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Affective Disorders. Overview What is a affective disorder? What is a affective disorder? Criteria for specific mood episodes and disorders Criteria for.

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1 Affective Disorders

2 Overview What is a affective disorder? What is a affective disorder? Criteria for specific mood episodes and disorders Criteria for specific mood episodes and disorders Pharmacological intervention Pharmacological intervention

3 Introduction The term affective is related to feelings, mood or emotion. The term affective is related to feelings, mood or emotion. Hippocrates first coined the term “melancholia” meaning “unshakable sadness”. Hippocrates first coined the term “melancholia” meaning “unshakable sadness”. Today known as depression Today known as depression So, affective disorder is a group of disorder that are related to mood and mainly include depression, mania and anxiety. So, affective disorder is a group of disorder that are related to mood and mainly include depression, mania and anxiety.

4 What is affective disorder? Mood is a person’s subjective emotional state Mood is a person’s subjective emotional state Affect is the objective appearance of mood Affect is the objective appearance of mood Mood disorders involve a depression or elevation of mood as the primary disturbance Mood disorders involve a depression or elevation of mood as the primary disturbance Can have other abnormalities such as anxiety. Can have other abnormalities such as anxiety.

5 Characterization Affective disorder is mainly characterized by: Affective disorder is mainly characterized by: Depression Depression Anxiety Anxiety Mania Mania

6 1. Major depression (Unipolar Depression) 2. Manic depressive illness (Bipolar Depression)

7 1. Major Depressive E pisode Depressed mood Depressed mood Anhedonia Anhedonia Decrease or increase in appetite OR significant weight loss or gain Decrease or increase in appetite OR significant weight loss or gain Persistently increased or decreased sleep Persistently increased or decreased sleep Psychomotor agitation or retardation Psychomotor agitation or retardation Fatigue or low energy Feelings of worthlessness or inappropriate guilt Decreased concentration or indecisiveness Recurrent thoughts of death, suicidal ideation, or suicide attempt Five or more symptoms present for ≥ 2 weeks

8 Psychosis is a symptom of mental illnesses characterized by a distorted or non-existent sense of reality. Psychotic disorders have different etiologies, each of which demands a unique treatment approach. Common psychotic disorders include major depression or mania with psychotic features, substance-induced psychosis, dementia with psychotic features, brief psychotic disorder, delusional disorder, schizophrenia. 2. Manic depressive illness (Bipolar Depression)

9 Symptoms of Anxiety Anxiety disorders encompass a constellation of symptoms, and include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, and acute stress. Anxiety disorders encompass a constellation of symptoms, and include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, and acute stress. Symptoms of anxiety also are often associated with depression and other medical conditions. Symptoms of anxiety also are often associated with depression and other medical conditions. Anxiety is common in MDD and bipolar disorder; however, may be a separate diagnosis. Anxiety is common in MDD and bipolar disorder; however, may be a separate diagnosis.

10 Major Depressive Disorder Presence of a major depressive episode Presence of a major depressive episode Episode not better explained by another diagnosis Episode not better explained by another diagnosis NO HISTORY of mania, hypomania, or mixed episode. NO HISTORY of mania, hypomania, or mixed episode.

11 Lifetime risk: Lifetime risk: 10%-25% for women 10%-25% for women 5%-12% for men 5%-12% for men Family history of MDD increases risk times Family history of MDD increases risk times Up to 20%-25% of patients with major medical comorbidity (CVD, diabetes, cancer) will develop MDD Up to 20%-25% of patients with major medical comorbidity (CVD, diabetes, cancer) will develop MDD Average age of onset in mid-20’s Average age of onset in mid-20’s Major Depressive Disorder

12 Major Depressive Disorder: Treatment basics Medications: Medications: Selective serotonin reuptake inhibitors (SSRIs) Selective serotonin reuptake inhibitors (SSRIs) Tricyclic antidepressants (TCAs) Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Monoamine oxidase inhibitors (MAOIs) Other: venlafaxine, mirtazapine, nefazodone, bupropion Other: venlafaxine, mirtazapine, nefazodone, bupropion Psychotherapy: Psychotherapy: Cognitive-behavioral therapy (CBT) Cognitive-behavioral therapy (CBT) Interpersonal therapy (IPT) Interpersonal therapy (IPT) Psychodynamic psychotherapy (e.g., psychoanalysis) Psychodynamic psychotherapy (e.g., psychoanalysis) Other Other Electroconvulsive therapy (ECT) Electroconvulsive therapy (ECT) Light therapy – primarily for SAD Light therapy – primarily for SAD

13 Major Depressive Disorder: Medications Treatment choice based on: Treatment choice based on: Severity Severity Side effect profile Side effect profile Risk of overdose Risk of overdose Other diagnoses (e.g., anxiety) Other diagnoses (e.g., anxiety) ?Family history of treatment response ?Family history of treatment response If psychosis is present, this must be treated If psychosis is present, this must be treated Medications may take up to 6 (8? 12?) weeks to be maximally effective Medications may take up to 6 (8? 12?) weeks to be maximally effective Efficacy 60%-80% overall (50%-60% for each) Efficacy 60%-80% overall (50%-60% for each)

14 Bipolar I Disorder At least one manic or mixed episode At least one manic or mixed episode No need for a prior depressive episode No need for a prior depressive episode

15 General Comments Symptoms cause significant impairment in social and/or occupational functioning. Symptoms cause significant impairment in social and/or occupational functioning. Symptoms do not result from a drug of abuse, medication, other treatment, or general medical condition Symptoms do not result from a drug of abuse, medication, other treatment, or general medical condition

16 Manic Episode Elevated (or irritable) mood for >1 week Elevated (or irritable) mood for >1 week Three or more of following (four if mood irritable): Three or more of following (four if mood irritable): Grandiosity Grandiosity Decreased need for sleep Decreased need for sleep Flight of ideas, racing thoughts Flight of ideas, racing thoughts Distractibility Distractibility Increased goal-directed activity Increased goal-directed activity Excessive involvement in pleasurable activities with high risk Excessive involvement in pleasurable activities with high risk

17 Causes Norepinephrine and serotonin cause functional deficit at specific nerve cell synapses that is associated with depression Norepinephrine and serotonin cause functional deficit at specific nerve cell synapses that is associated with depression On the other hand, excess of these neurotransmitters leading to mania. On the other hand, excess of these neurotransmitters leading to mania.

