Psychopharmacology Flashcards
Translation of extracellular signals into a form that can be interpreted by complex intracellular enzymatic machinery is achieved through a relatively small number of cellular mechanisms. The transmembrane signaling systems that are multicomponent in nature and generate intracellular second messengers define which class of central nervous system (CNS) receptors?
G protein–coupled receptors
The rate-limiting enzyme in serotonin (5-HT) biosynthesis that has been extensively investigated in psychiatric disorders is
Tryptophan hydroxylase
Through the use of more precise molecular cloning and pharmacological and biochemical studies, seven distinct 5-HT receptor families have been identified, many of which contain several subtypes. Which of the 5-HT receptor types is an excitatory ionotropic receptor?
5-HT3
Which of the 5-HT1 receptor subtypes is found in particularly high densities in several limbic structures, as well as on serotonergic neuron cell bodies, where they serve as autoreceptors regulating 5-HT neuronal firing rates?
5-HT1A
The blockade of which of the 5-HT receptors has been implicated in the weight gain induced by certain psychotropic agents?
5-HT2C
Dopamine synthesis requires the transport of which of the amino acids across the blood–brain barrier?
L-tyrosine
Which of the dopamine receptor subtypes is of great psychopharmacological interest because of clozapine’s high affinity for this receptor?
D4 receptor
Which are the two major excitatory amino acids in the central nervous system (CNS)?
Glutamate and aspartate
Where are the majority of dopamine (DA) neurons located in the brain?
substantia nigra
The principal noradrenergic cell group, which has the largest group of norepinephrine (NE)–containing neurons in the mammalian brain, is the
Locus coeruleus
The highest concentration of serotonin (5-HT)–containing neurons in the mammalian brain is found in the
Raphe nuclei of the brain stem
Pyramidal cells, the predominant neurons of the cerebral cortex, utilize what as a neuro-transmitter?
Glutamate.
The projection neurons of the basal ganglia utilize what as a neurotransmitter?
GABA
Deficits in which of the neuropeptides have consistently been linked with Alzheimer’s disease?
Somatostatin. The hypothalamus and limbic regions such as the amygdala and hippocampus have large numbers of somatostatin-containing neurons.
The opening of which of the following ion channels is the mechanism through which GABA decreases neuronal activity?
Chloride.
Classic learned helplessness animal models have a high degree of validity as a model for depression in all of the areas except
Duration. In rats, learned helplessness persists only for several days, whereas depression in humans may last for months.
What neuroendocrine response is well-established in depression?
Overactivity of the HPA axis as manifested by an increase in cortisol secretion
Combat veterans with PTSD showed _____ suppression to dexamethasone challenge.
enhanced
Taking medications with meals will usually decrease the rate of drug absorption, leading to a decreased peak plasma concentration and prolonged time to reach the maximum plasma concentration. For which of the selective serotonin reuptake inhibitor antidepressants does food increase plasma concentra-tions and shorten the time to reach the maximum plasma concentration?
Sertraline.
Which of the cytochrome P450 (CYP) enzymes is found in high concentrations in the luminal epithelium of the small intestine and leads to extensive presystemic metabolism?
CYP3A4.
Nearly all medications used in clinical psychopharmacology are cleared partially or completely by metabolism, primarily in the liver. Which drugs are an exception?
lithium and gabapentin
What are Phase I clinical trials?
Phase I involves testing multiple doses of a drug for bioavailability, pharmacokinetics, and side effects.
What are Phase II clinical trials?
Phase II studies are dose-finding studies in patients with a given disorder.
What are Phase III trials?
Phase III generally includes pivotal double-blind trials for demonstrating efficacy and safety/tolerability.
What are Phase IV trials?
Phase IV trials, which take place after a drug has received U.S. Food and Drug Administration (FDA) approval and is on the market, are conducted to help clarify potential uses of the drug.
Which of the antidepressants is a tetracyclic with a four-ring central structure?
maprotiline (Ludiomil)
Which is the least anticholinergic among the tricyclic and tetracyclic compounds?
Desipramine.
