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Psychopharmacology of Mood Disorders Dr. Lisa McMurray 6 Jan 2015 Based on a 2014 presentation by Dr. Kate Huntington.

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Presentation on theme: "Psychopharmacology of Mood Disorders Dr. Lisa McMurray 6 Jan 2015 Based on a 2014 presentation by Dr. Kate Huntington."— Presentation transcript:

1 Psychopharmacology of Mood Disorders Dr. Lisa McMurray 6 Jan 2015 Based on a 2014 presentation by Dr. Kate Huntington

2 Pre-test (true/false) All patients with symptoms of major depression should be treated with an antidepressant Mirtazapine causes drowsiness through its effects on the benzodiazepine receptor SNRIs such as Venlafaxine can cause diastolic hypertension

3 Pre-test (true/false) Trazodone is rarely tolerated at full therapeutic dosages due to significant sedation side effects Lithium is rarely tolerated due to multiple side effects and should be reserved only for treatment resistant bipolar patients Atypical antipsychotics are indicated as first line monotherapies for bipolar depression, mania and maintenance treatments

4 Objectives Describe the neurotransmitter systems and neuroanatomical pathways that are implicated in mood disorders List the common classes of antidepressant medications and give one example of each Describe first line pharmacologic treatment of major depressive disorder and bipolar disorder, across the lifespan Explain the mechanism of action and side effect profile of SSRI’s, SNRI’s TCA’s, Lithium and Valproic Acid List the common drug interactions with Lithium Describe monitoring of SSRI’s and mood stabilizers Describe the role of antipsychotic medication in the treatment of mood disorders

5 A few words on Memory and Mnemonics Memory Declarative Working memory: Rate limiting step Can only hold 7+/-2 pieces of information If you cannot hold it in working memory, it cannot eventually be encoded and stored Long term memory: Hippocampus triages and stores in hippocampus, prefrontal cortex and association areas Procedural

6 A few words on Memory and Mnemonics (2) Mnemonics assist learning by reducing/simplifying information This reduces the load on working memory, allowing larger pieces of information to be encoded and stored for later retrieval

7 A few words on Memory and Mnemonics (3) Why in psychiatry? – Less anatomical therefore less framework to add information to – Often looking at systems such as neurotransmitters with diffuse effects – Use of diagnostic criteria – High prevalence of mental illness and use of psychiatric meds in the general population necessitates easy access to this knowledge for any type of physician

8 Criteria for Depressive Disorders

9 Criteria for MDD (Major Depressive Disorder) Five of the following for at least 2 weeks, represents change from baseline, includes at least one of either mood or interest criteria Mood depressed (can be subjective or objective) Sleep changes Interests decreased with loss of pleasure (subjective or objective) feelings of Guilt or worthlessness Energy decreased Concentration decreased or problems thinking or making decisions (subjective or objective) Appetite changes which may be associated with weight loss or gain Psychomotor changes (must be objective) Suicidal thoughts, plans, or recurrent thoughts of death

10 Criteria for MDD (2) Causes distress or impairment in functioning Is in excess of what would be expected as a response to a significant loss (differentiate from the loss/emptiness of grief) Not due to a substance or another medical condition Symptoms are not better explained with a diagnosis of a psychotic disorder There has NEVER been a manic or hypomanic episode

11 A short personal video

12 What is wrong in Depression? Part I: Normal Monoamine Neurotransmission

13 Monoamine neurotransmitters: normal pathways, function and inactivation The main monoamine neurotransmitters are serotonin (5HT), norepinephrine (NE) and dopamine (DA) All three can be removed from the synapse by specific reuptake pumps and inactivated by monoamine oxidase (MAO). Feedback is provided to the neuron via autoreceptors, mostly at the somatodendritic end of the neuron

14 Normal monoamine neurotransmission Signal Electrical impulse Release of neurotransmitter to synapse 1. Couple with presynaptic receptor, providing feedback 2. Couple with post synaptic receptor Bind with G protein Activates “2 nd messenger system” Ultimately activates genes (leading to creation of enzymes, receptors, transcription factors and neurotrophic factors) 3. Reuptake and repackaging via reuptake pumps and inactivation via MAO



