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8/3/2019 Drugs for Mood Disorders Other
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Drugs for Mood Disorders
Drug Classes and Drugs to consider*
Antidepressants Drugs for bipolar disorders
Tricyclics Heterocyclics SSRIs MAO inhibitors Lithium(Carbamazepine)
(Valproic acid)(Lamotigrine)
Imipramine
ClomipramineAmitriptyline
Trazodone
BupropionMirtazapine
Fluoxetine
Paroxetine
Phenelzine
* Drugs in brackets have been already mentioned elsewhere
Learning Objectives
Mechanism of action
- Outline the amine hypothesis of mood.- Explain the mechanism of action of different classes of antidepressants.- Explain the mechanism of action of lithium.
Actions on organ systems- Describe the main pharmacological effects of antidepressants and lithium..
Pharmacokinetics- Describe the route of administration of drugs in each class..-Outline the pharmacokinetics of lithium.
Adverse effects, drug interactions and contraindications- Differentiate the main adverse effects of different antidepressants.- Describe the main adverse effects of l ithium.- Outline the main drug interactions of antidepressants- Outline the main contraindications of antidepressants.
Therapeutic uses- Describe the main therapeutic uses of antidepressants,-Describe the main therapeutic uses of lithium.-Outline the therapeutic uses of valproate and carbamazepine in bipolar disorders.
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CLASSIFICATION OF MOOD DISORDERS
Type Features
Depressive disorders
Major depressive disorder
(endogenous depression)
[about 25% of all depressions]
Depression is autonomous and isunresponsive to changes in life.Biological factors seem important
(family history).It can occur as a single episode ormay be recurrent.
Secondary mood disorder
(reactive depression)
[more than 60% of alldepressions}
Due to adverse life events, physicalillnesses, drugs, other psychiatricdisorders.
Bipolar disorders
Bipolar disorder
(Manic-depressive)
Cyclic. Mania-depression, usual;depression alone, occasional;
mania alone, rare.
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THE AMINE HYPOTHESIS OF MOOD
The hypothesis postulates that:
- Norepinephrine (NE) and serotonin (5-HT) are neurotransmitters in
pathways that function in the expression of mood.
- A functional decrease in the activityof these amines would result indepression, whereas a functional increase in the activitywould resultin mood elevation.
Evidence for this hypothesis includes the following:
1) Amphetamines which cause an increase of monoamines in the
synaptic cleft, temporarily raise mood.
2) Reserpine, which depletes monoamine stores in the CNS, can cause
depression.
3) Antidepressant drugs increase the levels of NE and 5-HT in the
synaptic cleft.
Difficulties with this hypothesis include the following:
1) Antidepressants increase amine availabili ty within hours, yet the
therapeutic effect is delayed of several weeks.
2) Synaptic concentrations of biogenic amines are not constantly
altered in depressed patients.
3) Post mortem studies do not show any decrease in brain Ne or 5-Ht
levels in depressed patients.4) Most antidepressant ultimately cause a down-regulation of amine
receptors (see below).
[Today brain imaging and biochemical studies do not support a single
biologic abnormality as common to most depressions. Neverthelessmost currently available antidepressants have they primary action onthe central adrenergic and/or the central serotonergic system.]
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PHARMACOLOGY OF ANTIDEPRESSANTS (1)
Mechanism of action
Acute mechanism
- The final molecular action of most antidepressants is an increaseavailability of NE and/or 5-HT in the synaptic cleft. This is due to thefollowing mechanisms:
1) Tricyclic antidepressants (TCADs)-Blockade of reuptake of NE and 5-HT in the brain.
2) Heterocyclic antidepressants (HEADS)-Mechanisms are often unclear(see specific agents below) but in mostcases the final result is the one mentioned above
3) Selective serotonin reuptake inhibitors (SSRIs)
-Selective blockade of the reuptake of 5-HT.4) Monoamine oxidase inhibitors- Non selective inhibition of both MAO A and MAO B.
- Selective inhibition of MAO B.
Long-term mechanism- Over time the increase availability of monoamines in the synaptic cleftcauses a down-regulation of postsynaptic CNS receptors (mainly
adrenergic and serotonergic). This occurs after 1-6 weeks of treatmentwhen the therapeutic effect becomes evident.
- This seems to indicate that down-regulation is the necessary eventand has suggested the dysregulation hypothesis of depression (theillness would be the result of a dysregulated neurotransmitter system
and antidepressants would reset the equilibrium in the system).
Pharmacological effects
- The antidepressant effect is usually evident within the first 2 weeks.
- Some central and many peripheral effects of antidepressants resultfrom blockade of cholinergic, adrenergic and histaminergic receptors(see table below)
Pharmacokinetics and administration- Variable oral bioavailability (0.25-0.70)- High or very high Vd.
