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Babbini, MD, PhD

Drugs for Mood Disorders

Drugs for Mood Disorders


Drug Classes and Drugs to consider *
Antidepressants Tricyclics Imipramine Clomipramine Amitriptyline Heterocyclics Trazodone Bupropion Mirtazapine SSRIs Fluoxetine Paroxetine MAO inhibitors Phenelzine Drugs for bipolar disorders Lithium (Carbamazepine) (Valproic acid) (Lamotigrine)

* 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 lithium. - 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.

Babbini, MD, PhD

Drugs for Mood Disorders

CLASSIFICATION OF MOOD DISORDERS Type Features

Depressive disorders
Major depressive disorder (endogenous depression) [about 25% of all depressions] Depression is autonomous and is unresponsive to changes in life. Biological factors seem important (family history). It can occur as a single episode or may be recurrent. Due to adverse life events, physical illnesses, drugs, other psychiatric disorders.

Secondary mood disorder (reactive depression) [more than 60% of all depressions}

Bipolar disorders
Bipolar disorder (Manic-depressive) Cyclic. Mania-depression, usual; depression alone, occasional; mania alone, rare.

Babbini, MD, PhD

Drugs for Mood Disorders

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 activity of these amines would result in depression, whereas a functional increase in the activity would result in 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 availability 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. Nevertheless most currently available antidepressants have they primary action on the central adrenergic and/or the central serotonergic system.]

Babbini, MD, PhD

Drugs for Mood Disorders

PHARMACOLOGY OF ANTIDEPRESSANTS (1) Mechanism of action Acute mechanism - The final molecular action of most antidepressants is an increase availability of NE and/or 5-HT in the synaptic cleft. This is due to the following 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 most cases 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 cleft causes a down-regulation of postsynaptic CNS receptors (mainly adrenergic and serotonergic). This occurs after 1-6 weeks of treatment when the therapeutic effect becomes evident. - This seems to indicate that down-regulation is the necessary event and has suggested the dysregulation hypothesis of depression (the illness 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 result from 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.

Babbini, MD, PhD

Drugs for Mood Disorders

REUPTAKE BLOCKING ACTIVITY AND RECEPTOR BLOCKING ACTIVITY OF ANTIDEPRESSANTS Drug Amine pump block 5-HT2 Tricyclics Imipramine Clomipramine Amitriptyline Heterocyclics Trazodone Bupropion Mirtazapine SSRI Fluoxetine Paroxetine +++ +++ 0,+ 0 0,+ 0 0 0 0 0 0 0 + 0,+ 0 0 0,+ 0 0 ++ 0 ++ 0 0 0 + + ++ 0 +++ +++ +++ ++ ++ +++ +++ 0 0 0 ++ ++ +++ ++ ++ +++ +++ ++ +++ NE DA Receptor block Alpha-1 M H1

Babbini, MD, PhD

Drugs for Mood Disorders

HETEROCYCLIC ANTIDEPRESSANTS: SPECIFIC AGENTS

Trazodone

Mechanism of action - It is still not clear. Serotonin is likely the mediator most involved in the antidepressant effect, since the drug weakly inhibits serotonin reuptake and act as a partial agonist or antagonist at some serotonergic receptors. 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)

Bupropion

Mechanism 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)

Mirtazapine

Mechanism of action - Blockade of presynaptic alpha-2 receptors, which results in increased release of norepinephrine from noradrenergic nerve endings, and of serotonin 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)

Babbini, MD, PhD

Drugs for Mood Disorders

ADVERSE EFFECTS OF ANTIDEPRESSANTS Drug Tricyclics Imipramine Clomipramine Amitriptyline Heterocyclics Trazodone Bupropion Mirtazapine SSRI Fluoxetine Paroxetine MAO inhibitors Phenelzine + +++ 0 + 0 0,+ 0,+ +++ +++ 0 0 0 0 0,+ 0 +++ 0 +++ + 0 0 0 + 0 ++ 0 0 0,+ 0 0 ++ ++ +++ ++ +++ ++ ++ +++ +++ ++ ++ +++ +++ +++ +++ Sedation Sexual A-chl Postural Cardiac dysfunction hypotension effects

A-chl: anticholinergic effects

Babbini, MD, PhD

Drugs for Mood Disorders

ADVERSE EFFECTS OF ANTIDEPRESSANTS Tricyclics - Drowsiness (the most common CNS effect), sedation, lassitude, fatigue, dysphoria, dizziness - Tremor, paresthesias, seizures (tricyclics lower the convulsive threshold) - 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 frequently ensues. 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%)