18 The precise cause of affective disorders remains elusive. Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).  Activity of NE and 5 -HT systems. Biogenic Theory of Depression

19 MAO COMT Amine neurotransmitters are either degraded (metab) or reuptaken Mito

20 The purpose of antidepressants is the increase the [neurotransmitters] in the synapse

21 Depression and Mania Monoamine Theory of Mental Depression Monoamine Theory of Mental Depression Depression is linked to low levels of norepinephrine and/or serotonin. Depression is linked to low levels of norepinephrine and/or serotonin. Mania is linked to high levels of norepinephrine and/or serotonin. Mania is linked to high levels of norepinephrine and/or serotonin. Bipolar mood disorder is alternating cycles of depression and mania. Bipolar mood disorder is alternating cycles of depression and mania

22 Drugs Used to Treat Depression Drugs that increase the level of norepinephrine and serotonin are used in the treatment of depression. Drugs that increase the level of norepinephrine and serotonin are used in the treatment of depression. Major antidepressant drug classes: Major antidepressant drug classes: Serotonin reuptake inhibitors (SSRIs) Serotonin reuptake inhibitors (SSRIs) Atypical SSRIs Atypical SSRIs Tricyclic antidepressants (TCAs) Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Monoamine oxidase inhibitors (MAOIs) 14-22

23 TREATMENT FOR DEPRESSION Psychotherapy Psychotherapy Electroconvulsive therapy Electroconvulsive therapy Natural alternatives Natural alternatives Medication Medication SSRIs SSRIs MAOIs MAOIs TCAs TCAs SNRIs SNRIs NDRIs NDRIs TeCAs TeCAs

24 NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS Neurotransmitters pass along signal Neurotransmitters pass along signal Smaller amount of neurotransmitters causes depression Smaller amount of neurotransmitters causes depression

25 MONOAMINE OXIDASE (MAO) AND DEPRESSION MAO catalyze deamination of intracellular monoamines MAO catalyze deamination of intracellular monoamines MAO-A oxidizes epinephrine, norepinephrine, serotonin MAO-A oxidizes epinephrine, norepinephrine, serotonin MAO-B oxidizes phenylethylamine MAO-B oxidizes phenylethylamine Both oxidize dopamine nonpreferentially Both oxidize dopamine nonpreferentially MAO transporters reuptake extracellular monoamine MAO transporters reuptake extracellular monoamine

26 MONOAMINE OXIDASE INHIBITORS (MAOIS) History History Isoniazid Isoniazid Iproniazid Iproniazid Isoniazid Iproniazid

27 MAOIs Isoniazide Antitubercular but too polar Iproniazide Antitubercular but CNS stimulant Which later shown to be MAOI resulting in  NE & 5-HT New antidepressant introduced but withdrawn due to liver toxicity, however, increased interest on hydrazines and hydrazides for antidepressants Thus MAOIs based on the hydrazine molecule have been extensively studied. Hydrazine, itself, has no MAOI activity Must have a free amino at one end to be active; a protonatable terminal N is necessary; those without a terminal N are prodrugs and must be bioactivated Must have at least one free hydrogen on each nitrogen hydrazines

28 Monoamine Oxidase Monoamine oxidase (MAO) is an enzyme found in adrenergic and serotonergic nerve endings. Monoamine oxidase (MAO) is an enzyme found in adrenergic and serotonergic nerve endings. Normal function of MAO is to break down norepinephrine and serotonin. Normal function of MAO is to break down norepinephrine and serotonin. In mental depression, there appears to be a decrease in the levels of brain norepinephrine and serotonin. In mental depression, there appears to be a decrease in the levels of brain norepinephrine and serotonin.

29 Monoamine Oxidase Inhibitors Consequently, the MAO inhibitors permit the levels of NE and serotonin in the brain to increase. Consequently, the MAO inhibitors permit the levels of NE and serotonin in the brain to increase. They have many drug interactions; caution must be exercised with use of other drugs. They have many drug interactions; caution must be exercised with use of other drugs.

30 Monoamine Oxidase Inhibitor Disadvantages of MOAIs: Disadvantages of MOAIs: Dietary restrictions—tyramine Dietary restrictions—tyramine Wine, beer, herring, certain cheeses Wine, beer, herring, certain cheeses Adverse effects: Adverse effects: Dry mouth, urinary retention, constipation, blurred vision, hypotension, weight gain, sexual dysfunction, liver damage that may be fatal Dry mouth, urinary retention, constipation, blurred vision, hypotension, weight gain, sexual dysfunction, liver damage that may be fatal CNS: restlessness, dizziness, insomnia, tremors, seizures, (intensified with over dosage) CNS: restlessness, dizziness, insomnia, tremors, seizures, (intensified with over dosage) 14-30

31 Monoamine Oxidase Inhibitor 14-31

32 MAOIS ON THE MARKET MAO Inhibitors (nonselective) MAO Inhibitors (nonselective) Phenelzine (Nardil) Phenelzine (Nardil) Tranylcypromine (Parnate) Tranylcypromine (Parnate) Isocarboxazid (Marplan) Isocarboxazid (Marplan) MAO-B Inhibitors (selective for MAO-B) MAO-B Inhibitors (selective for MAO-B) Selegiline (Emsam) Selegiline (Emsam)

33 MAOIS MECHANISM OF ACTION MAO contains a cysteinyl- linked flavin MAO contains a cysteinyl- linked flavin MAOIs covalently bind to N-5 of the flavin residue of the enzyme MAOIs covalently bind to N-5 of the flavin residue of the enzyme

34

35 MAOIS SIDE EFFECTS Drowsiness/FatigueConstipationNauseaDiarrheaDizziness Low blood pressure Lightheadedness, Decreased urine output Decreased sexual function Sleep disturbances Muscle twitching Weight gain Blurred vision Headache Increased appetite RestlessnessShakinessWeakness Increased sweating