17 What is wrong in depression? Theory one: The monoamine hypothesis There is insufficient amount of the monoamine neurotransmitters; increasing neurotransmitters causes a return to the normal state Evidence: Drugs that deplete monoamines can cause depression TCA’s and MAOI’s increase monoamines and are known to treat depression Norepinephrine and serotonin metabolites deficient in some depressed patients Problems: Monoamine levels are boosted immediately with antidepressant medications but the onset of therapeutic effect is delayed by weeks



20 What is wrong in depression? Theory two: neurotransmitter receptor hypothesis Depletion of monoamines causes compensatory up regulation (increased number and sensitivity) of postsynaptic neurotransmitter receptors; treatment response correlates with down regulation (decreased number and sensitivity) of receptors Evidence: Post mortem studies show increased number of 5HT2 receptors in the frontal cortex of some patients who commit suicide Depressed patients have been shown to have abnormal neurotransmitter receptors in platelets and lymphocytes

21 What is wrong in depression? Monoamine hypothesis of gene expression There are stress induced changes in the Monoamine signal transduction cascade, leading to inappropriate gene expression (eg. Reduced production of brain derived neurotrophic growth factor, and upregulated pre -and post-synaptic receptors) antidepressants may be able to reverse this though a cascade which ultimately results in upregulation of genes such as those for BDNF and down regulation of genes such as those for upregulated receptors Evidence for abnormally functioning neuronal system/gene expression: Probing monoamine receptors with agonists leads to deficient hormone output and neuronal firing rates Imaging studies show decreased hippocampal volume in depression

22 Summary: How do antidepressants work? There are three main monoamine neurotransmitters: serotonin, norepinephrine and dopamine In depression, the levels of these neurotransmitters is believed to be decreased, and the neurons in the circuits are functioning poorly, upregulating receptors and not producing enough of other proteins, such as BDNF Antidepressants work by increasing the amount of monoamines by blocking their reuptake or preventing their breakdown; this leads to a cascade of events which ultimately results in changes in gene products such as receptor proteins and BDNF.

23 MCQ Which of the following is not a monoamine neurotransmitter? A.Serotonin B.Glutamate C.Dopamine D.Norepinephrine

24 Monoamine-regulated CNS circuits



27 Norepinephrine (NE) Most of the cell bodies for the noradrenergic neurons are in the locus coeruleus. This is an important center for priorizing incoming stimuli and focusing attention. Noradrenergic projections regulate the following circuits: Psychomotor circuit (cerebellum and prefrontal cortex) Mood circuit (VM prefrontal cortex and amygdala) Sleep circuit (prefrontal cortex, basal forebrain, thalamus and hypothalamus) Apathy/Interest circuit (prefrontal cortex and hypothalamus) Mental energy circuit (prefrontal cortex) Physical energy circuit (spinal cord projections) Executive function and attention circuit (DL prefrontal cortex) There is also prominent noradrenergic involvement in the SNS and brainstem cardiovascular center

28 Copyright: / 123RF Stock Photo


30 Dopamine (DA) Dopaminergic cell bodies are located in the substantia nigra and the ventral tegmental area of the brainstem. Dopaminergic projections regulate the following circuits: Psychomotor circuit (striatum and prefrontal cortex) Mood circuit (VM prefrontal cortex and amygdala) Sleep circuit (prefrontal cortex, basal forebrain, thalamus and hypothalamus) Apathy/Interest circuit (prefrontal cortex, nucleus accumbens and hypothalamus) Mental energy circuit (prefrontal cortex) Physical energy circuit (striatum, hypothalamus and spinal cord projections) Executive function and attention circuit (DL prefrontal cortex) Dopamine is the “Goldilocks” monoamine when it comes to treating mood. Too much dopamine leads to abuse; not enough dopamine and the drug is no use.



33 Serotonin (5HT) Most of the serotonergic cell bodies are located in the raphe nucleus Serotonergic projections regulate the following circuits: Psychomotor circuit (cerebellum, striatum and prefrontal cortex) Mood circuit (VM prefrontal cortex and amygdala, 5HT1A receptors) Sleep circuit (prefrontal cortex, basal forebrain, thalamus and hypothalamus, 5HT2 receptors) Weight and appetite circuit (hypothalamus, 5HT3 receptors) Guilt/worthlessness/suicidality circuit (amygdala, VM and orbital PFC) There are also prominent descending serotonergic spinal cord projections and 5HT3 receptors in the GI system