Age-related changes in metabolism vary among tricyclic and tetracyclic compounds. For which of the trycyclics is metabolism relatively unaffected by aging?
nortriptyline and desipramine
A task force of the American Psychiatric Association reviewed a number of studies and recommended
therapeutic dosage ranges for selected tricyclic compounds. Which of the medications has a
recommended plasma level between 50 ng/mL and 150 ng/mL?
Nortriptyline.
All of the tricyclic and tetracyclic compounds are approved by the U.S. Food and Drug Administration
(FDA) for the treatment of depression except
Clomipramine.
Which of the tricyclic antidepressants (TCAs) carries the potential risk of neuroleptic malignant syndrome?
the 7-hydroxy metabolite of amoxapine has neuroleptic properties
What activity does fluoxetine have at histamine, adrenergic, and muscarinic sites?
none
Based on norfluoxetine’s half-life, how long would you need to wait, after discontinuing fluoxetine,
before beginning a patient on a monoamine oxidase inhibitor (MAOI)?
5 weeks.
What are the FDA-label indications for fluoxetine?
major depressive disorder, obsessive-compulsive disorder,
panic disorder, bulimia nervosa, and premenstrual dysphoric disorder
What are the features of serotonin syndrome?
abdominal pain, diarrhea, sweating, fever, tachycardia, elevated blood pressure, altered mental state (e.g., delirium), myoclonus, increased motor activity, irritability, hostility, and mood change
What are the FDA-label indications for sertraline?
major depressive disorder, OCD and pediatric OCD, PTSD, panic disorder, PMDD, and, most recently, social anxiety disorder
Sertraline and other selective serotonin reuptake inhibitors (SSRIs) have been associated with instances of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Which patient population group may be more vulnerable to this condition?
Seniors over 70 years of age
What are the FDA-label indications for paroxetine?
depression, panic disorder, OCD, PTSD, social anxiety disorder, and GAD
Unlike sertraline, paroxetine has a relatively high affinity for which monoamine receptor?
Norepinephrine transporter (NET)
Unlike paroxetine, sertraline has a relatively high affinity for which monoamine receptor?
Dopamine transporter (DAT)
What is a characteristic of paroxetine’s pharmacokinetic profile?
Most potent inhibitor of the CYP2D6 enzyme system of all SSRIs
Paroxetine has been found to be effective in treating depression associated with a number of medical
conditions. In one study, pretreatment with paroxetine was found to prevent induction of depression by
Interferon-α (IFN-α) treatment of malignant melanoma
In preregistration clinical trials, the most common side effect of paroxetine that resulted in patients drop-
ping out of the treatment study was
Nausea.
One possible safety concern in prescribing paroxetine to treat depression in adults is paroxetine’s tendency to
Decrease heart rate variability (HRV). Norepinephrine reuptake–inhibiting antidepressant drugs have been shown to cause further decreases in this electrophysiological variable.
What are fluvoxamine’s active metabolites?
At least 11 products of fluvoxamine hepatic metabolism have been identified, but none are thought to be
pharmacologically active.
Fluvoxamine is a potent inhibitor of the cytochrome P450 (CYP) 1A2 enzyme. A drug whose levels may rise as a result of inhibition of this enzyme by fluvoxamine is
tertiary-amine tricyclic antidepressants (imipramine, amitriptyline, clomipramine), clozapine, tacrine, theophylline, propranolol, and caffeine
Fluvoxamine also inhibits the cytochrome P450 (CYP) 2C19 enzyme. Which important medication is also metabolized by the CYP2C19 isoenzyme?
Warfarin
In postmarketing surveillance of fluvoxamine, the most commonly reported adverse event was
Suicidality (ideation, attempts, completed). The frequency of death while taking fluvoxamine was calculated at 0.9 per 100,000 patients. Suicide, mostly by overdose, was the cause of death in nearly half of these cases.
A possible explanation for the postulated modest superiority of S-citalopram over citalopram on some measures of antidepressant activity is
The R-enantiomer of citalopram may interfere with the activity of the S-enantiomer
Treatment with citalopram was used in the first phase of the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) trial. The primary outcome measure was depression remission, as measured by
two rating scales. What remission rates were reported at study exit for citalopram?
28%–33%
The most common adverse event associated with either citalopram or S-citalopram, as reported in clinical
trials, is
Nausea.
