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?– 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 class3. 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…– 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.

Bupropion

Activating Sedating

Venlafaxine, duloxetine

Fluoxetine

Sertraline, citalopram, escitalopram

Mirtazapine Trazodone

Tertiary TCA’s:Desipramine, amitriptyline

Secondary TCS’s:Nortriptyline, imipramine

Paroxetine

Step 2: What other considerations are relevant?

MirtazapineParoxetine

TCA’s (tertiary worse than secondary)

Bupropion

More Weight Gain Possible Weight LossSertraline

(Es)citalopramVenlafaxineDuloxetine

Other Considerations

Useful for Substance Abuse Issues• Bupropion for nicotine

• Mirtazapine for methamphetamine (4)

Useful for ADHD• Bupropion• Venlafaxine

Other ConsiderationsUseful 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 ConsiderationsParoxetine (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 :

Bupropion

Activating Sedating

Venlafaxine,

Fluoxetine

Sertraline, escitalopram,

MirtazapineTrazodone

Tertiary TCA’s:Desipramine, amitriptyline

Secondary TCS’s:Nortriptyline, imipramine

Paroxetine

duloxetinecitalopram

+Nicotine dependence,+Weight loss No sexual dysfunctionLowers seizure threshold

+Weight GainNo sexual dysfunction

VenlafaxineGood for pain, ADHD

Long half-life

Sertraline, escitalopram

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?- Sertraline - Escitalopram - Fluoxetine - Mirtazapine

Another case35 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?– 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?– 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. Acute maniaB. Acute depressionC. Prophylaxis against maniaD. Prophylaxis against depression

More PrinciplesYou 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)

• Lithium• Olanzapine (Zyprexa)• Quetiapine (Seroquel)• Aripiprazole (Abilify)• Lurasidone (Latuda)• Lamotrigine (Lamictal)• Risperidone (Risperidol)• +/-Valproic acid (Depakote)

My Bipolar Med List

Other Medications Sometimes Used In Bipolar Disorder

• 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• 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)

Day 0 Day 3 Day 5 Day 7 Day 10-16

-14

-12

-10

-8

-6

-4

-2

0

Placebo

Depakote Standard Titra-tion (start 250mg TID and titrate after blood level)

Lithium (start at 300 TID and titrate after blood level)

Depakote Loading (20-30mg/kg x3d, then 20mg/kg, then titrate af-ter blood level)

Olanzapine (10mg daily)

**

**

= p<.05 vs. placebo*Mea

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Rati

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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 DepressionDo 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

• 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• Nephrogenic diabetes insipidus • Renal failure• Thyroid fibrosis and failure

• Monitoring• Blood levels should be 0.7-1mEq/L• Patients also need renal and thyroid function monitored

Lithium Continued

• Lithium toxicity• 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 Stevens-Johnson 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

• Lithium• Valproic acid (Depakote)• Carbamazepine (Tegretol)• Oxcarbazepine (Trileptal)

• Risperidone (Risperidol)• Olanzapine (Zyprexa)• Quetiapine (Seroquel)• Aripiprazole (Abilify)

Depression Prophylaxis• Lithium• Valproic acid (Depakote)• Carbamazepine (Tegretol)• Oxcarbazepine (Trileptal)• Topiramate (Topamax)• Lamotrigine (Lamictal)• Risperidone (Risperidol)• Olanzapine (Zyprexa)• Quetiapine (Seroquel)• Aripiprazole (Abilify)• Antidepressants

Acute Depression• Lithium• Valproic acid (Depakote)• Carbamazepine (Tegretol)• Oxcarbazepine (Trileptal)• Topiramate (Topamax)• Lamotrigine (Lamictal)• Risperidone (Risperidol)• Olanzapine (Zyprexa)• Quetiapine (Seroquel)• Aripiprazole (Abilify)• Antidepressants

Mania Prophylaxis• Lithium• Valproic acid (Depakote)• Carbamazepine (Tegretol)

• Lamotrigine (Lamictal)• Risperidone (Risperidol)• Olanzapine (Zyprexa)• Quetiapine (Seroquel)• Aripiprazole (Abilify)

Options to both treat acute mood episodes and prevent future mood

episodes• Lithium• Atypical antipsychotics (quetiapine and olanzapine especially for depression)• Consider adding lamotrigine for depression prophylaxis if monotherapy isn’t

sufficient• Other combination therapy• (Could consider olanzapine/fluoxetine combination for bipolar depression)

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?– 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 ProfileWhat 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

– 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.

• 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.

– 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 ProfileWhat 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 Case33 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 Cases36 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 MedicationsDisulfram (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)

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

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 MedicationsStimulants

• 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 second-line 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.

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