36 MAOIS SIDE EFFECTS Side effects have put MAOIs in the second or third line of defense despite superior efficacy Side effects have put MAOIs in the second or third line of defense despite superior efficacy MAO-A inhibitors interfere with breakdown of tyramine MAO-A inhibitors interfere with breakdown of tyramine High tyramine levels cause hypertensive crisis (the “cheese effect”) High tyramine levels cause hypertensive crisis (the “cheese effect”) Can be controlled with restricted diet Can be controlled with restricted diet MAOIs interact with certain drugs MAOIs interact with certain drugs Serotonin syndrome (muscle rigidity, fever, seizures) Serotonin syndrome (muscle rigidity, fever, seizures) Pain medications and SSRIs must be avoided Pain medications and SSRIs must be avoided

37 THE RECEPTOR SENSITIVITY HYPOTHESIS Supersensitivity and up-regulation of post- synaptic receptors leads to depression Supersensitivity and up-regulation of post- synaptic receptors leads to depression Suicidal and depressed patients have increased 5HT-α 2 receptors Suicidal and depressed patients have increased 5HT-α 2 receptors

38 Tricyclic Antidepressants Drugs that block the reuptake of norepinephrine and serotonin back into the neuronal nerve endings Drugs that block the reuptake of norepinephrine and serotonin back into the neuronal nerve endings Produce varying degrees of sedation, anticholinergic effects, and alpha- adrenergic blocking effects Produce varying degrees of sedation, anticholinergic effects, and alpha- adrenergic blocking effects 14-38

39 Tricyclic Antidepressants 14-39

40 Tricyclic Antidepressants TCAs with a tertiary-amine side chain, including amitriptyline, doxepin, and imipramine, inhibit both norepinephrine and serotonin uptake. Clomipramine is somewhat selective for inhibition of serotonin uptake. Chemical modification of the TCA structure led to the earliest SSRI zimelidine. Imipramine has a phenothiazine-like structure (unlike the phenothiazines) had limited efficacy in schizophrenic patients, but improved symptoms of depression. Imipramine and related TCAs became the mainstay of drug treatment of depression until the later development of the SSRIs

41 Tricyclic Antidepressants TCAs with a tertiary-amine side chain, including amitriptyline, doxepin, and imipramine, inhibit both norepinephrine and serotonin uptake. Clomipramine is somewhat selective for inhibition of serotonin uptake. Chemical modification of the TCA structure led to the earliest SSRI zimelidine which, while effective, was withdrawn from the market due to serious adverse effects. One of the compounds, imipramine, which has a phenothiazine-like structure, modified behavior in animal models. Unlike the phenothiazines, imipramine had limited efficacy in schizophrenic patients, but improved symptoms of depression. Imipramine and related TCAs became the mainstay of drug treatment of depression until the later development of the SSRIs Fluoxetine and fluvoxamine were the first widely used SSRIs. At the same time, selective inhibitors of norepinephrine reuptake entered clinical development; while not approved for use in the U.S. for the treatment of depression, one norepinephrine reuptake inhibitor, atomoxetine, is used for the treatment of attention deficit hyperactivity disorder. Subsequent drug development efforts focused on serotonin and norepinephrine reuptake inhibitors (SNRIs), resulting in venlafaxine and duloxetine, which lack the complex receptor pharmacology exhibited by the TCAs

42 TRICYCLIC ANTIDEPRESSANTS (TCAS) Imipramine was first tried as an antipsychoti drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs. Imipramine was first tried as an antipsychoti drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs. Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania Imipramine

43 TCAS MECHANISM OF ACTION TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake TCAs also allow for the downregulation of post- synaptic receptors TCAs also allow for the downregulation of post- synaptic receptors All TCAs and SSRIs contain an essential amino group that appears to interact with Asp- 98 in hSERT All TCAs and SSRIs contain an essential amino group that appears to interact with Asp- 98 in hSERT

44 TCAS MECHANISM OF ACTION

45 TCAS SIDE EFFECTS Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence Histamine H1 receptor antagonism - sedation and weight gain Histamine H1 receptor antagonism - sedation and weight gain Adrenergic α receptor antagonism - postural hypotension Adrenergic α receptor antagonism - postural hypotension Direct membrane effects - reduced seizure threshold, arrhythmia Direct membrane effects - reduced seizure threshold, arrhythmia Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety) Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

46 SELECTIVE SEROTONIN REUPTAKE INHIBITORS Most commonly prescribed class Most commonly prescribed class Current drugs Current drugs Mechanism of action Mechanism of action Side effects Side effects Serotonin

47 Selective Serotonin Reuptake Inhibitors SSRIs were introduced from SSRIs were introduced from including fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine. including fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine. The FDA has approved fluvoxamine for treatment of obsessive-compulsive disorder and social anxiety disorder, but not depression. The FDA has approved fluvoxamine for treatment of obsessive-compulsive disorder and social anxiety disorder, but not depression. Citalopram is labeled for use in premenstrual dysphoric disorder. Citalopram is labeled for use in premenstrual dysphoric disorder. All of the SSRIs show a clear improvement in safety margin compared to the TCAs and are much safer in overdose. All of the SSRIs show a clear improvement in safety margin compared to the TCAs and are much safer in overdose.

48 Selective Serotonin Reuptake Inhibitors The SSRIs are effective in treating major depression. The SSRIs are effective in treating major depression. In typical studies SSRI treatment results in ~ 35% of patients enjoying a remission, In typical studies SSRI treatment results in ~ 35% of patients enjoying a remission, SSRIs also are anxiolytics with demonstrated efficacy in the treatment of generalized anxiety, panic, social anxiety, and OCD. SSRIs also are anxiolytics with demonstrated efficacy in the treatment of generalized anxiety, panic, social anxiety, and OCD. Sertraline and paroxetine also have been approved for the treatment of posttraumatic stress disorder (PTSD). Sertraline and paroxetine also have been approved for the treatment of posttraumatic stress disorder (PTSD).