- Extensive metabolism by the liver (some metabolites are active).- Half-lives are long (8-36 hours).- Administered PO, IM , IV.
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REUPTAKE BLOCKING ACTIVITY
AND RECEPTOR BLOCKING ACTIVITY OF ANTIDEPRESSANTS
Drug Amine pump block Receptor block
2 15-HT NE DA Alpha-1 M H
Tricyclics
Imipramine +++ ++ 0 ++ ++ +++
Clomipramine +++ +++ 0 ++ ++ ++
Amitriptyline ++ +++ 0 +++ +++ +++
Heterocyclics
Trazodone + 0 0 ++ 0 ++
Bupropion 0,+ 0,+ ++ 0 + 0
Mirtazapine 0 0 0 0 + +++
SSRI
Fluoxetine +++ 0,+ 0,+ 0 0 0
Paroxetine +++ 0 0 0 0 0
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HETEROCYCLIC ANTIDEPRESSANTS: SPECIFIC AGENTS
TrazodoneMechanism of action
- It is still not clear. Serotonin is likely the mediator most involved in theantidepressant effect, since the drug weakly inhibits serotonin reuptake
and act as a partial agonist or antagonist at some serotonergicreceptors.
Adverse effects
- Drowsiness (up to 40%) dizziness.
- Postural hypotension- Xerostomia (up to 30%)- Priapism, sexual dysfunctions
Therapeutic uses
- Depression (second choice drug, mainly in patients with agitation and
insomnia)
BupropionMechanism of action
- It is still unknown. The drug is very closely related to diethylpropion(an amphetamine-like drug). It blocks mainly the reuptake of dopamine,
but the doses are higher than those needed for a clinical effect.
Adverse effects
- Insomnia (up to 30%), tremor (up to 20%), seizures (dose-dependent).- Appetite reduction, weight loss (up to 28 %)
- Xerostomia, constipation (10%)
Therapeutic uses- Depression (second choice drug)- Attention deficit hyperactivity disorder- Smoking cessation (20-25% of success)
MirtazapineMechanism of action
- Blockade of presynaptic alpha-2 receptors, which results in increased
release of norepinephrine from noradrenergic nerve endings, and ofserotonin from serotonergic nerve endings.
Adverse effects
- Sedation and drowsiness (up to 40%) dizziness.- Constipation (10%), appetite stimulation, weight gain (up to 15%)
- Therapeutic uses
- Depression (second choice drug)
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ADVERSE EFFECTS OF ANTIDEPRESSANTS
Drug Sedation Sexual
dysfunction
A-chl Postural
hypotension
Cardiac
effects
Tricyclics
Imipramine ++ ++ ++ ++ +++
Clomipramine ++ +++ +++ ++ +++
Amitriptyline +++ ++ +++ +++ +++
Heterocyclics
Trazodone +++ + 0 ++ 0,+
Bupropion 0 0 + 0 0
Mirtazapine +++ 0 0 0 0
SSRI
Fluoxetine 0,+ +++ 0 0 0,+
Paroxetine 0,+ +++ 0 0 0
MAO inhibitors
Phenelzine + +++ 0 + 0
A-chl: anticholinergic effects
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ADVERSE EFFECTS OF ANTIDEPRESSANTS
Tricyclics- Drowsiness (the most common CNS effect), sedation, lassitude,
fatigue, dysphoria, dizziness
- Tremor, paresthesias, seizures (tricyclics lower the convulsivethreshold)
- Pseudoparkinsonism (rare)- Aggravation of psychosis- Anticholinergic effects (xerostomia, blurred vision, constipation,
urinary retention)- Postural hypotension- Cardiac arrhythmias [patients with long Q-T intervals are at greater
risk]- Cardiomyopathy- Weight gain
- Sexual dysfunction- Galactorrhea (in females), gynecomastia (rare).- SIADH (rare)
- Overdosage: tricyclics have a narrow therapeutic index.Manifestations include agitation, delirium, hyperpyrexia, convulsions,
coma, cardiac arrhythmias, circulatory collapse. Death frequentlyensues.
SSRIs
- Nervousness, dizziness, insomnia
- Gastrointestinal disturbances (nausea, diarrhea)- Sexual dysfunction (up to 30%)
- Tremor, akathisia, dystonias (rare)- SIADH (rare)- Serotonin syndrome (see interactions below). Manifestation include
cardiovascular instability, sweating, hyperthermia, muscle rigidity,myoclonus, hyperreflexia, tremor, seizures. The syndrome can be fatal.