What are 4 irreversible inhibitors of MAO-B?
Phenlzine, Isocarboxazid, Tranylcypromine, Selegiline
Which of the monoamine oxidase inhibitors (MAOIs) is a nonhydrazine irreversible MAOI that is chemically similar to amphetamine?
Tranylcypromine.
For which of the following monoamine oxidase inhibitors (MAOIs) is a transdermal patch now available?
Selegiline.
In regard to pharmacological profile, trazodone may be best described as
A mixed serotonergic agonist–antagonist
You start your patient, a 72-year-old man, on trazodone, advising him to take the medication at bedtime.
He calls you the next day to tell you that he was light-headed and dizzy and almost fell when he got out of
bed that morning. Knowing the pharmacological profile of trazodone, you attribute this side effect to which
of the following properties of the drug?
Potent antagonist of postsynaptic α 1 -adrenergic receptors
A relatively rare (1 in 6,000) but dramatic side effect associated with trazodone is
Priapism.
Nefazodone carries a black box warning on its package insert for which of the following risks?
Liver failure.
Concurrent use of nefazodone should be avoided with which medication?
Digoxin.
The extended-release (XL) formulation of bupropion was approved by the U.S. Food and Drug Administration (FDA) for which indications?
Bupropion first received FDA approval in 1985 for treatment of depression. In 1997, bupropion was ap-
proved for the indication of smoking cessation under the name Zyban, and in 2006, bupropion XL received
FDA approval for prophylaxis of seasonal depression.
Describe bupropion’s pharmacological profile.
Bupropion inhibits the reuptake of dopamine and norepinephrine by acting as a nonselective inhibitor of DAT and NET
What is the primary liver cytochrome P450 (CYP) isoenzyme involved in the metabolism of bupropion?
2B6
A major nonpsychiatric use of bupropion is for treatment of
Smoking cessation. Studies by Segraves et al. (2001) also demonstrated that bupropion may be helpful in treatment of hypoactive sexual desire disorder (HSDD). Later, a double-blind, placebo-controlled trial supported this finding and also revealed increases in sexual arousal, orgasm completion, and sexual satisfaction in women with HSDD receiving bupropion (Segraves et al. 2004).
What is a common side effect of bupropion?
Mild weight loss
Mirtazapine may be described as a
It is a potent serotonin 2 (5-HT 2 ), serotonin 3 (5-HT 3 ), and central α2 -adrenergic receptor antagonist (De Boer 1996; Kooyman and Zwart 1994)
Why is mirtazapine sedating?
Mirtazapine has high affinity for H1 receptors (De Boer 1996)
What is the clearance half-life of mirtazapine?
The elimination half-life of mirtazapine is 20–40 hours
What effect does mirtazapine have on the CYP system?
In vitro data suggest that mirtazapine is unlikely to have clinically significant effects on the metabolism of drugs by CYP enzymes (Barkin et al. 2000; Fawcett and Barkin 1998; Kent 2000).
Venlafaxine undergoes extensive metabolism in the liver by which of the cytochrome P450
(CYP) isoenzymes?
2D6.
Which side effect associated with venlafaxine is generally not found in patients receiving
selective serotonin reuptake inhibitors (SSRIs)?
Unlike the SSRIs, venlafaxine is associated with a small increase in pulse rate and a dose-dependent in-
creased risk of elevated blood pressure (Thase 1998).
Duloxetine inhibits the activity of which of the liver cytochrome P450 (CYP) isoenzymes?
2D6.
You wish to prescribe a benzodiazepine to an elderly patient for treatment of an anxiety disorder. You re-
alize that selecting a benzodiazepine that is conjugated rather than metabolized by oxidation would be
desirable. Which of the benzodiazepines are metabolized by conjugation?
temazepam, oxazepam, and lorazepam
Describe buspirone’s pharmacological profile.
At presynaptic 5-HT 1A receptors located in the dorsal raphe buspirone acts as a full agonist, inhibiting neuronal serotonin synthesis and firing, whereas at postsynaptic receptors in hippocampus and cortex it functions as a partial agonist. Buspirone is relatively inactive in receptor binding studies in vitro at noradrenergic, cholinergic, and histaminergic sites.
