To a degree not entirely supported by the
evidence, atypicals have replaced typicals in
most cases.
• Consider clozapine for refractory cases.
• Consider a depot injection for patients with
poor medication adherence histories.
What if my patient isn’t getting better
even though the dose is maxed out?
• Again, consider switching to another agent,
maybe to olanzapine or clozapine.
• The use of multiple antipsychotics is NOT
supported by the evidence
– Although there is good evidence that you will increase
their risk of side effects
– Efforts to avoid multiple antipsychotics are actually
part of the meaningful use part of Obamacare
• There is also no evidence for exceeding FDA
recommended doses in multiple studies
– Beyond ~70% occupancy of dopamine receptors, the
antipsychotic efficacy doesn’t increase, but side
effects do.
Now for a Case
33 yo man with a history of schizophrenia who was
brought into the hospital by police after jumping off a
twenty foot freeway overpass, shouting that he was being
chased by demons. After being medically cleared, he is
brought to the PES in five point restraints, shouting that
he will kill one of the nursing aids for “cursing his family.”
He is also yelling at “demons” that no one else can see.
• What diagnoses would you consider?
- Substance intoxication, schizophrenia
• What medications would you consider?
- Olanzapine
- Haloperidol
- Risperidone (though it isn’t injectable)
More Cases
36 yo woman with a history of schizophrenia who comes into
your clinic requesting a second opinion on her medication
regimen. She has been stable on risperidone for three years,
but has gained thirty pounds and her primary care doctor has
told her that she is at risk for diabetes. She is also getting
married in four months and would like to start a family, but
has not had a period in two years.
• What would you consider doing?
–
–
–
–
Aripiprazole
Ziprasidone
Could consider switching to a medium potency typical
Could add metformin, which has been shown to mildly reduce
weight gain associated with antipsychotics and to reverse
infertility (20)
Please sir, may I have another…Case
• 76 yo woman with a history of severe dementia who is admitted for failure
to thrive. You are asked to consult by the medical team who is managing
her electrolyte abnormalities and acute kidney injury from dehydration.
Her baseline is somewhat unclear, but since admission she has been
intermittently agitated and pulling out her lines. The medicine team has
placed her in soft restraints, but would like your help picking a medicine.
• What diagnoses would you consider?
– Delirium, dementia
• What medications would you consider?
– Haloperidol
– Quetiapine
– Pretty much any other antipsychotic
• What further workup would you need before making a recommendation?
– An EKG, especially given her electrolyte abnormalities
• What would you tell her family when you finally get ahold of them?
– About the increased all cause mortality associated with antipsychotics in
demented elderly patients.
Sedative/Hypnotics
Benzodiazapines
• GABA agonists, similar to (but not the same as)
barbituates or alcohol
• Potent but short term and highly addictive anxiolytics
that often produce rebound anxiety
• Used to prevent and/or treat alcohol withdrawal, anxiety,
anesthesia, and catatonia
• Similar withdrawal to alcohol, including risk of seizures,
delirium tremens, vital sign instability, death
• Unlike barbituates (which they largely replaced)
benzodiazapines do not depress respiration alone (and
are therefore much safer in single-drug overdose);
however, in combination with other sedatives, they
contribute significantly to respiratory depression.
Sedative/Hypnotics
Eszopiclone, Zopidem, Zaleplon
• Selective GABA agonists developed to replace
benzodiazapines as sleep aids, but without as much
addictive potential.
• Some studies have argued that they do not separate
from placebo as sleep aids for long term use beyond 30
days, but otherwise they generally do what they were
designed to.
• Side effects include bizarre sleep behaviors; massive
sleep eating, sleep driving, sleep sex, etc.
Sedative/Hypnotics
Trazodone
• An antidepressant now used as a sleep aid
due to its potent antihistaminic activity.
• 1/10,000 chance of priapism in men.
Sobriety Support Medications
Disulfram (Antabuse)
• Inhibits the activity of alcohol dehydrogenase,
causing toxic metabolites to build up if alcohol
is ingested. These produce a violent acute
illness characterized by vomiting,
flushing/sweating, fevers and chills, etc.