MAO inhibitors- Headache, insomnia, nightmares, nervousness.- Switch into mania ( about 10% of patients with bipolar disorders)
- Postural hypotension, edema- Hypertensive crisis (see interactions below); is rare but can be lethal.- Weight gain
- Sexual dysfunction (about 20%)
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ANTIDEPRESSANT DRUG INTERACTIONS
of clinical importance
Interacting Drug Effect of the interaction
TricyclicsCNS depressants Additive effects
ClonidineMethyldopa
The hypotensive effect is abolished oreven reversed
NorepinephrineEpinephrine
Enhanced sympathomimetic activity
MAO inhibitors Hypertensive crisis
Amphetamines Enhanced CNS and sympathomimetic
effects
Drugs which prolong Q-Tintervals
Cardiac arrhythmias
SSRI
MAO inhibitors Serotonin syndrome
Most antidepressants,
Benzodiazepines,Beta-blockers,
Antiepileptic drugs,Methadone, etc.
SSRI are inhibitors of the cytochrome
P450 system and therefore can increasethe effects of several drugs
MAO inhibitors
Sympathomimetic amines,certain foods
Hypertensive crisis
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CONTRAINDICATIONS AND PRECAUTIONS OF ANTIDEPRESSANTS
Tricyclics and heterocyclics
- Cardiac disease ( Long Q-T intervals, arrhythmias, myocardial
infarction, etc.)- Glaucoma- Gastroesophageal reflux disease, hiatal hernia
- Prostatic hypertrophy- Seizure disorders, Parkinsons disease- Pregnancy (tricyclics are included in pregnancy category D by FDA)
- Suicidal ideation- Children
- Elderly (antimuscarinic effects may be enhanced)
SSRIs
- Seizure disorders- Hepatic disease (liver clearance can be decreased)
- Anorexia (SSRIs can decrease hunger)- Hyponatremic states- Concurrent therapy with other antidepressants, benzodiazepines, beta-
blockers, methadone, etc.- Children
THERAPEUTIC USESOF ANTIDEPRESSANTS
- Depression (especially major depressive episodes)
- Panic disorder (tricyclics, SSRIs)- Obsessive-compulsive disorders (SSRIs, clomipramine)- Enuresis (tricyclics)
- Chronic pain, neuropathic pain- Eating disorders (bulimia nervosa)- Social phobia (SSRIs)
- Generalized anxiety disorders (SSRIs)- Attention deficit hyperactivity disorders (bupropion, imipramine)
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PHARMACOLOGY OF LITHIUM (1)
Drug
- Lithium is a small monovalent cation (MW: 6.9).
Mechanism of action- Lithium is classified as a mood-stabilizing drug because it can reduceboth manic and depressive symptoms of bipolar disorder.
- The precise mechanism of its therapeutic effect is unknown but isgenerally related to the following actions:
1)Actions on second messengers
-Lithium inhibits inositol monophosphatase, an enzyme involved in the
2phosphatidylinositol pathway. This leads to depletion of PIP , which is
3 3the precursor of IP and DAG. Therefore the synthesis of IP and
3DAG is inhibitedand the activity of many receptors that are IP /DAGlinked is depressed.
This could cause an inhibition of overactive circuits in mania.(this is a
major current hypothesis about lithium mechanism of action)
- Lithium also inhibits the hormone-induced production of cAMP and
inhibit NE-sensitive adenylyl cyclase.
2)Actions on electrolytes and ion transport
- Lithium can mimic the role of NA+ in excitable tissues. It goes acrossmembranes an substitute sodium in action potential, but is not pumpedout by NA+/K+ ATPase. Therefore it tends to accumulate inside the
cells, displacing Na+.
Pharmacological effects
- At therapeutic doses lithium has no mental effects on normal
individual.- The calming effect in manic patients develops slowly (several days orweeks).
Pharmacokinetics- Oral bioavailability: 100%- Distribution in total body water
- No metabolism- Excretion: 95% in the urine- Half -life: 20 hours
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PHARMACOLOGY OF LITHIUM (2)
Adverse effects
CNS- Intention hand tremor (15%).
- Sedation, drowsiness.- Motor hyperactivity, ataxia, aphasia.- Mental confusion (with very high doses)
Metabolic/Endocrine system-Hypothyroidism (5-8%)[TSH-induced production of cAMP in thyroidcells is inhibited]
- Weight gain (up to 30%)
Urinary system
- Polyuria, polydipsia (30%) (ADH-induced production of cAMP in the
collecting tubule is inhibited)- Chronic interstitial nephritis.
- Edema (frequent, likely due to NA+ retention).
Gastrointestinal system- Nausea, epigastric bloating, diarrhea (6-20%)
Cardiovascular system- Sinus bradycardia, SA block ,AV block
Other systems- Leukocytosis (very frequent)- Acneiform skin eruptions
Overdosage- Lithium has a narrow therapeutic index (about 2)and lithium plasma
levels must always be monitored.Symptoms of overdosage include lethargy , apathy, unsteady gait ,mental confusion, muscle twitches, seizures, stupor, coma anc
cardiovascular collapse.