The most common adverse event associated with buspirone treatment, as reported from clinical trials, is
Dizziness.
Describe the profile of agomelatine.
Agomelatine acts as an agonist at MT 1 and MT 2 receptors. In addition, agomelatine is a 5-HT 2C antagonist.
In addition to NET and SERT inhibition, name an additional mechanism of milnacipran.
AMPA receptor antagonist
Which of the first-generation antipsychotics belongs to the piperidine phenothiazine class of agents?
Thioridazine (Mellaril) and its metabolite, mesoridazine (Serentil). The use of these agents has been virtually extinguished by a black box warning about significant QTc prolongation that was added in 2000.
Haloperidol, the best-known classic antipsychotic, belongs to which of the classes of first-generation antipsychotics?
Butyrophenones have a piperidine ring with a three-carbon chain ending in a carbonyl-substituted p-fluorobenzene ring.
Two large-scale government-sponsored studies in the United States (Clinical Antipsychotic Trials of Inter-
vention Effectiveness [CATIE]) and the United Kingdom (Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study [CUtLASS]) were conducted to determine whether there were differences on a vari-
ety of parameters between first-generation and second-generation antipsychotic agents. What was one of
the major findings from these studies?
There were no differences in effectiveness between FGAs and SGAs.
What is the estimated yearly incidence of tardive dyskinesia in adult patients receiving FGAs?
Tardive dyskinesia has an estimated yearly incidence of 5% among adults and as high as 25% in the elderly who receive continuous conventional antipsychotic therapy and has been a major source of litigation
in past psychiatric practice.
Which antidepressant, when combined with clozapine, will dramatically increase clozapine plasma levels?
Fluvoxamine.
Most clinical guidelines for the treatment of schizophrenia recommend the use of clozapine in which circumstances?
After a patient has failed to respond to an FGA and a second-generation antipsychotic (SGA).
Agranulocytosis is a potentially lethal side effect in patients taking clozapine. Approximately what per-
centage of patients in the United States who were registered through the Clozaril National Registry de-
veloped agranulocytosis?
0.38%.
In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), olanzapine had
The longest time to discontinuation in the trial.
In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), the most cost-effective medication was
Perphenazine.
The estimated annual rate of tardive dyskinesia in olanzapine-treated patients is
0.5%
Which of the receptor-binding properties of quetiapine may explain its low rates of extrapyramidal side effects (EPS) and lack of prolactin elevation?
Rapid dissociation from the dopamine 2 (D 2 ) receptor
In comparisons of weight gain with quetiapine versus olanzapine, risperidone, perphenazine, and ziprasidone in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) phase I study, quetiapine
Was second highest (after olanzapine) in producing the most weight gain
A unique mechanism of action of aripiprazole that distinguishes it from all other available antipsychotic
agents is
Partial agonist activity at D 2 receptors
The most frequently reported adverse effect associated with aripiprazole treatment is
Headache.
How does aripiprazole affect prolactin?
Overall, aripiprazole treatment is associated with a low incidence of EPS-related symptoms and with minimal or no effects on weight gain, QTc interval, or circulating levels of cholesterol, glucose, and prolactin.
Aripiprazole is metabolized primarily by the hepatic CYP enzymes . . .
2D6 and 3A4
The elimination half-life for aripiprazole is . . .
75 hours
The pharmacokinetic profiles of risperidone and 9-hydroxyrisperidone (paliperidone) differ in which way?
Absorption of paliperidone is increased 50% when taken with food, whereas risperidone’s absorption is unaffected by food.
Risperidone was developed specifically to exploit the apparent pharmacological advantages of combining ___ antagonism with D 2 blockade.
5-HT2
Name two weight-neutral antipsychotics.
molindone and ziprasidone
Risperidone is the only atypical antipsychotic agent that produces which adverse effect?
Increased serum prolactin
What are the FDA label indications for risperidone?
schizophrenia, bipolar mania, and irritability associated with autism
Ziprasidone has a low propensity to produce weight gain. What pharmacological effects of ziprasidone may explain this clinical finding?
Low affinity for histamine (H1) receptors
What daily dosage range of ziprasidone is associated with lower rates of medication discontinuation?
120–160 mg.
How long until steady state levels of lithium?