• Will react with other sources of alcohol in
sensitive people, including mouthwash, hand
sanitizer, cough syrup, etc.
• Potentially hepatotoxic, but less so than
ongoing alcohol abuse.
Sobriety Support Medications
Naltrexone
• Opioid antagonist that inhibits a major reward network
in the brain.
• In opioid abuse, it makes any high impossible
• In alcohol abuse, decreases rate and severity of relapse
by reducing cravings
• Evidence supports its use in gambling addiction, and a
combination naltrexone/bupropion has been FDA
approved as a weight loss drug.
• Also potentially hepatotoxic, but again, less so than
ongoing alcohol abuse.
Sobriety Support Medications
Acamprosate
• Works to reduce cravings in alcohol abuse,
though the mechanism is not well understood
• Primary side effects are GI (diarrhea, nausea)
• Studies support possibly using it in combination
with naltrexone
• Not hepatotoxic
Sobriety Support Medications
Methadone
• Long acting opioid that occupies mu receptors
and thus prevents both opioid withdrawal
symptoms and the possibility of getting high
from other opioids (when dosed high enough).
• Must be dispensed through a federally
approved program
• Carries the same risk as any other opioids
(withdrawal, respiratory depression, etc)
Sobriety Support Medications
Suboxone
• Long acting opioid partial agonist (buprenorphine) mixed
with an opiod antagonist (naloxone).
• If taken orally, naloxone is not bioavailable, and suboxone
provides activity at opioid (mu) receptors, preventing
withdrawal symptoms
• If inappropriately injected, naloxone is bioavailable and
induces rapid withdrawal
• Because buprenorphine is a partial agonist, is much safer
in overdose than methadone
• Can be dispensed from an office setting.
Sobriety Support Medications
Varenicline (Chantix)
• Nicotinic agonist used in smoking cessation.
• Carries a black box warning for “serious
neuropsychiatric side effects” including
depression, agitation, suicidal behavior.
• Clearly, close monitoring is warranted.
• Other side effects include GI upset,
insomnia, strange dreams
ADHD Medications
Stimulants
• Appropriately used to treat ADHD (and only ADHD).
Evidence does not generally support their use as a adjunct
in treating depression.
• There are no differences between methylphenidate and
dextroamphetamine salts significant enough that you
should remember them at this point.
• Essentially, you try one class and if it doesn’t work, switch
to the other.
• Side effects include appetite loss, weight loss, insomnia,
growth retardation, increased anxiety, hypertension,
tachycardia.
• There are many formulations to try to balance maximizing
coverage of the medication while minimizing the side
effects (for example, to achieve coverage for ADHD during
the evening so that homework can get done, but not at
night in order to avoid insomnia).
ADHD Medications
Atomoxetine (Strattera)
• A norepinepherine reuptake inhibitor initially
developed as an antidepressant, is a secondline non-stimulant agent used to treat ADHD
in cases where stimulants fail or in cases
where the side effects prove intolerable. In
general it has lower efficacy but fewer and
less severe side effects.
Alpha Antagonists
• Guanfacine and clonidine are alpha-2 receptor
antagonists that can also be calming in ADHD
patients, in anxious patients, and in other
behaviorally dysregulated people (TBI, various
developmental delays, etc.).
• Clonadine is used in opioid withdrawal to mitigate
anxiety and discomfort
• Prazosin is a centrally acting alpha-1 antagonist that
has been shown to reduce trauma-specific
nightmares in PTSD and is being investigated for
treatment of hyperarousal symptoms.
• The major side effect of any of these is hypotension.
Dementia Medications
Acetylcholinesterase Inhibitors
• Donepezil, rivastigmine, galantamine.
• Act to increase acetylcholine in brain synapses,
somewhat counteracting the neuronal losses that
accompany Alzheimer's Disease
• They slow the loss of memory and function, but do
no delay the ultimate course or end point of the
disease
• Generally well tolerated, with GI side effects
predominant
– Can cause loss of appetite, which can worsen failure
to thrive
Dementia Medications
Memantine
• A NMDA antagonist, believed to slow the
progression (but, again, not the ultimate end
point) of dementia by mitigating neuronal
excitotoxicity
• Only outperforms placebo in moderate
dementia or worse
• Also generally well tolerated.