49 Selective Serotonin Reuptake Inhibitors SSRIs block the reuptake of serotonin back into the serotonergic nerve endings. SSRIs block the reuptake of serotonin back into the serotonergic nerve endings. This increases the serotonin available to work on the system. This increases the serotonin available to work on the system. SSRIs are relatively selective, that is, 10-fold or more, for inhibition of SERT relative to NET. SSRIs are relatively selective, that is, 10-fold or more, for inhibition of SERT relative to NET. SSRIs are the preferred treatment for major depression and effective for PTSD and OCD. SSRIs are the preferred treatment for major depression and effective for PTSD and OCD.

50 SSRI treatment causes stimulation of 5-HT 1A and 5- HT 7 autoreceptors on cell bodies in the raphe nucleus and of 5-HT 1D autoreceptors on serotonergic terminals. With repeated treatment with SSRIs, there is a gradual down-regulation and desensitization of these autoreceptor mechanisms. In addition, down-regulation of postsynaptic 5- HT 2A receptors may contribute to antidepressant efficacy directly or by influencing the function of noradrenergic and other neurons via serotonergic heteroreceptors. Selective Serotonin Reuptake Inhibitors

51 1-51 All of the SSRIs are orally active and possess elimination half-lives consistent with once-daily dosing. In the case of fluoxetine, the combined action of the parent and the desmethyl metabolite norfluoxetine allows for a once weekly formulation (PROZAC WEEKLY). CYP2D6 is involved in the metabolism of most SSRIs and the SSRIs are at least moderately potent inhibitors of this isoenzyme.. SSRI: Pharmacokinetics

52 1-52 This creates a significant potential for drug interaction for post-menopausal women taking the breast cancer drug and estrogen antagonist, tamoxifen. The parent molecule is converted to a more active metabolite by CYP2D6. SSRIs may inhibit this activation and diminish the therapeutic activity of tamoxifen. Since venlafaxine and desvenlafaxine are weak inhibitors of CYP2D6, these antidepressants are not contraindicated in this clinical situation. However, care should be used in combining SSRIs with drugs that are metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., warfarin, tricyclic antidepressants, paclitaxel). Selective Serotonin Reuptake Inhibitors

53 Adverse effects: Adverse effects: GI disturbances GI disturbances Dry mouth Dry mouth Sexual dysfunction Sexual dysfunction Headache Headache Nervousness Nervousness Insomnia Insomnia Tremors Tremors 14-53

54 Selective Serotonin Reuptake Inhibitors The SSRIs, unlike the TCAs, do not cause major cardiovascular side effects. The SSRIs, unlike the TCAs, do not cause major cardiovascular side effects. The SSRIs are generally free of antimuscarinic side effects (dry mouth, urinary retention, confusion), The SSRIs are generally free of antimuscarinic side effects (dry mouth, urinary retention, confusion), Do not block histamine or adrenergic receptors, and are not sedating. Do not block histamine or adrenergic receptors, and are not sedating.

55 Selective Serotonin Reuptake Inhibitors Excessive stimulation of brain 5-HT 2 receptors may result in insomnia, increased anxiety, irritability, and decreased libido, worsening prominent depressive symptoms. Excessive stimulation of brain 5-HT 2 receptors may result in insomnia, increased anxiety, irritability, and decreased libido, worsening prominent depressive symptoms. Excess activity at spinal 5-HT 2 receptors causes sexual side effects including erectile dysfunction, and ejaculatory delay. Excess activity at spinal 5-HT 2 receptors causes sexual side effects including erectile dysfunction, and ejaculatory delay.

56 Selective Serotonin Reuptake Inhibitors Stimulation of 5-HT 3 receptors in the CNS and periphery contributes to GI effects- nausea, diarrhea and emesis. Stimulation of 5-HT 3 receptors in the CNS and periphery contributes to GI effects- nausea, diarrhea and emesis.

57 Selective Serotonin Reuptake Inhibitors 14-57

58 Atypical SSRIs They block reuptake of serotonin and act on other neurotransmitters and receptors as well. (NE and/or Dopamine) They block reuptake of serotonin and act on other neurotransmitters and receptors as well. (NE and/or Dopamine) Like the SSRIs, they have little effect in blocking cholinergic, adrenergic, or histamine receptors. Like the SSRIs, they have little effect in blocking cholinergic, adrenergic, or histamine receptors

59 Atypical SSRIs 14-59

60 Appears to act via multiple mechanisms: enhances noradrenergic and dopaminergic neurotransmission via reuptake inhibition Appears to act via multiple mechanisms: enhances noradrenergic and dopaminergic neurotransmission via reuptake inhibition Also involve the presynaptic release of NE and DA. Also involve the presynaptic release of NE and DA. Indicated for depression, prevention of seasonal depressive disorder, and as a smoking cessation treatment. Indicated for depression, prevention of seasonal depressive disorder, and as a smoking cessation treatment. Improve symptoms of attention deficit hyperactivity disorder (ADHD). Improve symptoms of attention deficit hyperactivity disorder (ADHD). Used in combination with SSRIs to obtain a greater antidepressant response. Used in combination with SSRIs to obtain a greater antidepressant response. Atypical SSRIs:Bupropion

61 The terminal phase of bupropion elimination has a t 1/2 of 21 hours. The terminal phase of bupropion elimination has a t 1/2 of 21 hours. The elimination involves both hepatic and renal routes. The elimination involves both hepatic and renal routes. Decreased dose should also be made in cases of renal impairment. Decreased dose should also be made in cases of renal impairment. Atypical SSRIs:Bupropion

62 Adverse effects: Adverse effects: At doses higher than that recommended for depression (450 mg/day), the risk of seizures increases significantly. At doses higher than that recommended for depression (450 mg/day), the risk of seizures increases significantly. The use of extended release formulations often blunts the maximum concentration observed after dosing. The use of extended release formulations often blunts the maximum concentration observed after dosing. Atypical SSRIs:Bupropion

63 Drug interaction: Drug interaction: The major route of metabolism is CYP2B6. The major route of metabolism is CYP2B6. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Atypical SSRIs:Bupropion