4-5 days
Describe some mechanisms of lithium?
A. It is a noncompetitive inhibitor of inositol monophosphatase.
B. It decreases levels of protein kinase C isoenzymes in the frontal cortex and hippocampus.
C. It inhibits glycogen synthase kinase-3 (GSK-3).
D. It mimics Wnt signaling.
On average, studies of deaths among individuals with bipolar disorder indicate that what percentage of completed suicides?
Twenty-five percent to 50% of bipolar patients attempt suicide during their lifetime (Compton and Nemeroff 2000). On average, studies of deaths among individuals with bipolar disorder indicate that 19% complete suicide (see Goodwin and Jamison 1990).
A recent review of the effects of lithium exposure during pregnancy yielded what findings?
First-trimester exposure to lithium results in 0.05%–0.1% prevalence of Ebstein’s anomaly, and relative risk is 10–20 compared with the general population (Cohen and Rosenbaum 1998).
What is the desirable serum level for valproate?
Treatment with valproate for bipolar disorder is usually begun at a dosage of 15–20 mg/kg/day. The drug can be “orally loaded” at 20–30 mg/kg/day in patients with acute mania to induce more rapid response. The dosage of valproate is increased according to the patient’s response and side effects, usually by 250–500 mg/day every 1–3 days, to serum concentrations of 45–125 μg/mL.
What are some predictors of treatment response to valproate in patients with bipolar disorder?
A. Mixed mania.
B. Irritability.
C. Prior nonresponse to lithium.
D. Rapid cycling.
In adults, the most common adverse event associated with long-term valproate use is
Weight gain.
What anti-depressant has been reported to increase serum valproate levels?
Fluoxetine
What is the major difference in oxcarbazepine’s metabolism in comparison with carbamazepine’s metabolism?
Oxcarbazepine does not cause autoinduction and yields substantially less heteroinduction than carbam-azepine.
Recent research has found that the risk of developing a serious rash with carbamazepine may be much higher in certain populations. Which patient population should be genetically tested before starting carbamazepine?
Recent evidence indicates that the risk of serious rash may be 10 times as high in some Asian countries and strongly linked to the HLA-B*1502 allele.
Which side effect occurs more frequently with oxcarbazepine than with carbamazepine?
Hyponatremia occurs with oxcarbazepine (Friis et al. 1993) and may be the main adverse effect that occurs more commonly than with carbamazepine. Oxcarbazepine, like carbamazepine, may produce transaminase elevations and gastrointestinal adverse effects but is associated with less weight gain than valproate (Rattya et al. 1999).
Carbamazepine has been shown to decrease serum concentrations of which anti-epileptic?
Carbamazepine increases lamotrigine metabolism and approximately halves blood lamotrigine concentrations.
How is gabapentin eliminated?
unchanged in urine
Gabapentin is approved by the U.S. Food and Drug Administration (FDA) to treat what condition?
Postherpetic neuralgia in adults
When used in the treatment of alcohol withdrawal syndrome, gabapentin has produced what benefits?
A. Decrease in reported sleep disturbances.
B. Reduction in number of drinks per day.
C. Reduction in craving for alcohol.
D. Increase in the percentage of days abstinent.
Pregabalin was the first medication to receive an FDA indication for treatment of what condition?
Fibromyalgia.
Lamotrigine has been shown to
Inhibit glutamate release secondary to ischemia.
How is lamotrigine metabolized?
Metabolism is primarily achieved by competitive glucuronic acid conjugation.
Oral lamotrigine is approved by the U.S. Food and Drug Administration (FDA) for which psychiatric indication?
Maintenance treatment of bipolar I disorder.
The side effect most likely to complicate lamotrigine’s use in psychiatric practice is
Rash.
What other side effects are noted for lamotrigine?
headache, changes in sleep habits, nausea, and dizziness
Preliminary data suggest that the use of lamotrigine during the first trimester may result in
Cleft lip or palate
The addition of which medication to lamotrigine therapy will result in an increase in the half-life of lamotrigine?
Valproate.
Describe the pharmacological properties of topiramate?