42 MCQ Mr. Flynt presents with symptoms of loss of appetite and weight loss, feelings of worthlessness and thoughts of death, psychomotor changes, sleep disturbance, decreased attention, decreased interests and low physical and mental energy. Which neurotransmitters should be targeted in order to treat all of his symptoms? – A: serotonin – B: norepinephrine – C: dopamine – D: A and B – E: A, B and C

43 Treatment


45 SSRI: Mechanism of Action In depression, the serotonin neuron has a relative deficiency of serotonin and the autoreceptors and postsynaptic receptors are malfunctioning and sending faulty signals When the reuptake pump is blocked and the level of serotonin increases in the somatodendritic area, this sends a message to the nucleus to pump up quality control on the production of autoreceptors The new and improved autoreceptors detect a deficiency of serotonin and increase production and release of neurotransmitter to the synapse Increased levels of serotonin in the synapse send a message to the post synaptic neuron to correct the production of its gene products including receptors and neurotrophic growth factors







52 SSRI: Side Effect Profile Headache Anxiety and Agitation (mood and psychomotor circuits) Nausea (weight/appetite circuit and GI receptors) Diarrhea (peripheral GI 5HT3 & 5HT4 receptors) Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (sleep circuit)

53 SSRIs: Less common but more serious side effects UGI bleeding (platelet dysfunction), esp. in combo with NSAID’s or other blood-thinning agents SIADH Osteoporosis and fractures in the elderly Serotonin syndrome QT prolongation/sudden death SSRI discontinuation syndrome (slow taper) Flu-like symptoms Insomnia Nausea Imbalance Sensory disturbances Hyperarousal (agitation/anxiety)

54 Norepinephrine & Dopamine Reuptake Inhibitor:Mechanism of Action (Bupropion/Wellbutrin) Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s

55 NDRI: Side Effect Profile Seizures (not with extended release formulations & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) Headache, Hypertension (SNS activation) Agitation (mood and psychomototr circuits) and Anticholinergic (relative decrease in parasympathetic tone) Rash Emesis, decreased appetite and weight loss (SNS activation) Sleep disruption, Shaking and Sweating (sleep and psychomotor circuits and SNS activation)

56 Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action (Venlafaxine/Effexor, Desvenlafaxine/Pristiq, Duloxetine/Cymbalta) Blockade of serotonin reuptake at lower dose range Blockade of serotonin and norepinephrine reuptake in mid dose range Blockade of serotonin, norepinephrine and dopamine reuptake at very high dosages

57 SNRI: Side Effect Profile As with SSRI’s in lower to mid dose range As with NDRI in mid to high dose range

58 SNRI: more serious side effects Diastolic Hypertension As with SSRI’s

59 NaSSA: Mechanism of Action NaSSA: Noradrenergic and specific serotonergic antidepressant Blocks Alpha 2 autoreceptors on norepinephrine neurons & heteroreceptors on Serotonin neurons, causing more NE & 5HT to be released (puts the brakes on the brakes) NE neurons from the locus coeruleus innervate midbrain raphe 5HT neurons. Therefore, increased NE causes a further increase in 5HT release Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep & sexual side effects Blocks 5HT3, blocking GI side effects from peripheral receptors & from brainstem chemoreceptor trigger zone Blocks H1 histamine receptors, causing sedation & weight gain


61 NaSSA: Side Effect Profile Weight gain (H1 blockade) (Anticholinergic: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare; bowel & bladder lose their tone & the heart goes off alone) – in reality Mirtazapine has very weak and usually clinically insignificant anticholinergic activity Drowsiness (H1 blockade) Equilibrium

62 NaSSA: Rare but Dangerous Side Effects Neutropenia Serotonin syndrome Hepatotoxicity SIADH QT prolongation/sudden death

63 SARI: Mechanism of Action Serotonin 2A antagonists/reuptake inhibitors (Trazodone/Desyrel) Primarily blocks 5HT2A, reducing sexual dysfunction & sleep disruption & increasing effect of 5HT1A stimulation (5HT2A & 5HT1A oppose one another’s actions in several ways) Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A (therapeutic effects) H1 blockade causes sedation Alpha One blockade leads to orthostatic hypotension

64 SARI: Side Effect Profile Orthostatic hypotension Sedation

65 SARI: Rare but Dangerous Side Effects Serotonin syndrome

66 MCQ The following medication targets primarily the neurotransmitter serotonin: – A: escitalopram – B: mirtazepine – C: venlafaxine – D: Bupropion – E: Duloxetine