64 Paroxetine, fluoxetine are potent inhibitors of CYP2D6. Paroxetine, fluoxetine are potent inhibitors of CYP2D6. This inhibition can result in disproportionate increases in plasma concentrations of drugs metabolized by CYP2D6. This inhibition can result in disproportionate increases in plasma concentrations of drugs metabolized by CYP2D6. A prominent interaction is the increase in TCA exposure that may be observed during co-administration of TCAs and SSRIs. A prominent interaction is the increase in TCA exposure that may be observed during co-administration of TCAs and SSRIs. : Drug interaction : Selective Serotonin Reuptake Inhibitors

65 MAOIs enhance the effects of SSRIs due to inhibition of serotonin metabolism. MAOIs enhance the effects of SSRIs due to inhibition of serotonin metabolism. Administration of these drugs together can produce synergistic increases in extracellular brain serotonin, leading to the serotonin syndrome. Administration of these drugs together can produce synergistic increases in extracellular brain serotonin, leading to the serotonin syndrome. Other drugs that may induce the serotonin syndrome include: methylenedioxymethamphetamine. Other drugs that may induce the serotonin syndrome include: methylenedioxymethamphetamine. : Drug interaction : Selective Serotonin Reuptake Inhibitors

66 SSRIs should not be started until at least 14 days following discontinuation of treatment with an MAOI. SSRIs should not be started until at least 14 days following discontinuation of treatment with an MAOI. For all SSRIs, 14 days should pass prior to beginning treatment with an MAOI following the end of treatment with an SSRI. Exception: fluoxetine. For all SSRIs, 14 days should pass prior to beginning treatment with an MAOI following the end of treatment with an SSRI. Exception: fluoxetine. : Drug interaction : Selective Serotonin Reuptake Inhibitors

67 Drug interaction: Drug interaction: The major route of metabolism is CYP2B6. The major route of metabolism is CYP2B6. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Atypical SSRIs:Bupropion

68 Drug interaction: Drug interaction: The major route of metabolism is CYP2B6. The major route of metabolism is CYP2B6. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Atypical SSRIs:Bupropion

69 Drug interaction: Drug interaction: The major route of metabolism is CYP2B6. The major route of metabolism is CYP2B6. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Does not appear to be metabolised by CYP2D6 and this drug is frequently administered with SSRIs. Atypical SSRIs:Bupropion

70 SSRIS SIDE EFFECTS AnhedoniaApathyNausea/vomiting Drowsiness or somnolence Headache Bruxism (involuntarily grinding of the teeth) Extremely vivid and strange dreams DizzinessFatigue Changes in sexual behavior Suicidal thoughts

71 Summary Q: What was the first Antidepressant, and what is its mech of action? Iproniazid Iproniazid Q: Describe the clinical effects of tyramine toxicity ncreases the release of NE ncreases the release of NE When a person is on an MAOI and also consumes tyramine containing foods/drinks, there is NE overload which can cause hypertensive crisis. When a person is on an MAOI and also consumes tyramine containing foods/drinks, there is NE overload which can cause hypertensive crisis.

72 MAOIs Second line treatment, due to side effect profile Second line treatment, due to side effect profile potentially lethal food and drug interactions potentially lethal food and drug interactions Still used for refractory depression Still used for refractory depression

73 Adverse Effects of TCA's Adverse Effects of TCA's Significant Overdose Potential due to narrow therapeutic window. Significant Overdose Potential due to narrow therapeutic window. Cardiovascular Toxicity (potential for fatal cardiac arrythmia). Cardiovascular Toxicity (potential for fatal cardiac arrythmia). Side effects: Side effects: anti-histaminergic (weight gain, drowsiness) anti-histaminergic (weight gain, drowsiness) anti-cholinergic (constipation, blurred vision, dry mouth, drowsiness again) anti-cholinergic (constipation, blurred vision, dry mouth, drowsiness again) anti-alpha adrenergic (dizziness, decreased BP) anti-alpha adrenergic (dizziness, decreased BP) )

74 Compare the efficacy and side effects for Secondary amine TCA's vs Tertiary amine TCA's Tertiary amines have greater alpha, histamine 1, and muscarinic blockade. Tertiary amines have greater alpha, histamine 1, and muscarinic blockade. Secondary amines are newer, have fewer side effects, are less sedating, and hold less overdose risk. Secondary amines are newer, have fewer side effects, are less sedating, and hold less overdose risk.

75 Issues in antidepressant therapy Important issue in the use of antidepressants is a phenomenon known as the "switch" from a depressed episode to a manic or hypomanic episode, a challenge in managing bipolar illness. Important issue in the use of antidepressants is a phenomenon known as the "switch" from a depressed episode to a manic or hypomanic episode, a challenge in managing bipolar illness. For this reason, antidepressants are not recommended as monotherapy for bipolar illness. For this reason, antidepressants are not recommended as monotherapy for bipolar illness. SSRIs and bupropion may be somewhat less likely to induce the switch from depression to mania than antidepressants from other pharmacological classes. SSRIs and bupropion may be somewhat less likely to induce the switch from depression to mania than antidepressants from other pharmacological classes.

76 Issues in antidepressant therapy A controversial issue regarding the use of all antidepressants is their relationship to suicide. A controversial issue regarding the use of all antidepressants is their relationship to suicide. The FDA has issued a "black box" warning regarding the use of SSRIs and a number of other antidepressants in children and adolescents, particularly during the early phase of treatment, due to the possibility of an association between antidepressant treatment and suicide. The FDA has issued a "black box" warning regarding the use of SSRIs and a number of other antidepressants in children and adolescents, particularly during the early phase of treatment, due to the possibility of an association between antidepressant treatment and suicide.

77 Drugs Serotonin Receptor Antagonists Serotonin Receptor Antagonists Several antagonists of the 5-HT 2 family of receptors are effective antidepressants, although most agents of this class affect other receptor classes as well. The class includes two pairs of close structural analogues, trazodone and nefazodone, as well as mirtazapine and mianserin (not marketed in the U.S.).