A. Inhibits voltage-gated sodium channels in a voltage-sensitive, use-dependent manner.
B. Increases brain γ-aminobutyric acid A (GABA-A) levels.
C. Antagonizes glutamate receptors of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate subtype.
D. Negatively modulates high-voltage-activated calcium channels.
What CYP enzyme is inhibited by topiramate?
CYP 2C19
Data from randomized, placebo-controlled clinical trials suggest that topiramate is efficacious in the treatment of
Bulimia nervosa.
As a carbonic anhydrase inhibitor, topiramate may reduce serum blood levels of what?
Sodium bicarbonate
Which acetylcholinesterase inhibitor is no longer recommended for clinical use in the US?
Tacrine
Which of the acetylcholinesterase inhibitors (AChEIs) has been postulated to be of greater benefit in the treatment of Alzheimer’s disease because it increases butyrylcholinesterase (BChE) in the hip-pocampus and cortex while decreasing acetylcholinesterase (AChE) activity?
Rivastigmine
Which of the acetylcholinesterase inhibitors (AChEIs) is unique in that it also modulates neuronal nicotinic receptors?
Galantamine.
Benzodiazepines affect sleep architecture in which way?
Most benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings. All benzodiazepines increase time spent in stage 2 sleep. Benzodiazepines also affect the quality of the slow-wave sleep (SWS) pattern. Thus, stages 3 and 4 sleep are suppressed and remain so during the period of drug administration. The decrease in stage 4 sleep is accompanied by a reduction in nightmares.
Methamphetamine is most frequently associated with which complications?
A. Coronary artery disease.
B. Subarachnoid hemorrhage.
C. Rhabdomyolysis.
D. Parkinsonism.
Modafinil is a new psychostimulant approved by the U.S. Food and Drug Administration (FDA) for the treatment of
excessive daytime sleepiness associated with narcolepsy, sleep apnea, and residual sleepiness after standard treatment for shift work sleep disorder
A common side effect of modafinil reported in clinical trials is
Headache.
A significant National Institute of Mental Health (NIMH)–funded study, Sequenced Treatment Alternatives to Relieve Depression (STAR*D), was an evidence-based approach to the treatment of major depressive disorder. Which of the following are findings from this study?
At 6-month naturalistic follow-up, the patients who remitted earlier in their course of treatment and those with less resistant depression (i.e., those who remitted with level 1 or level 2 treatment) were less likely to have relapsed at follow-up.
Vulnerability factors for the development of depression include what?
A. Female sex.
C. Family history of a mood disorder.
D. Exposure to severe traumatic events during childhood.
E. Serious medical illness.
A 42-year-old female patient whom you are treating for depression asks you about alternative treatments for depression. Which of the alternative therapies has received the most investigation in depression?
Exercise.
A number of new atypical antipsychotic medications and antiepileptic agents are being studied as potential anti-manic agents. Thus far, however, the only randomized, controlled clinical trial to demonstrate effcacy was for
Asenapine.
Which of the mood stabilizers has demonstrated efficacy as monotherapy for acute bipolar depression?
A. Lithium. B. Lamotrigine. C. Olanzapine (with Fluoxetine). D. Quetiapine. E. Lurasidone
Which laboratory studies should be ordered to monitor a patient receiving lithium maintenance treatment?
Serum creatinine, lithium level, and thyroid function test.
Among the cognitive functions known to be disturbed in schizophrenia, which is considered the most severe?
Verbal declarative memory impairment.
Symptoms exhibited during the schizophrenia prodromal period include what?
A. Depressed mood.
B. Decreased motivation.
C. Decreased concentration.
D. Social withdrawal.
Which risk factor for the development of tardive dyskinesia is most important?
Age.
What anticonvulsants have been shown to be effective for social phobia?
Gabapentin and pregabalin
In a meta-analysis of generalized anxiety disorder (GAD) studies, the medication that showed the strong-est effect size was
Pregabalin. The α2δ calcium channel antagonist pregabalin was superior to placebo in four studies of GAD (Feltner et al. 2003; Pande et al. 2003; Pohl et al. 2005; Rickels et al. 2005).
Which class of medications has not demonstrated effectiveness in the treatment of posttraumatic stress disorder (PTSD), especially when symptoms of intrusion or avoidance/numbing are prominent?
Benzodiazepines.