67 TCA: Mechanism of Action Tricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2° amines (eg nortriptyline, desipramine) HISTORY Originally developed as treatment for schizophrenia (similar 3- ringed chemical structure); found ineffective for psychosis but helpful for depression. Therapeutic effects and side effects from blocking Serotonin, Norepinephrine & Dopamine Reuptake Some also have 5HT2 blocking ability (blocks sex & sleep side effects) Side effects from blocking H1 histamine receptors, muscarinic receptors, alpha one adrenergic receptors & sodium channels in the heart & brain

68 TCA: Side Effect Profile Antihistamine – weight gain & sedation Anticholinergic – (remember toxidrome from NaSSA and NDRI) Anti-alpha adrenergic – dizziness, orthostatic hypotension Blockade of fast sodium channels – prolongation of QTc (risk of Torsades)

69 TCA: Rare but Dangerous Side Effects Torsades de Pointes EKG – rule out bradycardia and prolonged QTc Lytes – rule out electrolyte imbalance Make sure not on type 1 or 3 antiarrythmic drugs SIADH Serotonin Syndrome

70 MAOI: Mechanism of Action Monoamine oxidase inhibitors: “the classics” (phenylzine/nardil, tranylcypromine/parnate) Reversible inhibitor: (moclobemide/mannerix ) HISTORY: The first clinically effective antidepressants Originally, an anti-tuberculosis drug, found to decrease comorbid depression Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA

71 MAOI: Side Effect Profile Side effects related to increase in serotonin norepinephrine & dopamine (see SSRI’s & NDRI’s) Orthostatic hypotension

72 MAOI: Rare but Dangerous Side Effects Hyperthermia i.e.Serotonin Syndrome even more susceptible than with other serotonergic antidepressants; need to avoid anything that has serotonergic effects such as antidepressants and opioids) When you see an MAOI, get a pharmacy consult, the patient should consult their pharmacist about any over - the – counter medications Hypertensive crisis Consult the dietician Re: MAOI diet Patients need to avoid all foods with tyramine (aged foods such as aged cheeses and wines or tap beer) and any medications with noradrenergic effects (cold remedies, stimulants etc) Hepatotoxicity Teratogenicity Blood dyscrasias

73 Serotonin Syndrome: HARMED Hyperthermia Agitation/Autonomic instability Rigidity/Reflexes increased MyoClonus/tremors Encephalopathy Diaphoresis

74 For reference only

75 MCQ Serotonin syndrome is most likely to be caused by the combination of which two medications? A: Duloxetine(SNRI) and Mirtazepine (NaSSA) B: Citalopram (SSRI) and Trazodone (SARI) C: Bupropion(NDRI) and Fluvoxamine (SSRI) D: Phenylzine (MAOI)and Fluoxetine(SSRI) E: Venlafaxine (SNRI) and Lithium

76 Hypertensive Crisis Norepinephrine is the amine most closely linked with control of blood pressure MAO normally inactivates norepinepherine Tyramine, an amine present in aged foods, causes release of norepinepherine In the presence of MAOI, this increased NE cannot be broken down, resulting in a hypertensive crisis

77 Choice of initial treatment in MDD Medication indicated in mild to moderate depression if preferred by patient over psychotherapy Medication indicated in moderate to severe depression with or without psychotherapy or ECT (BA has also been shown to be effective even in severe depression) Psychotic depression requires either combination antipsychotic and antidepressant or ECT (ECT is gold standard)

78 Treatment choices in children Concerns were raised about the safety of antidepressants (Paroxetine and Venlafaxine) in children and youth in 2004 Further metaanalyses and epidemiologic studies now confirm that antidepressants in children and youth are safe with close (weekly) monitoring. Problems with Venlafaxine and Paroxetine may have been related to poor adherence and discontinuation symptoms

79 Starting Antidepressants: General Guidelines Start with a reuptake inhibitor (SSRI, SNRI, NDRI) or mirtazapine (i.e. not a TCA or MAOI) Start at lowest possible dose (half of this with anxiety and in the elderly and medically frail) Increase by this increment about every five half lives (or about once a week) until one of the following endpoints: Intolerable side effects Full response Maximum dose Continue to monitor regularly (once a week initially) for therapeutic effects, side effects and safety (suicidality)

