[10.22] Antipsychotics, Antidepressants, Mood Stabilizers V2.1.pdf

Ventral Tegmental Area to Prefrontal Cortex

What is the projection of the mesocortical pathway?

Ventral Tegmental Area to Nucleus Accumbens

What is the projection of the mesolimbic pathway?

Substantia Nigra to Basal Ganglia or striatum

What is the projection of the nigrostriatal pathway?

Arcuate nucleus to median eminence of the hypothalamus

What is the projection of the tuberoinfundibular pathway?

Negative symptoms

Decreased dopamine in the mesocortical pathway leads to what in schizophrenia?

Positive symptoms

Increased dopamine in the mesolimbic pathway leads to what?

Extrapyramidal symptoms or EPS

Blocking dopamine in the nigrostriatal pathway leads to what?

Increased prolactin or hyperprolactinemia

Blocking dopamine in the tuberoinfundibular pathway leads to what?

D2 receptors

Antipsychotics primarily exert their action on which receptors?

72 percent

What percentage of D2 receptors must be occupied for therapeutic antipsychotic action?

Greater than 80 percent

At what level of D2 receptor occupancy do side effects like parkinsonism manifest?

Binding affinity and duration of binding

Antipsychotic effects depend on what two D2 receptor factors?

Amygdala or orbitofrontal cortex

Aggressive symptoms in schizophrenia are hypothetically linked to malfunctions in which brain areas?

Dorsolateral prefrontal cortex

Cognitive symptoms are hypothetically linked to which brain area?

Nucleus accumbens reward circuits

Negative symptoms are linked to malfunctions in which circuits?

Dopamine Receptor Antagonists

What does the acronym DRA stand for?

1955

In what year was Chlorpromazine, the first antipsychotic, introduced?

Antihistamine effect

What was Chlorpromazine initially used for in surgery?

Parenteral or IM

Which route of administration is preferred for DRAs in emergencies?

3 to 5 days

How long does it take for DRAs to reach a steady state level?

Approximately 24 hours

What is the average half life of most DRAs?

More weight gain and sedation

What are the common side effects of low potency DRAs?

Extrapyramidal symptoms or EPS

High potency DRAs are more likely to cause what?

CYP450

Most DRAs are metabolized by which enzyme system?

Positive symptoms

DRAs have a dramatic effect on which type of schizophrenia symptoms?

Constriction of facial expression and akinesia

What two side effects of DRAs might mimic negative symptoms?

Haloperidol

Which drug is the most used first generation antipsychotic?

Pure D2 antagonist

What is the mechanism of action for Haloperidol?

30 minutes

How long does Haloperidol stay in the receptor in vitro, leading to frequent EPS?

Haloperidol

Which DRA is the only one in the Philippine ER setting with an immediate effect?

Chlorpromazine

Which drug causes the most sedation among the DRAs?

Fluphenazine and Haloperidol

Name two phenothiazine or butyrophenone derivatives that cause the most EPS.

Seizure threshold

Antipsychotics may lower what medical baseline, requiring a careful history?

H1 histamine receptors

Sedation in antipsychotics is due to the blockade of which receptors?

Tuberoinfundibular pathway

Hyperprolactinemia is due to D2 blockade in which specific pathway?

Gynecomastia

What is the term for breast enlargement in males caused by hyperprolactinemia?

Neuroleptic Malignant Syndrome or NMS

What is the most severe and potentially fatal side effect of all antipsychotics?

Severe EPS

NMS is thought to be due to what?

Diaphoresis

What is the most common symptom of NMS involving excessive sweating?

Lead pipe rigidity

What type of muscular rigidity is characteristic of NMS?

Dantrolene

What is the antidote for Neuroleptic Malignant Syndrome?

Skeletal muscle relaxant

What class of drug is Dantrolene?

Removing the offending agent and supportive treatment

What is the primary management for NMS?

IV fluids

What should be given to an NMS patient if they are diaphoretic or dehydrated?

Serotonin Dopamine Antagonist

What does the acronym SDA stand for?

5 HT2A

Aside from D2, which serotonin receptor do SGAs antagonize?

Presynaptic neurons of the prefrontal cortex

Antagonism of 5 HT2A occurs specifically in which area to improve cognition?

Kiss and run hypothesis

What is the term for atypical antipsychotics dissociating from D2 receptors quickly?