References (with my recommendations in red).
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Prescriber’s guide to using 3 new antidepressants: Vilazodone, levomilnacipran, vortioxetine. Current
Psychiatry 2015 February;14(2):28-29, 32-26. Ahmed Z. Elmaadawi, MD et al.
The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010
Mar;55(3):126-35. Sinyor, M et al.
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments metaanalysis. Lancet. 2009 Feb 28;373(9665):746-58. doi: 10.1016/S0140-6736(09)60046-5. Cipriani, A et al.
Mirtazapine to Reduce Methamphetamine Use: A Randomized Controlled Trial. Arch Gen Psychiatry.
2011;68(11):1168-1175. doi:10.1001/archgenpsychiatry.2011.124. Grant N. Colfax, MD et al.
The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety
outcomes. Arch Gen Psychiatry. 2007 Oct;64(10):1132-43. March JS et al.
24- and 36-week outcomes for the Child/Adolescent Anxiety Multimodal Study (CAMS). J Am Acad Child
Adolesc Psychiatry. 2014 Mar;53(3):297-310. doi: 10.1016/j.jaac.2013.11.010. Epub 2013 Nov 28. Piacentini,
J, PhD et al.
Course and outcome following a first episode of mania: Four-year prospective data from the Systematic
Treatment Optimization Program (STOP-EM). J Affect Disord. 2015 Apr 1;175:411-7.
doi:10.1016/j.jad.2015.01.032. Epub 2015 Jan 22. Gignac, A et al.
Diagnosis and treatment of bipolar disorders in adults: a review of the evidence on pharmacologic
treatments. Am Health Drug Benefits. 2014 Dec;7(9):489-99. Jann, MW.
The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium,
olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry.
2003 Jul;64(7):841-6. Hirschfeld RM et al.
Balanced efficacy, safety, and tolerability recommendations for the clinical management of bipolar
disorder. Bipolar Disord. 2012 May;14 Suppl 2:1-21. doi: 10.1111/j.1399-5618.2012.00989.x. Malhi, GS et al.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Review of evidence for use of antidepressants in bipolar depression. Prim Care Companion CNS Disord. 2014
Oct 16;16(5). doi: 10.4088/PCC.14r01653. eCollection 2014. McInerney, SJ et al.
Antidepressants for bipolar disorder: A meta-analysis of randomized, double-blind, controlled trials. Neural
Regen Res. 2013 Nov 5;8(31):2962-74. doi: 10.3969/j.issn.1673-5374.2013.31.009. Zhang Y, et al.
The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar
disorders. Am J Psychiatry. 2013 Nov;170(11):1249-62. doi: 10.1176/appi.ajp.2013.13020185. Pacchiarotti, I et
al.
Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 Apr
26;356(17):1711-22. Epub 2007 Mar 28. Sachs, GS et al.
Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement
from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the
American Academy of Pediatrics. Circulation. 2007 Jun 12;115(23):2995-3014. Epub 2007 May 22. Jenkins, KJ
et al.
Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments metaanalysis. Lancet. 2013 Sep 14;382(9896):951-62. doi: 10.1016/S0140-6736(13)60733-3. Epub 2013 Jun 27.
Leucht, S et al.
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep
22;353(12):1209-23. Epub 2005 Sep 19. Lieberman, JA et al.
Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled
Trials. Schizophr Bull. 2014 Dec 20. pii: sbu170. [Epub ahead of print]. Fusar-Poli, P et al.
The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings. Schizophr
Bull. 2015 May;41(3):674-86. doi: 10.1093/schbul/sbv001. Epub 2015 Feb 25. deBoer, MK et al.
Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode
schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2012 Aug;169(8):81321. doi: 10.1176/appi.ajp.2012.11091432. Wu, RR et al.