80 Choice of Initial Treatment in children/youth Mild to moderate depression: – Start with psychotherapy or non-medication interventions as first line – Second line is to add medication; best evidence is for Fluoxetine; other SSRI’s could be considered next Moderate to severe depression: – First line is to consider medication but depending on patient/family preference, may also start with psychotherapy or monitoring Note that the clinical presentation in children and youth can change quickly; they may appear severely depressed one week then by the next week be in a new relationship and everything is better…

81 Choice of Initial Antidepressant in Adults There is comparable efficacy between and within classes of medication, therefore, initial selection is based on: Symptom profile (i.e. target circuits; see next slide) Side effect profile in relation to the individual patient Patient preference Cost History of previous response of the patient or family members Comorbid psychiatric or medical illnesses Potential drug-drug interaction The BEST antidepressant is the one that a patient will actually take acutely and for the long haul

82 Goals of antidepressant therapy REMISSION of symptoms and maintaining that level of improvement in order to prevent relapse and recurrence Rate of relapse is significantly less for patients who achieve full remission of symptoms Patients who have been ill longer tend to be more treatment resistant; there is also evidence of hippocampal atrophy with prolonged illness, leading to the concept of disease progression and the hope that this can be modified by treating all mood episodes to the point of remission


84 Bipolar Disorder DSM5 Criteria

85 Criteria BPD I (Bipolar Disorder Type I) At least one manic episode

86 Criteria BPAD II (Bipolar Disorder Type II) Presence or history of one or more Major Depressive Episode Presence or history of at least one hypomanic episode There has never been a manic episode

87 Criteria Manic Episode A period of persistently elevated, expansive, or irritable mood persistently increased goal directed activity or energy Causes impairment in functioning, hospitalization or psychosis Present most of the day every day for one week or less if hospitalized Not due to substance use of GMC

88 Criteria Manic Episode (2) Associated with 3 other criteria if mood is elevated or expansive 4 other criteria if mood is irritable Grandiosity or inflated self esteem Sleep (decreased need) Talkative (speech is increased in rate or pressure) Pleasurable activities with Painful consequences Activity increased/Agitation Ideas (flight of) or experience of “racing thoughts” Distractible (i.e. attention easily drawn to irrelevant stimuli)

89 Criteria Hypomanic Episode Same as Mania except: – Only needs to last 4 days – Not hospitalized – Not psychotic – Unequivocal change in function (observable to others) but no significant impairment in function

90 Could Mr. Flynt have BPAD? A: yes B: no

91 Treatment of BPAD

92 What is a “mood stabilizer”? Originally, these medications treated mania and prevented its recurrence, thus treating and stabilizing the manic pole of bipolar disorder More recent medications can be thought of as treating one of the following phases: – Acute bipolar depression – Acute bipolar mania – Maintenance

93 Lithium: Mechanism of Action MOA is unclear Thought to be involved in: Modulating second messenger systems (ie G protein-coupled receptors, through which most hormones and neurotransmitters mediate their effects) which leads to: Increasing GABA activity Reducing glutamate activity Stabilizing catecholamine receptors Blocking the effects of some hormones (eg. ADH and TSH) on end organs Works in acute bipolar mania, depression and maintenance phases Decreases suicide, deliberate self harm and death from all causes in patients with mood disorders

94 Lithium: Side Effect Profile Lethargy Insipidis Tremor/Teratogen (increased risk Ebstein’s anomaly (0.1% vs 0.005%) in first trimester) Hypothyroid Increased weight Vomitting, nausea, GI Miscellaneous: EKG changes (T wave flattening or inversion), acne, hair loss

95 Lithium: Toxicity Narrow therapeutic index!!! Anything that affects water and electrolyte imbalance can contribute to Lithium toxicity (CAUTION with flu, dehydation, meds) Levels are increased by NSAIDS, thiazide diuretics, ACEI, tetracycline, anticonvulsants Levels are decreased by caffeine, salt, osmotic diuretics (mannitol) and carbonic anhydrase inhibitors

96 Lithium: Toxicity There is delayed distribution and elimination in the brain relative to serum therefore early signs are peripheral and later signs are central unless high level is chronic, in which case peripheral and central symptoms will occur simultaneously Peripheral symptoms: nausea, vomiting, cramping, diarrhea Central symptoms: tremulousness, hyperreflexia, ataxia, mental status changes, coma, seizures Can lead to irreversible neurotoxicity including cognitive impairment, peripheral neuropathy and cerebellar dysfunction Hospitalize for levels >2.0 or based on clinical symptoms