15 seconds

How fast do atypicals like clozapine and quetiapine dissociate from D2 receptors?

Weight gain

What is a substantial cardiovascular or metabolic side effect of most SDAs?

Clozapine

Which drug is the prototype SGA and the gold standard for efficacy in schizophrenia?

Treatment resistant schizophrenia

Clozapine is the drug of choice for what specific condition?

Failure of two other antipsychotics

How is treatment resistant schizophrenia defined?

Suicidality

Clozapine is effective in reducing aggression, violence, and what other major risk?

Agranulocytosis

What is the most feared and severe side effect of Clozapine?

Absolute neutrophil count or ANC

What must be routinely checked for patients on Clozapine?

Immune system problems

Clozapine is contraindicated in patients with what medical issue?

Olanzapine

Which drug is more potent than Clozapine but has the highest incidence of metabolic problems?

Triglycerides and insulin resistance

Olanzapine increases which two metabolic markers?

Orodispersible tablets

In what form is Olanzapine available that melts quickly in the mouth?

Quetiapine

Which drug and its active metabolite norquetiapine both exert pharmacologic effort?

Histamine receptors

At low doses, Quetiapine acts on which receptors to cause sedation?

Serotonin and norepinephrine

At higher doses, Quetiapine acts on which two systems to be a mood stabilizer?

Dopamine receptors

At the highest dose of 400 to 800 mg, Quetiapine has what effect?

1200 mg

What is the maximum dose of Quetiapine for mania?

Risperidone

Which drug closely resembles first generation antipsychotics at higher doses?

Children and adolescents

Risperidone is the only SDA approved for use in which group?

Paliperidone

What is the active metabolite of Risperidone?

Aripiprazole

Which drug is a partial dopamine agonist?

Negative symptoms

Because it is a partial agonist, Aripiprazole is useful for which type of symptoms?

Non sedating

What is the sedation profile of Aripiprazole?

Aripiprazole

Which drug is a very good adjunct for MDD when combined with Escitalopram?

SDA or SGA

In an elderly patient with Parkinson s, which class of antipsychotics is a good option?

Euthymic

What is the term for a normal mood?

Bipolar I

Mania is typically seen in which disorder?

Bipolar II

Hypomania is typically seen in which disorder?

4 manic episodes in a year

What defines rapid cycling mania?

Dysthymia

What is the term for mild depression that lasts for at least 2 years?

Double depression

What occurs when a patient with dysthymia suddenly has a major depressive dip?

Mixed episode

What occurs when a patient meets criteria for both a manic and major depressive episode?

Serotonin, Norepinephrine, and Dopamine

What are the three neurotransmitters responsible for depression in the monoamine system?

Memory and sleep

Serotonin is responsible for which two functions according to the monoamine model?

Concentration, alertness, vigilance, and energy

Norepinephrine is responsible for which four functions?

Pleasure

Dopamine is responsible for which primary behavioral function?

Deficiency of monoamine neurotransmitters

What is the classic theory of depression?

Upregulation of monoamine receptors

The secondary theory of depression focuses on what change in postsynaptic receptors?

Brain Derived Neurotrophic Factor or BDNF

The modern monoamine hypothesis points to a deficiency in what factor?

Sustains viability of brain neurons

What is the normal role of BDNF?

Atrophy and apoptosis of neurons in the hippocampus and PFC

A deficiency in BDNF leads to what structural brain changes?

Acutely increases but chronically depletes

Under stress, what happens to NE and DA levels initially vs over time?

MAOIs

What was the first class of modern antidepressants in the 1950s?

Serotonin syndrome

What is a dangerous sympathetic overload side effect of MAOIs?

Not available

Are MAOIs available in the Philippines?

Inhibit reuptake of NE and Serotonin

What is the mechanism of action for TCAs?

Peripheral nervous system

TCAs are not widely used because they have significant side effects in which system?

Drowsiness

What is a common side effect of Tetracyclic and SARIs?

Selective Serotonin Reuptake Inhibitor

What does the acronym SSRI stand for?

Serotonin transporter or SERT

SSRIs work by potent inhibition of which transporter?

Downregulation of receptors

In a depressed state, receptors are upregulated; what happens after starting SSRIs?

Initially increase in somatic dendritic area

Where do SSRIs first increase neurotransmitters before the electrical impulse speeds up?