Pregnancy- Disagreement exists about the teratogenic effects of lithium, but thedrug is rated pregnancy category D by FDA (Ebsteins anomaly of thetricuspid valve is the main teratogenic effect).
Drug interactions
- Diuretics and NSAIDs decrease lithium clearance.- Neuroleptics increase the neurotoxicity of lithium.
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PHARMACOLOGY OF LITHIUM (3)
Contraindications and precautions
- Hypothyroidism
- Hyponatremia (lithium reduces Na+ reabsorption by renal tubules)- Dehydration
- Seizure disorder, parkinsonism- Cardiac disease- Organic brain syndrome
Therapeutic uses
- Bipolar disorder- Depression (to prevent recurrence or as an adjunct to antidepressants
in treatment-resistant patients)- Schizoaffective disorder, schizophrenia (as an adjunct to neurolepticsin treatment-resistant patients).
- Neutropenia
OTHER MOOD-STABILIZING DRUGS
Valproate
- Valproate (valproic acid) is an anticonvulsant drug that is considered
today a first-line agent (together with lithium) in the treatment of bipolardisorder.
- The mechanism of the therapeutic effect is unknown but it may reducesensitization of brain to repeated episodes of mood swing.
- It appears especially useful in patients with rapid cycling of manic anddepressive episodes.
- Adverse effects include GI complains (anorexia, nausea, diarrhea),sedation, tremor, thrombocytopenia and weight gain.(Valproate is discussed in detail under antiseizure drugs)
Carbamazepine
- Carbamazepine is an anticonvulsant drug (structurally related totricyclics) that is considered today a second-line agent in the treatment
of bipolar disorder (about 60% of patients who do not respond to lithiumwill respond to carbamazepine).
- The mechanism of the therapeutic effect is unknown but it may reducesensitization of brain to repeated episodes of mood swing.
- Adverse effects are similar to those of tricyclic antidepressants.(Carbamazepine is discussed in detail under antiseizure drugs)
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Drugs for mood disorders(practice questions)
1) Which of the following statements regarding tricyclic antidepressants are correct?
(Check all that apply)
A) They increase monoamine availability in the synaptic cleft of central neuronsB) They have good anticonvulsant activityC) They have a high addiction liability
D) They are potent inhibitors of liver P450 enzymesE) They often cause sedation and drowsinessF) They often cause hypertension
2) Which of the following is likely a common mechanism of the long-term therapeutic
effectiveness of tricyclic antidepressants and MAO inhibitors?
A) Inhibition of monoamine metabolismB) Enhanced dopaminergic transmissionsC) Down-regulation of central receptors
D) Enhanced cholinergic transmissionE) Impaired glutamatergic transmission
3) Which of the following statements best describes a current hypothesis about the
molecular mechanism of action of lithium?
A) Activation of the synthesis of adenylyl cyclaseB) Activation of the synthesis of inositol monophosphataseC) Inhibition of serotonin reuptake into serotonergic terminals
D) Inhibition of norepinephrine reuptake into adrenergic terminals
3E) Inhibition of the synthesis of IP and DAG
4) Which of the following statements correctly pair the drugs used in mood disorders with
the molecular mechanism most likely associated with their therapeutic effect?
(Check all that apply)
A) Trazodone - activates GABAergic receptors in the CNSB) Amitriptyline - inhibits dopamine reuptake into brain nerve endings
C) Paroxetine -inhibits serotonin reuptake into brain nerve endingsD) Lithium - blocks serotonergic receptors in the CNS
E) Mirtazapine - blocks presynaptic alpha-2 receptors
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5) Which of the following is a common adverse effect of tricyclic antidepressants,
especially during the first week of treatment?
A) InsomniaB) Diarrhea
C) Urge incontinence
d) Postural hypotensionE) Psychological dependence
6) A serotonin syndrome can occur when SSRIs are given together with which of the
following drug classes?
A) BenzodiazepinesB) Neuroleptics
C) NitratesD) Thiazides
E) Beta-blockersF) MAO inhibitors
7)The following table shows the molecular actions of some antidepressant drugs.
Drug
Blockade of
NE reuptake 5-HT reuptake M receptors H1 receptors
1 - +++ - -
2 ++ +++ ++ +++
3 - + - +
4 +++ - + -
5 - - - +++
+ represents degree of activity; - represents negligible activity
Which of the following drugs is most likely to be imipramine?
A) Drug 1B) Drug 2
C) Drug 3D) Drug 4E) Drug 5
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8) Tricyclic antidepressants are contraindicated, or should be used with caution, in which
of the following disease states?
