Drugs for Mood Disorders Other

8/3/2019 Drugs for Mood Disorders Other

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Babbini, MD, PhD Drugs for Mood Disorders

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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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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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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?


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?


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


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


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


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


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

Documents

Drugs for Mood Disorders Other