78

79 the nucleus of the brain that uses serotonin, and locations to which its neurons project: 5HT neurons project to: 5HT neurons project to: Frontal Frontal Limbic Limbic Brainstem Brainstem Hypothalamus Hypothalamus

80 Serotonin Antagonist & Reuptake Inhibitors Its an SSRI that also blocks the 5HT2A-R (overall, its less activating and more sedating than the SSRI's Its an SSRI that also blocks the 5HT2A-R (overall, its less activating and more sedating than the SSRI's Used to treat depression, anxiety, insomnia Used to treat depression, anxiety, insomnia AND no associated weight gain OR sexual dysfunction AND no associated weight gain OR sexual dysfunction Adverse: Sedation, orthostatic hypotention, priapism (rare Adverse: Sedation, orthostatic hypotention, priapism (rare Yet its rarely used, not 1st line Yet its rarely used, not 1st line

81 Serotonin vs Norepinephrine Therapeutic Effects and Side Effects Overall, Serotonin is more of a calming agent, NE more of a stimulating agent Overall, Serotonin is more of a calming agent, NE more of a stimulating agent Serotonin - therapeutically acts on mood, anxiety, and obsessions Serotonin - therapeutically acts on mood, anxiety, and obsessions NE - acts on mood, attention, and improves low energy states. NE - acts on mood, attention, and improves low energy states. Serotonin side effects - sexual dysfunction, GI, Insomnia, Akasthesia Serotonin side effects - sexual dysfunction, GI, Insomnia, Akasthesia NE side effects - Tremor, elevated BP/HR, urinary retention NE side effects - Tremor, elevated BP/HR, urinary retention

82 5-HT 1 Receptors preferentially couple to G i/o ; inhibit adenylyl cyclase. The 5-HT 1A, 5-HT 1B, & 5-HT 1D activate a receptor- operated K + channel and inhibit a voltage-gated Ca 2+ channel. The 5-HT 1A is found in raphe nuclei of the brainstem- functions as an inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons. Another 5-HT 1 subtype, the 5-HT 1D/1B, functions as an autoreceptor on axon terminals, inhibiting 5-HT release.

83 5-HT 2 Receptors 3subtypes of 5-HT 2 couple to Gq/G 11 proteins and activate phospholipase C, generating 2 second messengers: diacylglycerol and inositol trisphosphate. 3subtypes of 5-HT 2 couple to Gq/G 11 proteins and activate phospholipase C, generating 2 second messengers: diacylglycerol and inositol trisphosphate. 5-HT 2A and 5-HT 2C receptors also activate phospholipase A 2 -release of arachidonic acid. 5-HT 2A and 5-HT 2C receptors also activate phospholipase A 2 -release of arachidonic acid. 5-HT 2A : broadly distributed in the CNS, serotonergic terminal. Also in prefrontal, parietal, and somatosensory cortex, in blood platelets and smooth muscle cells. 5-HT 2A : broadly distributed in the CNS, serotonergic terminal. Also in prefrontal, parietal, and somatosensory cortex, in blood platelets and smooth muscle cells. 5-HT 2B found in stomach fundus, where they are abundant. The expression of 5-HT 2B receptors is highly restricted in the CNS. 5-HT 2B found in stomach fundus, where they are abundant. The expression of 5-HT 2B receptors is highly restricted in the CNS.

84 5-HT 3 Receptors The 5-HT 3 receptor is the only monoamine neurotransmitter receptor function as a ligand-operated ion channel. The 5-HT 3 receptor is the only monoamine neurotransmitter receptor function as a ligand-operated ion channel. Activation of 5-HT 3 elicits a rapidly desensitizing depolarization, mediated by the gating of cations. Activation of 5-HT 3 elicits a rapidly desensitizing depolarization, mediated by the gating of cations. Located on parasympathetic terminals in the GI tract, including vagal and splanchnic afferents. In the CNS, in the solitary tract nucleus and in the area postrema. Located on parasympathetic terminals in the GI tract, including vagal and splanchnic afferents. In the CNS, in the solitary tract nucleus and in the area postrema. 5-HT 3 receptors in both the GI tract and the CNS participate in the emetic response, providing a basis for the anti-emetic property of 5-HT 3 receptor antagonists. 5-HT 3 receptors in both the GI tract and the CNS participate in the emetic response, providing a basis for the anti-emetic property of 5-HT 3 receptor antagonists.

85 5-HT 4 Receptors 5-HT 4 couple to G s to activate adenylyl cyclase. 5-HT 4 couple to G s to activate adenylyl cyclase. distributed throughout the body. on neurons of the superior and inferior colliculi and in the hippocampus in CNS. distributed throughout the body. on neurons of the superior and inferior colliculi and in the hippocampus in CNS. In the GI tract, 5-HT 4 are located on neurons of the myenteric plexus and on smooth muscle and secretory cells. In the GI tract, 5-HT 4 are located on neurons of the myenteric plexus and on smooth muscle and secretory cells. Stimulation of the 5-HT 4 receptor evokes secretion and facilitates the peristaltic reflex. Stimulation of the 5-HT 4 receptor evokes secretion and facilitates the peristaltic reflex. Effects of pharmacological manipulation of 5-HT 4 receptors on memory and feeding in animal models suggest possible clinical applications in the future Effects of pharmacological manipulation of 5-HT 4 receptors on memory and feeding in animal models suggest possible clinical applications in the future

86 5-HT Receptors on CNS A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion. A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion. The principal cell bodies of 5-HT neurons are located in raphe nuclei of the brainstem and project throughout the brain and spinal cord. The principal cell bodies of 5-HT neurons are located in raphe nuclei of the brainstem and project throughout the brain and spinal cord. release of serotonin occurs at sites of axonal swelling, termed varicosities, which do not form distinct synaptic contacts. Such non-synaptic release is consistent with the idea that 5-HT acts as a neuromodulator as well as a neurotransmitter. release of serotonin occurs at sites of axonal swelling, termed varicosities, which do not form distinct synaptic contacts. Such non-synaptic release is consistent with the idea that 5-HT acts as a neuromodulator as well as a neurotransmitter.