A) HypertensionB) Panic disorder
C) Obsessive-compulsive disorders
D) Cardiac diseaseE) Enuresis
9) Which of the following statements regarding the pharmacokinetics of lithium are
correct?
(Check all that apply)
A) Oral absorption is moderate due to a substantial first-pass effect
B) Volume of distribution is 42 litersC) Passage into the CNS is very limited
D) Excretion occurs virtually entirely in urineE) Plasma half-life is long ( 20 hours)
10) A 75-year-old woman complained of significant weight loss, forgetfulness, insomnia,
and sadness. She also reported that she was discouraged, fearful, very anxious and
sometimes she sweated and her heart beat quickly The woman, who has being suffering
from paroxysmal atrial tachycardia for five years, has been recently diagnosed with
cancer of the pancreas. Considering clinical picture and side effect profiles, which of the
following would be an appropriate therapeutic regimen for this patient?
A) Imipramine and chlorpromazineB) Amitriptyline and bupropion
C) Phenelzine and lorazepamD) Haloperidol and buspironeE) Fluphenazine and lithium
11) A 22-year-old man presented to his physician complaining of a distressing and
embarrassing behavior. For the past five months he had being experiencing an
irresistible urge to disinfect with alcohol any object in his room and to wash his hands
again and again. He was distressed by the unreasonable time he spent on such activitiesand by his behavior he knew to be inappropriate, but he felt that he could not stop. He
denied any substance abuse or use of medications. The physician sent the man to a
psychiatrist who visited the patients and ordered a behavioral therapy and drug
treatment. Which of the following drugs was most likely prescribed?
A) Amitriptyline
B) Lithium
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C) FluoxetineD) HaloperidolE) Diazepam
F) Clozapine
12) A 65-year-old woman has been recently diagnosed with endogenous depression. Thepatient has been suffering from hypothyroidism for 5 years and exertional angina for one
year. Which of the following drugs would be most appropriate for this patient?
A) Amitriptyline
B) FluoxetineC) ImipramineD) Lithium
E) LorazepamF) Haloperidol
13) A 72-year-old man was brought for psychiatric evaluation by his daughter who
reported that recently her father showed little interest in usual activities, was irritable,
very anxious, and had trouble falling asleep. He also frequently became agitated over
insignificant things. The patient has been suffering from focal cortical epilepsy for 15
years and from glaucoma for 5 years. After doing a history and physical examination, a
provisional diagnosis of agitated depression was made. Which of the following drugs
would be appropriate for this patient?
A) Bupropion
B) AmitriptylineC) FluoxetineD) Trazodone
E) Imipramine
14) A 32-year-old man was accompanied to the clinic by his mother who stated that her
son had been exhibiting most unusual behavior over the last few weeks. He was euphoric
most of the day, stayed up later and later at night, and frequently awakened his parents
shouting and screaming. Recently he experienced problems at work. Upon arriving at the
clinic he had trouble sitting still or listening and became increasingly irritable throughout
the examination. Which of the following pairs of drugs would be most helpful for thepatients condition?
A) Fluoxetine and diazepamB) Imipramine and lithium
C) Fluoxetine and haloperidolD) Imipramine and haloperidolE) Chlorpromazine and lithium
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15) A 47-year-old woman presented to the hospital complaining of depression,
hopelessness about her condition, sleep disturbances and poor appetite. She had had
seven previous hospitalizations for manic or depressive episodes and had experienced
five severe mood swings in the past year, including episodes of depression and
hypomania. Despite adequate plasma levels, she had not responded to lithium. Which of
the following drugs would be appropriate for this patient?
A) Clozapine
B) ThioridazineC) Fluoxetine*) Carbamazepine
E)AmitriptylineF) Diazepam
16) A 67-year-old man complained of polyuria and polydipsia. The man recently
diagnosed with manic-depressive illness, has been receiving lithium for three weeks.
Which of the following is the most likely cause of the patients symptoms?
A) Blockade of Na+ reabsorption in the thick ascending loop of HenleB) Blockade of the ADH-induced increase of cAMP in the collecting tubuleC) Increased glucose plasma levels
D) Stimulation of the thirst center in the hypothalamusE) Blockade of vasopressin secretion from the pituitary
17) A 37-year-old man presented to the hospital complaining of persistent, intolerablepain in his left leg. The man, who had suffered from the amputation of his left leg
following an accident at work, four months ago, referred that he tried several over the
counter pain-killer medications without success. Physical examination revealed that pain
could be elicited by a non-noxious stimulus applied to the region of amputation. Which of
the following drugs would be appropriate to treat the patients pain?
