Intro to neuropsychopharmacology I

Question 1

Recall the two major classes of DSM-5 mood disorders.

Answer 1

Bipolar & related disorders

Depressive disorders (including major depressive disorder)

Question 2

Describe some of the criteria required for diagnosis of Major Depressive Disorder.

Answer 2

At least one of: Depressed mood or diminished interest/pleasure

At least three of: Weight change, sleep disturbance, fatigue, feelings of worthlessness/guilt, agitation and difficulty concentrating, and suicidal ideation (this one mandates immediate intervention)

Question 3

Recall the locations of nuclei responsible for secretion of the following neurotransmitters:

Norepinephrine, Serotonin, Dopamine, GABA

Answer 3

Norepinephrine: Locus ceruleus (to all of CNS)

Serotonin: Raphe nucleus (to most of CNS)

Dopamine: Substantia nigra pars reticulosa and ventral tegmentum (several pathways, mostly to prefrontal & limbic)

GABA: Many (basal ganglia, hippocampus, hypothalamus, amygdala)

Question 4

Describe the early and modified monoamine theories of depression.

Answer 4

Previously, it was thought that inadequate monoamine (NE/Serotonin) release caused depression. However, delay of effect and the effect of some other drugs have contested this.

Modified: Depression is due to an imbalance between monoamine receptor and transmission.

Question 5

Describe the five classes of drugs used to treat depression in this lecture.

Answer 5

Tricyclics (block NE/serotonin reuptake, common structure)

SSRIs (block serotonin reuptake at SERT)

SNRIs (block NE/serotonin reuptake)

Atypical antidepressants (fit none of the above groups)

MAOIs (block MAO to increase synaptic serotonin)

Question 6

Why may tolerance be seen with drugs that block monoamine reuptake?

Answer 6

Neurotransmission may downregulate the post-synaptic receptor (?)

Do any drugs directly target the receptor?

Question 7

Name a few SSRIs.

What are their approved uses?

What are their side effects?

Answer 7

Fluoxetine, paroxetine, sertraline, citalopram.

Approved for depression, OCD, panic and social anxiety disorders, PTSD, generalized anxiety disorders, as well as PMS and menopausal hot flashes.

Side effects include nausea, insomnia, sexual dysfunction, and (rarely) serotonin syndrome.

Question 8

Name the top 3 symptoms seen in SSRI withdrawal.

How quickly do these symptoms manifest?

Answer 8

Dizziness, light-headedness, and vertigo/faintness.

Symptoms begin 1-7 days after stopping an SSRI.

Question 9

Compare the kinetics and uses for fluoxetine and sertraline.

Answer 9

Fluoxetine is long-lasting, and is also approved for PMS.

Sertraline is shorter acting and with fewer effects on drug metabolism. It is also approved for OCD, PTSD, and Panic disorder.

Question 10

Describe the kinetics and usages for Duloxetine.

What class of drug does this belong to?

Answer 10

Duloxetine has a 12-18 hour half-life, and is approved for pain disorders including osteoarthritis, fibromyalgia, as well as neuropathic and back pains.

It is an SNRI. These behave more like SSRIs than TCAs.

Question 11

What are the uses of Bupropion?

What is the mechanism of action of Mirtazapine?

Answer 11

Bupropion is used to help nicotine withdrawal, as well as for seasonal affective disorder. There is some weak NE/dopamine blocking as well.

Mirtazapine blocks alpha-2 presynaptic receptors. This increases appetite, useful for AIDS patients who are wasting.

Question 12

Describe the kinetics and metabolism of tricyclic antidepressants.

What are their side effects?

What are some important drug interactions?

Answer 12

They are rapidly absorbed and highly distributed in brain and heart. They tend to be long-lived.

They decrease REM/S4 sleep and are anticholinergic (cause sedation, cardiac tachyarrythmias). They can be acutely toxic (fever, seizures, coma).

They affect many other drugs, including sympathomimetics and blocking guanethidine uptake.

Question 13

What are the uses for clomipramine?

What are the uses of amitriptyline?

Which of these is a prodrug?

Answer 13

Clomipramine is for OCD as well as depression.

Amitriptyline is also used for treatment of chronic pain.

The slides mention amitriptyline, but clomipramine is also converted to an active metabolite in vivo.

Question 14

What are some exampes of MAOIs?

What are they used for?

What are their side effects?

Answer 14

Phenelzine, Selegiline.

For depression, as well as sleep disorders (narcolepsy).

They can be acutely toxic, and prevent metabolism of tyramine.

Question 15

What are some nonpharmacological treatments for depression?

Answer 15

Electroconvulsive shock therapy and Transcranial magnetic stimulation.

Cortical electrical stimulation is still experimental.