87 Sleep-Wake Cycle Control of the sleep-wake cycle is one of the first behaviors in which a role for 5-HT was identified. Control of the sleep-wake cycle is one of the first behaviors in which a role for 5-HT was identified. Depletion of 5-HT with p-chlorophenylalanine, a tryptophan hydroxylase inhibitor, elicits insomnia that is reversed by the 5-HT precursor, 5- hydroxytryptophan. Depletion of 5-HT with p-chlorophenylalanine, a tryptophan hydroxylase inhibitor, elicits insomnia that is reversed by the 5-HT precursor, 5- hydroxytryptophan. Conversely, treatment with L-tryptophan or with nonselective 5-HT agonists accelerates sleep onset and prolongs total sleep time. Conversely, treatment with L-tryptophan or with nonselective 5-HT agonists accelerates sleep onset and prolongs total sleep time.

88 Aggression and Impulsivity 5-HT serves a critical role in aggression and impulsivity. 5-HT serves a critical role in aggression and impulsivity. Pharmacological studies of aggressive behavior in laboratory animals suggest a role for 5-HT. Pharmacological studies of aggressive behavior in laboratory animals suggest a role for 5-HT. 5-HT 1B receptors in the development of neuronal pathways important in aggression or a direct role in the mediation of aggressive behavior. 5-HT 1B receptors in the development of neuronal pathways important in aggression or a direct role in the mediation of aggressive behavior.

89 Anxiety and Depression The effects of 5-HT–active drugs in anxiety and depressive disorders, like the effects of selective serotonin reuptake inhibitors (SSRIs), strongly suggest a role for 5-HT in the neurochemical mediation of these disorders. Mutant mice lacking the 5-HT transporter display anxiety and a "depressive-like" phenotype. The effects of 5-HT–active drugs in anxiety and depressive disorders, like the effects of selective serotonin reuptake inhibitors (SSRIs), strongly suggest a role for 5-HT in the neurochemical mediation of these disorders. Mutant mice lacking the 5-HT transporter display anxiety and a "depressive-like" phenotype.

90 Anxiety and Depression

91 Mech of Action: Serotonin-Norepinephrine Reuptake Inhibitors SNRIs inhibit both SERT and NET. SNRIs cause enhanced serotonergic and/or noradrenergic neurotransmission. SNRIs inhibit both SERT and NET. SNRIs cause enhanced serotonergic and/or noradrenergic neurotransmission. Similar to the action of SSRIs, the initial inhibition of SERT induces activation of 5-HT 1A and 5-HT 1D autoreceptors. Similar to the action of SSRIs, the initial inhibition of SERT induces activation of 5-HT 1A and 5-HT 1D autoreceptors. This action decreases serotonergic neurotransmission by a negative feedback mechanism until these serotonergic autoreceptors are desensitized. This action decreases serotonergic neurotransmission by a negative feedback mechanism until these serotonergic autoreceptors are desensitized. Then, the enhanced serotonin concentration in the synapse interact with postsynaptic 5-HT receptors. Then, the enhanced serotonin concentration in the synapse interact with postsynaptic 5-HT receptors.

92 Serotonin Receptor Antagonists antagonists of the 5-HT 2 are effective antidepressants, although most agents of this class affect other receptor classes as well. antagonists of the 5-HT 2 are effective antidepressants, although most agents of this class affect other receptor classes as well. The class includes two pairs of close structural analogues, trazodone and nefazodone, mirtazapine (REMERON, others) and mianserin. The class includes two pairs of close structural analogues, trazodone and nefazodone, mirtazapine (REMERON, others) and mianserin. Trazodone and nefazodone block 5-HT 2 and alfa 1 adrenergic receptors. Trazodone also inhibits the serotonin transporter, but is markedly less potent relative to its blockade of 5-HT 2A receptors. Trazodone and nefazodone block 5-HT 2 and alfa 1 adrenergic receptors. Trazodone also inhibits the serotonin transporter, but is markedly less potent relative to its blockade of 5-HT 2A receptors.

93 Differential Diagnosis: Other mood and anxiety disorders Symptoms of mood disorders may overlap (e.g., dysthymia and MDD) Symptoms of mood disorders may overlap (e.g., dysthymia and MDD) Diagnosis is often based on history – and patient’s memory of past symptoms may be unreliable Diagnosis is often based on history – and patient’s memory of past symptoms may be unreliable

94 Medical conditions Thyroid abnormalities Thyroid abnormalities Cortisol abnormalities Cortisol abnormalities Parkinson’s disease Parkinson’s disease Multiple sclerosis Multiple sclerosis Epilepsy Epilepsy Brain tumor Brain tumor Cancer (e.g., pancreatic) Cancer (e.g., pancreatic) Dementia Dementia Traumatic brain injury Traumatic brain injury Autoimmune disorders Autoimmune disorders Stroke Huntington’s disease Chronic infections Certain medications: Steroids Interferon Beta-blockers Isotretinoin (Accutane) Oral contraceptives Antidepressants (!!) Everything else?!?

95 Substance-induced mood disorder Alcohol: depression Alcohol: depression Cocaine: hypomania, mania Cocaine: hypomania, mania Amphetamines: hypomania, mania Amphetamines: hypomania, mania PCP, ketamine: hypomania, mania Heroin: depression? Marijuana: depression? Mood symptoms with intoxication or withdrawal Mood symptoms with intoxication or withdrawal May take weeks-months to normalize mood May take weeks-months to normalize mood Substance use highly comorbid in mood disorders Substance use highly comorbid in mood disorders (bipolar I > bipolar II > MDD) (bipolar I > bipolar II > MDD)

96 Long-term effects: Antidepressant drugs Long-term effects of antidepressant drugs evoke adaptive or regulatory mechanisms that enhance the effectiveness of therapy. These responses include increased adrenergic or serotonergic receptor density or sensitivity, increased receptor-G protein coupling and cyclic nucleotide signaling, induction of neurotrophic factors, and increased neurogenesis in the hippocampus. hanced serotonergic or noradrenergic neurotransmission achieved by an alternative pharmacological mechanism. Long-term effects of antidepressant drugs evoke adaptive or regulatory mechanisms that enhance the effectiveness of therapy. These responses include increased adrenergic or serotonergic receptor density or sensitivity, increased receptor-G protein coupling and cyclic nucleotide signaling, induction of neurotrophic factors, and increased neurogenesis in the hippocampus. hanced serotonergic or noradrenergic neurotransmission achieved by an alternative pharmacological mechanism.