A) Phenobarbital
B) AcetaminophenC) FluoxetineD) Amitriptyline
E) DiazepamF) Lithium
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18) A 16-year-old girl was admitted to an eating disorder clinic because of a three month
history of binge eating, vomiting and purging episodes occurring from twice per week to
four times a day. After physical examination and lab tests a psychotherapy was started
and a drug treatment was ordered. Which of the following drugs was most likely
prescribed?
A) DiazepamB) PhenobarbitalC)Fluoxetine
D) HaloperidolE) ClozapineF) Lithium
19) A 2-year-old girl was rushed to the ER after she was found to have swallowed several
pills of her mothers psychotropic medication. She exhibited dry mouth, mydriasis, hot
cheeks and palpitations. Within an hour she showed myoclonic jerking. ECG showed
prolonged QT intervals. Which of the following drugs most likely caused the patients
symptoms?
A) ZolpidemB) AmitriptylineC) Trazodone
D) FluoxetineE) DiazepamF) Lithium
20) A 31-year-old man presented to the hospital complaining of marked sedation, painful
and persistent penile erection and dizziness upon standing up rapidly. The man has been
suffering from endogenous depression for two years and recently his antidepressant
therapy was changed because of failure of the preceding treatment. Which of the
following drugs most likely caused the patients symptoms?
A) AmitriptylineB) ClomipramineC) Bupropion
D) Lithium
E) FluoxetineF) Trazodone
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Drugs for mood disorders(answers and explanations)
1) Answer: AE
(Katzung, pp 480, 493, Brunton, pp 438)
Tricyclic antidepressant are potent inhibitors of norepinephrine and serotonin reuptake intopresynaptic terminals and therefore increase monoamine availability in the synaptic cleft ofcentral neurons. Sedation and drowsiness are common adverse effects of tricyclic
antidepressants which can be related, at least in part, to their pronounced H1 blocking action.
B, C) Tricyclic antidepressant are devoid of anticonvulsant activity (actually they decrease
seizure threshold) and are not drug of abuse.
D)Actually SSRIs, not tricyclic antidepressants, are Inhibitors of liver p450 enzymes.
F) By blocking alpha-1 receptors tricyclic antidepressants tend to cause hypotension, not
hypertension.
2) Answer: C
(Katzung, pp 480, Brunton, pp 439)Tricyclic antidepressant inhibit monoamine reuptake into presynaptic terminal and Mao inhibitors
inhibit monoamine metabolisms. In bot cases there is an increase availability of monoamines inthe synaptic cleft which in turn causes a down regulation of postsynaptic CNS receptors (mainlyadrenergic and serotonergic). This could explain why most antidepressant drugs exert their
molecular effects in a matter of hours whereas their antidepressant effect is delayed of somedays, and seems to indicate that down-regulation is the necessary event for antidepressantefficacy. These findings have suggested the dysregulation hypothesis of depression: the
illness would be the result of a dysregulated neurotransmitter system and antidepressants wouldrepair or reset the equilibrium in the system.
A) MAO inhibitors, but not tricyclic antidepressants, inhibit monoamine metabolism
B, D, E) (see explanation above)
3) Answer: E
(Katzung, pp 470, Brunton, pp 486)Lithium inhibits inositol monophosphatase, an enzyme involved in the phosphatidylinositol
2 3pathway. This leads to depletion of PIP , which is the precursor of both IP and DAG. Therefore
3 3the synthesis of IP and DAG is inhibited and the activity of many receptors that are IP /DAGlinked is depressed. This could cause an inhibition of overactive circuits in mania.
A, B)Actually lithium inhibits the synthesis of these two enzymes.
C, D) Lithium does not affect serotonin or norepinephrine reuptake.
4) Answer: CE
(Katzung, pp 483, Koda-kimble pp 79-22)
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Paroxetine is a SSRI even more selective that fluoxetine, that is it inhibits exclusively serotoninreuptake. Mirtazapine blocks presynaptic alpha-2 receptors, which results in increased releaseof norepinephrine from noradrenergic nerve endings, and of serotonin from serotonergic nerve
endings.
A) Trazodone is an antidepressant. Antidepressant drugs do not interact with the GABAergic
system.
B)Amitriptyline inhibits norepinephrine and serotonin, not dopamine reuptake.D) Lithium is a small ion and therefore cannot act as antagonist at serotonergic receptors.
5) Answer: D
(Katzung, pp 485, Brunton, pp 446)
All tricyclic antidepressants block alpha-1 adrenergic receptors and therefore can cause posturalhypotension, especially during the first week of treatment. Autonomic effects usually undergotolerance, at least partially, so the symptom tends to diminish over time.
A, B, C)Actually tricyclic antidepressants tend to cause sleepiness, constipation and overflow
incontinence.
E) Tricyclic antidepressants do not cause psychological dependence and therefore they are not
drug of abuse.