Question 16

What are the criteria for a diagnosis of schizophrenia?

Answer 16

Two or more symptoms, of which one must be a positive symptom (eg Delusions, hallucinations), distinct from negative symptoms (catatonic behavior, blunted affect social withdrawal, etc)

Question 17

What is the proposed pathophysiology of schizophrenia?

Answer 17

Hyperactivity of dopaminergic neurons, especially in the limbic system.

Compare this with Parkinson’s disease.

Question 18

Describe the four dopaminergic pathways.

Answer 18

1. Mesolimbic (from ventral tegmentum to limbic system; affects arousal, memory, motivation, etc)
2. Mesocortical (from ventral tegmentum to frontal lobe; affects cognition and communication)
3. Nigrostriatal (from substantia nigra to striatum; review Neuro)
4. Tuberoinfundibular (hypothalamus to pituitary; affects prolactin release–dopamine is basically prolactin releasing hormone)

Question 19

Distinguish between the D₁ and D₂ receptors.

Which do most antipsychotics preferentially antagonize?

Answer 19

D₁ is excitatory, D₂ is inhibitory. Both are GPCRs, but according to wikipedia, D₁ activates Gs, while G₂ activates Gi.

Binding to D₂ is generally greater than D₁.

Question 20

What function do many atypical antipsychotics have in addition to dopamine blockade?

What advantages do they offer over traditional antipsychotics?

Answer 20

Many exhibit antagonism of 5-HT receptors. The lecture slides specifically mention 5-HT₂ receptors in the forebrain.

They seem to be more effective in treating negative symptoms. They also have better side-effect profiles.

Question 21

What side effects do antipsychotics cause?

Answer 21

Sedation and extrapyramidal effects (eg dystonias, akathisia, parkinsonism and tardive dyskinesia)

Anticholinergic effects including orthostatic hypotension, neuroendocrine disturbance, allergic effects, increased seizures, sometimes weight gain.

Thioridazine causes cardiotoxicity.

Question 22

What is neuroleptic malignant syndrome, and how is it treated?

Answer 22

A potentially fatal reaction to anti-psychotics characterized by hyperthermia and muscle contractures (not the same thing as malignant hyperthermia).

Treatment includes cooling and dantrolene.

Question 23

Describe the side-chain, potency, and side effects of 3 typical antipsychotic drugs (Chlorpromazine, Thioridazine, Fluphenazine).

Answer 23

Chlorpromazine: Aliphatic side chain, low potency with marked sedation & anti-cholinergic effect.

Thioridazine: Piperidine side chain, low potency and sedative but with fewer anticholinergic/extrapyrimidal effect.

Fluphenazine: Piperazine side chain, high potency with fewer side effects overall.

Question 24

Haloperidol

What class of drug is it?

What is its primary indication?

Answer 24

Haloperidol (Haldol) is an atypical antipsychotic.

It is used to treat acute psychosis and aggression–often in psychiatric emergency situations.

Question 25

Clozapine

What unique receptor does it antagonize?

What are its side effects?

Answer 25

Clozapine

D₄ (as well as 5-HT₂ and some muscarinics)

It promotes seizures and can cause fatal agranulocytosis.

Question 26

Olanzapine

What receptors does it antagonize?

What are its side effects?

Answer 26

Olanzapine

D_1/2 and 5-HT₂*

It is associated with weight gain and complications with diabetes. Abuse of olanzapine has been reported.

*Something important to understand is that the atypical antipsychotics bind a very broad range of receptors. Clozapine binds just about every dopamine and serotonin receptor–wiki it.

Question 27

Risperidone

Which receptors does it most strongly antagonize?

How does it compare to clozapine?

Answer 27

Risperidone

D₂, 5-HT₂.

Like Olanzapine and Quetiapine, it has fewer side-effects than Clozapine. It is also available as an IM bolus.

Question 28

Quetiapine

Describe its uses.

Is it long-acting, or short-acting?

Answer 28

Quetiapine

Asides from schizophrenia/bipolar disorder, it can also improve depression.

It has a “shorter” half-life than the other atypicals.

Question 29

Aripiprazole

What is remarkable about its pharmacodynamics?

What are its indications?

Answer 29

Aripiprazole

Unlike the other atypicals, it agonizes D₂.

It can also be used as an adjunctive in depression.

Question 30

Atypical Antipsychotics Wildcard

Which can be used to augment depression?

Which are approved for tourette’s?

Why do you think many atypicals reduce nausea.

Answer 30

Augmentation: Quetiapine and Aripiprazole (and Olanzapine?)

Tourette’s: Haloperidol. Pimozide?

The 5-HT₃ centrally influences vomiting. Many antipsychotics bind a broad range of 5-HT receptors.