97 Long-term effects: Antidepressant drugs Chronic treatment with some antidepressants that interact directly with monoamine transporters (e.g., SSRIs, SNRIs, or NE reuptake inhibitors) reduces the expression and activity of 5-HT or NE transporters in the brain, which results in enhanced serotonergic or noradrenergic neurotransmission. Sustained signaling via NE or 5-HT increases the expression of specific downstream gene products, particularly brain-derived neurotrophic factor (BDNF). Chronic treatment with some antidepressants that interact directly with monoamine transporters (e.g., SSRIs, SNRIs, or NE reuptake inhibitors) reduces the expression and activity of 5-HT or NE transporters in the brain, which results in enhanced serotonergic or noradrenergic neurotransmission. Sustained signaling via NE or 5-HT increases the expression of specific downstream gene products, particularly brain-derived neurotrophic factor (BDNF).

98 Suggested history/workup Review of current and past psych sx/dx Review of current and past psych sx/dx Get collateral history Get collateral history Review prior treatments and response Review prior treatments and response Family history Family history Medical history Medical history Current medications Current medications Substance use history Substance use history Social history Social history Review of systems Workup CBC Electrolytes Renal function Liver Function TSH RPR? HIV? Imaging?

99 Treatment/management ALWAYS ASSESS FOR SUICIDE!!! ALWAYS ASSESS FOR SUICIDE!!! Ideation, plan, intent, means, risk factors Ideation, plan, intent, means, risk factors Choose medications carefully and thoughtfully Choose medications carefully and thoughtfully Don’t give up too soon Don’t give up too soon Can always incorporate some behavioral and CBT techniques (e.g., behavioral activation) Can always incorporate some behavioral and CBT techniques (e.g., behavioral activation) Address perpetuating factors (medical problems, psychosocial stressors) Address perpetuating factors (medical problems, psychosocial stressors) Treat the acute AND chronic aspects of the illness (i.e., preventive management) Treat the acute AND chronic aspects of the illness (i.e., preventive management)

100 Case #1a Mr. M is a 34 y/o man who presents with 1- month history of sad mood and decreased motivation to go to work. He reports difficulty falling asleep at night and multiple mid-cycle awakenings. His appetite and energy are normal. Mr. M is a 34 y/o man who presents with 1- month history of sad mood and decreased motivation to go to work. He reports difficulty falling asleep at night and multiple mid-cycle awakenings. His appetite and energy are normal. What other questions do you have? What other questions do you have? What is your working diagnosis? What is your working diagnosis? What is your initial treatment plan? What is your initial treatment plan?

101 Case #1b Mr. M returns one month later. He continues to have sad mood, decreased motivation, and feels that things are getting worse. Mr. M returns one month later. He continues to have sad mood, decreased motivation, and feels that things are getting worse. What other questions do you have? What other questions do you have? What is your working diagnosis? What is your working diagnosis? What is your treatment plan? What is your treatment plan?

102 Case #2a Ms. T is a 19 y/o female college student who presents to the emergency room with a several day history of bizarre behavior at school. Her friends say she hasn’t slept for 4-5 days, is talking “a mile a minute,” and is trying to help everybody do their homework stating, “you’ll never find a better tutor than me!!” Ms. T is a 19 y/o female college student who presents to the emergency room with a several day history of bizarre behavior at school. Her friends say she hasn’t slept for 4-5 days, is talking “a mile a minute,” and is trying to help everybody do their homework stating, “you’ll never find a better tutor than me!!” What other questions do you have? What other questions do you have? What is your working diagnosis? What is your working diagnosis? What is your treatment plan? What is your treatment plan?

103 Case #2b Ms. T does well during the hospitalization and is discharged in about 8 days. She returns to clinic in 4 weeks and says she thinks she’s ready to come off the medication. Ms. T does well during the hospitalization and is discharged in about 8 days. She returns to clinic in 4 weeks and says she thinks she’s ready to come off the medication. What other questions do you have? What other questions do you have? What do you tell her? What do you tell her?

104 Case #2c Ms. T stops her medications. She returns to see you in another 4 weeks and tells you she feels great – especially since she’s “off of those mind- dulling drugs.” She feels much more alert and is able to accomplish “more than ever before.” She says she is doing well with just 5 hours sleep per night and feels that she’s finally “found” herself. Ms. T stops her medications. She returns to see you in another 4 weeks and tells you she feels great – especially since she’s “off of those mind- dulling drugs.” She feels much more alert and is able to accomplish “more than ever before.” She says she is doing well with just 5 hours sleep per night and feels that she’s finally “found” herself. What other questions do you have? What other questions do you have? What is your working diagnosis (has it changed)? What is your working diagnosis (has it changed)? What is your treatment plan? What is your treatment plan?

105 Case #2d Ms. T refuses to re-start medications. Eight weeks later, she is brought into the emergency room after an acetaminophen OD. You evaluate her during the medical hospitalization. She reports 4-5 weeks of worsening “emptiness,” difficulty falling asleep, racing thoughts, and feeling “revved up.” She has had increasing SI over the past week. Ms. T refuses to re-start medications. Eight weeks later, she is brought into the emergency room after an acetaminophen OD. You evaluate her during the medical hospitalization. She reports 4-5 weeks of worsening “emptiness,” difficulty falling asleep, racing thoughts, and feeling “revved up.” She has had increasing SI over the past week. What other questions do you have? What other questions do you have? What is your working diagnosis (has it changed)? What is your working diagnosis (has it changed)? What is your treatment plan? What is your treatment plan?

106 Case #3a Patient is a 6-7 y/o gray male donkey who complains that “no one really cares about me.” He states that he generally feels down and never has enough energy. Patient is a 6-7 y/o gray male donkey who complains that “no one really cares about me.” He states that he generally feels down and never has enough energy. What other questions do you have? What other questions do you have? What is your working diagnosis? What is your working diagnosis? What is your treatment plan? What is your treatment plan?

107 Case #3b He returns 4 weeks later and tells you he doesn’t really feel any better. He returns 4 weeks later and tells you he doesn’t really feel any better. What other questions do you have? What other questions do you have? What is your working diagnosis? What is your working diagnosis? What is your treatment plan? What is your treatment plan?


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