Babbini, MD, PhD

Drugs for Mood Disorders

ANTIDEPRESSANT DRUG INTERACTIONS of clinical importance Interacting Drug Tricyclics CNS depressants Clonidine Methyldopa Norepinephrine Epinephrine MAO inhibitors Amphetamines Drugs which prolong Q-T intervals SSRI MAO inhibitors Most antidepressants, Benzodiazepines, Beta-blockers, Antiepileptic drugs, Methadone, etc. MAO inhibitors Sympathomimetic amines, certain foods Hypertensive crisis Serotonin syndrome SSRI are inhibitors of the cytochrome P450 system and therefore can increase the effects of several drugs Additive effects The hypotensive effect is abolished or even reversed Enhanced sympathomimetic activity Hypertensive crisis Enhanced CNS and sympathomimetic effects Cardiac arrhythmias Effect of the interaction

Babbini, MD, PhD

Drugs for Mood Disorders

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, betablockers, methadone, etc. - Children

THERAPEUTIC USES OF 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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Babbini, MD, PhD

Drugs for Mood Disorders

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 reduce both manic and depressive symptoms of bipolar disorder. - The precise mechanism of its therapeutic effect is unknown but is generally related to the following actions: 1) Actions on second messengers -Lithium inhibits inositol monophosphatase, an enzyme involved in the phosphatidylinositol pathway. This leads to depletion of PIP2 , which is the precursor of IP3 and DAG. Therefore the synthesis of IP3 and DAG is inhibited and the activity of many receptors that are IP3/DAG linked 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 across membranes an substitute sodium in action potential, but is not pumped out 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 or weeks). Pharmacokinetics - Oral bioavailability: 100% - Distribution in total body water - No metabolism - Excretion: 95% in the urine - Half -life: 20 hours

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Babbini, MD, PhD

Drugs for Mood Disorders

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 thyroid cells 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 the drug is rated pregnancy category D by FDA (Ebsteins anomaly of the tricuspid valve is the main teratogenic effect). Drug interactions - Diuretics and NSAIDs decrease lithium clearance. - Neuroleptics increase the neurotoxicity of lithium.

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Babbini, MD, PhD

Drugs for Mood Disorders

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 neuroleptics in 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 bipolar disorder. - The mechanism of the therapeutic effect is unknown but it may reduce sensitization of brain to repeated episodes of mood swing. - It appears especially useful in patients with rapid cycling of manic and depressive 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 to tricyclics) that is considered today a second-line agent in the treatment of bipolar disorder (about 60% of patients who do not respond to lithium will respond to carbamazepine). - The mechanism of the therapeutic effect is unknown but it may reduce sensitization 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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Babbini, MD, PhD

Drugs for Mood Disorders

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 neurons B) They have good anticonvulsant activity C) They have a high addiction liability D) They are potent inhibitors of liver P450 enzymes E) They often cause sedation and drowsiness F) 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 metabolism B) Enhanced dopaminergic transmissions C) Down-regulation of central receptors D) Enhanced cholinergic transmission E) 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 cyclase B) Activation of the synthesis of inositol monophosphatase C) Inhibition of serotonin reuptake into serotonergic terminals D) Inhibition of norepinephrine reuptake into adrenergic terminals E) Inhibition of the synthesis of IP3 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 CNS B) Amitriptyline - inhibits dopamine reuptake into brain nerve endings C) Paroxetine -inhibits serotonin reuptake into brain nerve endings D) Lithium - blocks serotonergic receptors in the CNS E) Mirtazapine - blocks presynaptic alpha-2 receptors

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Babbini, MD, PhD

Drugs for Mood Disorders

5) Which of the following is a common adverse effect of tricyclic antidepressants, especially during the first week of treatment? A) Insomnia B) Diarrhea C) Urge incontinence d) Postural hypotension E) Psychological dependence 6) A serotonin syndrome can occur when SSRIs are given together with which of the following drug classes? A) Benzodiazepines B) Neuroleptics C) Nitrates D) Thiazides E) Beta-blockers F) MAO inhibitors 7)The following table shows the molecular actions of some antidepressant drugs. Blockade of NE reuptake 5-HT reuptake M receptors ++ +++ +++ +++ + ++ + H1 receptors +++ + +++

Drug 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 1 B) Drug 2 C) Drug 3 D) Drug 4 E) Drug 5

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Babbini, MD, PhD

Drugs for Mood Disorders

8) Tricyclic antidepressants are contraindicated, or should be used with caution, in which of the following disease states? A) Hypertension B) Panic disorder C) Obsessive-compulsive disorders D) Cardiac disease E) 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 liters C) Passage into the CNS is very limited D) Excretion occurs virtually entirely in urine E) 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 chlorpromazine B) Amitriptyline and bupropion C) Phenelzine and lorazepam D) Haloperidol and buspirone E) 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 activities and 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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Babbini, MD, PhD

Drugs for Mood Disorders

C) Fluoxetine D) Haloperidol E) Diazepam F) Clozapine 12) A 65-year-old woman has been recently diagnosed with endogenous depression. The patient 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) Fluoxetine C) Imipramine D) Lithium E) Lorazepam F) 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) Amitriptyline C) Fluoxetine D) 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 the patients condition? A) Fluoxetine and diazepam B) Imipramine and lithium C) Fluoxetine and haloperidol D) Imipramine and haloperidol E) Chlorpromazine and lithium