6) Answer: F
(Katzung, pp 486, Brunton, pp 449)The concomitant use of a SSRI (and virtually of any agent with serotonin potentiating activity)and a MAO inhibitor can cause a serious adverse reaction called serotonin syndrome. The
syndrome is a rare but potentially fatal interaction which typically includes restlessness,myoclonus, hyperreflexia, blood pressure instability, sweating, penile erection, shivering, tremor,
seizures and coma. The pathophysiological mechanism of the syndrome is still uncertain.A, B, C; D; E) These drug classes do not cause the serotonin syndrome when given
concomitantly with SSRIs.
7) Answer: B
(Katzung, pp 485, Brunton, pp 432)Imipramine is a tricyclic antidepressant. All drugs of this class are able to block the reuptake of
both norepinephrine and serotonin into the presynaptic terminals. In addition they exert ablocking activity on muscarinic receptors (which accounts for their anticholinergic effects) and on
H1 receptors (which accounts, at least in part, for their sedating activity).A, C, D, E) (see explanation above)
8) Answer: D
(Koda-Kimble pp 79-26, Brunton, pp 7446)Tricyclic antidepressants have cardiac depressive actions and increase the QT interval (these
effects are similar to those of class 1a antiarrhythmic agents) and are therefore contraindicated
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in patients with cardiac disease (arrhythmias, myocardial infarction, etc.).
A) Tricyclic antidepressants tend to cause hypotension due to alpha-1 blocking actions an
therefore are not contraindicated in hypertension.
B, C , E) These disorders are indications, not contraindications, for the use of tricyclic
antidepressants
9) Answer: BDE
(Katzung, pp 469, Brunton, pp 486)
Lithium is a small ion that crosses easily every cell membrane and is distributed in total bodywater. Therefore its volume of distribution is abut equal to the volume of body water, that is 42liters in a normal person. For the same reason excretion occurs virtually entirely in the urine.
The half life of lithium is about 20 hours which imply that it takes about 3-4 days to reach thesteady state plasma level.
A) Lithium is not metabolized and therefore there is no fir pass effect. Its bioavailability is 100%
C) Since lithium crosse easily any cell membrane it distributes widely into the CNS.
10) Answer: C
(Katzung, pp 484, Brunton, pp 451)
The symptoms of the patient suggest that she is suffering from depression and anxiety, likelybecause of the tumor diagnosis. Pancreatic carcinoma is the type of cancer most frequentlyassociated with depressive symptoms. Since the patient has been suffering from an arrhythmia,
tricyclic antidepressants are contraindicated. MAO inhibitors are best suited for depressedpatients of old age with considerable attendant anxiety, like in the present case. Since thewoman is suffering from insomnia, lorazepam before going to bed is appropriate.
A, B) (see explanation above)
D, E ) Neuroleptics are devoid of antidepressive properties.
11) Answer: C
(Katzung, pp 483, Brunton, pp 450)The symptoms of the patient suggest that he is suffering from an obsessive-compulsive disorder.
SSRIs are today the drugs of choice for obsessive-compulsive disorders and their effectivenessgives support to the hypothesis that these disorders are due to a dysfunction in central
serotonergic transmission.
A, B, D, E, F) These drug have minimal or no efficacy in obsessive-compulsive disorders.
12) Answer: B
(Katzung, pp 484, Brunton, pp 451)Tricyclic antidepressants and SSRIs are about equally effective in the general depressed patient
population (even if patient depressed enough to be hospitalized respond better to tricyclics), sothe choice of the drug in a specific patient is influenced mainly by the patient history of previousresponse and contraindications. Since this patient is suffering from angina tricyclic
antidepressants are contraindicated.
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A, C) (see explanation above)
D) Lithium is mainly used prophylactically to prevent both mania and depression. Even if it has a
therapeutic effect in the acute stage of depressive disorders, the effect is less than that oftricyclic or SSRIs. Moreover it is contraindicated in the present case since the patient is sufferingfrom hypothyroidism.
E, F) These drugs are devoid of antidepressant activity.
13)Answer: D
(Koda-Kimble, pp 79-25, Brunton, pp 436)Trazodone is a heterocyclic antidepressant that can be useful in patient with agitation andinsomnia, due to its sedative properties. All the other listed drug are relatively contraindicated in
the present case ((see explanation below)
A) Bupropion is a heterocyclic antidepressant that can cause insomnia (up to 30%) and
seizures. Therefore is not suitable for a patient who has trouble falling asleep and is sufferingfrom epilepsy.
B, E) Tricyclic antidepressants are contraindicated in patient with glaucoma because of their
antimuscarinic activity and in epileptic patients because they lower the seizure threshold.
C) SSRIs like fluoxetine are contraindicated in patients with insomnia and epilepsy because of
their CNS stimulating effects.