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Babbini, MD, PhD

Drugs for Mood Disorders

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) Thioridazine C) Fluoxetine *) Carbamazepine E)Amitriptyline F) 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 Henle B) Blockade of the ADH-induced increase of cAMP in the collecting tubule C) Increased glucose plasma levels D) Stimulation of the thirst center in the hypothalamus E) Blockade of vasopressin secretion from the pituitary 17) A 37-year-old man presented to the hospital complaining of persistent, intolerable pain 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) Acetaminophen C) Fluoxetine D) Amitriptyline E) Diazepam F) Lithium

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Babbini, MD, PhD

Drugs for Mood Disorders

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) Diazepam B) Phenobarbital C)Fluoxetine D) Haloperidol E) Clozapine F) 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) Zolpidem B) Amitriptyline C) Trazodone D) Fluoxetine E) Diazepam F) 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) Amitriptyline B) Clomipramine C) Bupropion D) Lithium E) Fluoxetine F) Trazodone

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Babbini, MD, PhD

Drugs for Mood Disorders

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 into presynaptic terminals and therefore increase monoamine availability in the synaptic cleft of central 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 in the synaptic cleft which in turn causes a down regulation of postsynaptic CNS receptors (mainly adrenergic 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 some days, and seems to indicate that down-regulation is the necessary event for antidepressant efficacy. These findings have suggested the dysregulation hypothesis of depression: the illness would be the result of a dysregulated neurotransmitter system and antidepressants would repair 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 pathway. This leads to depletion of PIP2 , which is the precursor of both IP3 and DAG. Therefore the synthesis of IP3 and DAG is inhibited and the activity of many receptors that are IP3 /DAG linked 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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Babbini, MD, PhD

Drugs for Mood Disorders

Paroxetine is a SSRI even more selective that fluoxetine, that is it inhibits exclusively serotonin reuptake. Mirtazapine blocks presynaptic alpha-2 receptors, which results in increased release of 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 postural hypotension, especially during the first week of treatment. Autonomic effects usually undergo tolerance, 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 a blocking 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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Babbini, MD, PhD

Drugs for Mood Disorders

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 body water. Therefore its volume of distribution is abut equal to the volume of body water, that is 42 liters 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 the steady 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, likely because of the tumor diagnosis. Pancreatic carcinoma is the type of cancer most frequently associated with depressive symptoms. Since the patient has been suffering from an arrhythmia, tricyclic antidepressants are contraindicated. MAO inhibitors are best suited for depressed patients of old age with considerable attendant anxiety, like in the present case. Since the woman 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 effectiveness gives 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), so the choice of the drug in a specific patient is influenced mainly by the patient history of previous response and contraindications. Since this patient is suffering from angina tricyclic antidepressants are contraindicated.

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Babbini, MD, PhD

Drugs for Mood Disorders

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 of tricyclic or SSRIs. Moreover it is contraindicated in the present case since the patient is suffering from 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 and insomnia, 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 suffering from 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 manic disorder. Lithium is a drug of choice for bipolar disorders, since it reduces both the frequency and 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 therapeutic effects. Therefore an adjunctive medication is used during the first days of therapy. Neuroleptics are 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 poor response 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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Babbini, MD, PhD

Drugs for Mood Disorders

the action of vasopressin on renal adenylyl cyclase. This leads to elevated circulating levels of vasopressin and lack of responsiveness of the collecting tubule, i.e. nephrogenic diabetes insipidus. 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 is stimulated, 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 chronic phantom limb pain, that is pain that is referred to a limb that no longer exists. Phantom limb pain is 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 often respond poorly to these drugs but is often relieved by tricyclic antidepressants. The analgesic properties of tricyclic antidepressants are independent of their antidepressant properties since they can produce analgesia directly through modulation of the descending inhibitory noradrenergic 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 bulimia nervosa, 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 for bulimia 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 tricyclic antidepressant. These drugs have a pronounced antimuscarinic activity (dry mouth, mydriasis, hot cheeks, palpitations), lower seizure threshold (myoclonic jerking) and prolong the QT interval on 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 postural hypotension (dizziness upon standing up rapidly) due to its alpha-1 blocking activity. In addition

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Babbini, MD, PhD

Drugs for Mood Disorders

it has been associated with a rare condition known as priapism (persistent and painful erection of 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, 11th ed., McGraw Hill, New York, 2006 - Katzung BG Basic and clinical Pharmacology, 9th ed., McGraw Hill, New York, 2004 - Koda-Kimble MA, Young LY, Kradian WA, Guglielmo BJ, Alldredge BK, Corelli RL Applied Therapeutics: The Clinical Use Of Drugs, 8th ed, Lippincott Williams & Wilkins, New York, 2005

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