14) Answer: E
(Katzung, pp 470, Brunton, pp 489)
The symptoms and signs of the patient suggest that he is suffering from an acute manicdisorder. Lithium is a drug of choice for bipolar disorders, since it reduces both the frequencyand the magnitude of mood swings (remission of the manic phase can be as high as 80%).
However it has a slow onset of action, taking as long as 1 to 2 weeks to fully exert its therapeuticeffects. Therefore an adjunctive medication is used during the first days of therapy. Neurolepticsare most often employed for this purpose, but benzodiazepines are sometimes used.
A, B, C, D)All these combinations have at least one drug that is not effective in manic disorders.
15) Answer: D
(Katzung, pp 472, koda-Kimble, pp 80-18)The woman is most likely affected by a bipolar disorder resistant to lithium therapy.Carbamazepine and valproate, two anticonvulsant drugs, are considered a useful alternative to
lithium when the latter is not effective. The patient experienced five mood swings in the past
year, and therefore she is a so called rapid cycler. About 70% of rapid cyclers have poorresponse to lithium.
A, B, C, E, F) (see explanation above)
16) Answer: B
(Katzung, pp 471, Brunton, pp 488)
Polyuria and polydipsia are common side effects of lithium due, at least in part, to inhibition of
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the action of vasopressin on renal adenylyl cyclase. This leads to elevated circulating levels ofvasopressin and lack of responsiveness of the collecting tubule, i.e. nephrogenic diabetesinsipidus.
A, C) Lithium has no effect on renal reabsorption of sodium and on glucose plasma levels.
D) Stimulation of the thirst center in the hypothalamus is the consequence, not the cause , of
polyuria.
E) Since the collecting tubule is less sensitive to vasopressin the secretion of the hormone isstimulated, not blocked.
17) Answer: D
(Katzung, pp 483, Koda-Limble, pp 9-30)
The history and the symptom of the patient strongly suggest that he is suffering from chronicphantom limb pain, that is pain that is referred to a limb that no longer exists. Phantom limb painis a type of neuropathic pain, that is a pain caused by damage of neural structures. Unlike
nociceptive pain which is effectively alleviated by NSAIDs and opioids, neuropathic pain oftenrespond poorly to these drugs but is often relieved by tricyclic antidepressants. The analgesic
properties of tricyclic antidepressants are independent of their antidepressant properties sincethey can produce analgesia directly through modulation of the descending inhibitorynoradrenergic and serotonergic pathways.
A, B, C, E, F)All these drugs are minimally or not effective in neuropathic pain.
18) Answer: C
(Katzung, pp 483 Burton, pp 450)
The history and the symptoms of the patient clearly indicate that she is affected by bulimianervosa, a chronic disorder with multiple episodes of relapse and remission, which usually occur
in late adolescence. If medications are required, SSRIs are considered drugs of choice forbulimia nervosa.
A, B, D, E, F) These drugs are not effective in bulimia nervosa.
19) Answer: B
(Katzung, pp 486, Brunton, pp 450)The history and the signs of the patient strongly suggest that the girl was poisoned by a tricyclicantidepressant. These drugs have a pronounced antimuscarinic activity (dry mouth, mydriasis,
hot cheeks, palpitations), lower seizure threshold (myoclonic jerking) and prolong the QT intervalon ECG by increasing the effective refractory period.
A, C, D, E, F) Poisoning by these drugs does not cause all the signs exhibited by the patient.
20) Answer: F
(Koda-kimble, pp 79-25, Brunton, pp 447)The symptoms and signs of the patient suggest that trazodone is the antidepressant he was
taking. Trazodone causes sedation, due at least in part to its H1 blocking activity, and posturalhypotension (dizziness upon standing up rapidly) due to its alpha-1 blocking activity. In addition
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it has been associated with a rare condition known as priapism (persistent and painful erectionof the penis).
A, B, C, D, E) These drugs do not cause all the symptoms exhibited by the patient.
DRUGS FOR MOOD DISORDERS
Answer key
1) AE
2) C
3) E
4) CE
5) D
6) F
7) B
8) D
9) BDE
10) C
11) C
12) B
13) D
14) E
15) D
16) B
17) D
18) C
19) B
20) F
Bibliography
- Brunton LL
Goodman & Gilmans The Pharmacological Basis Of Therapeutics, 11 ed., McGraw Hill,th
New York, 2006
- Katzung BG
Basic and clinical Pharmacology, 9 ed., McGraw Hill, New York, 2004th
- Koda-Kimble MA, Young LY, Kradian WA, Guglielmo BJ, Alldredge BK, Corelli RL
Applied Therapeutics: The Clinical Use Of Drugs, 8 ed, Lippincott Williams & Wilkins, Newth
York, 2005