97 Lithium: Initial Work-up Lytes, BUN, Cr (renally excreted) TSH (5% hypothyroidism) BhCG (risk of teratogenicity) Calcium, albumin CBC Also consider: EKG with rhythm strip (contraindicated with sick sinus syndrome) Metabolic baseline including baseline weight, BMI, waist circumference, BP, fasting glucose and lipid profile Personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease

98 Lithium: Ongoing Monitoring Lithium level every five days until steady state is reached then at 3-6 months, with signs of dehydration or toxicity or with change in medications or salt intake Repeat kidney functions, TSH and EKG every 6-12 months BMI monthly for three months and then 3x per year Waist circumference at the umbilicus, BP, fasting glucose and lipid profile repeat at 3 months and then annually

99 Lithium : Rx Reference only Adult Dosing 600 – 1500 mg/d (bid dosing) Level 0.5 – 1.2 Geriatric Dosing 150 – 600 mg/d (bid dosing) Level 0.4 – 0.8

100 Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis Term first coined by Graham Goddard in 1967 while studying learning in rats using low intensity electrical brain stimulation Over time the rats became sensitized to this and began to have seizures when they received this low intensity signal Likened to kindling in starting a fire in that the stimulus is not enough to cause the event on its own but when repeated enough leads to an episode

101 Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis Robert Post drew the parallel to BPAD where the initial episode is often precipitated by a stressor but when cycles continue untreated, the brain can become “kindled” and future episodes can occur with little or no precipitant Dysfunctional cation (Na &Ca) pumps leading to an imbalance between excitatory (glutamate) & inhibitory (GABA) neurotransmitters may contribute to this kindling phenomenon Anticonvulsants are thought to prolong inactivation of cation channels during activity, preventing spread of activity & leading to downstream changes in GABA & glutamate


103 Valproic Acid: treatment effects Indicated for bipolar mania and for maintenance phase First line for bipolar depression in combination with lithium or SSRI/bupropion Second line monotherapy for bipolar depression

104 Valproic Acid: Acute Side Effect Profile STUN Sedation (31%) Tremor (10-29%) Unsteadiness (dizziness) Nausea (20%) /GI Teratogenic – avoid in women of childbearing age

105 Valproic Acid: longer term side effect monitoring On the surface: – Acne, hair loss Under the surface: – weight gain, edema Systemic: – blood dyscrasias (esp plt dysfn) – liver dysfunction +/- elevated ammonia levels – reproductive changes incl menstrual irregularities (up to 45%), PCOD, teratogenicity (5-15%)

106 Valproic Acid: Initial Work-up & Ongoing Monitoring Initial CBC + LFT’s, BhCG in women Epival level q2-4 days until steady state reached Consider: Metabolic baseline including baseline weight and BMI Baseline personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease Baseline waist circumference at the umbilicus, BP, fasting glucose and lipid profile Ongoing Repeat tests monthly x 6 months then Q6mos or if symptoms develop BMI monthly for three months and then 3x per year Waist circumference at the umbilicus, BP, fasting glucose and lipid profile repeat at 3 months and then annually

107 Valproic Acid: Rx Reference only Starting dose: 250 qhs (geriatrics) 250 bid-tid (adults) Dose range: 750 – 3000 mg/d (bid dosing) Levels: 350 – 800 umol/l


109 Lamotrigine: Treatment effects Treats bipolar depression First line maintenance treatment

110 Lamotrigine: Side Effect Profile Rash – 0.3% adults / 1% in children. With slow titration risk was reduced to 0.01% comparable to other anticonvulsants. Activation (3-8%), Ataxia Spaced out (cognitive slowing), Sedation, Sleep disturbances H/A, Hypersensitivity reactions

111 Lamotrigine: Rx Start with mg/d Increase every 2 weeks by mg Usual maintenance dose is 200 mg in 2 divided doses

112 Atypical Antipsychotics All atypical antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole, ziprazidone) are indicated to treat bipolar mania Quetiapine is first line monotherapy for bipolar depression Risperidone LAI, olanzapine and quetiapine are first line maintenance treatments Further details on mechanism of action, side effects, initial work up and monitoring to be covered during psychosis week

113 Choice of Treatment in BPAD (Bipolar Affective Disorder) First line for acute mania: Lithium, Valproic Acid atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole) taper and discontinue antidepressants First line for acute bipolar depression: Lithium lamotrigine quetiapine do not use antidepressant monotherapy First line for maintenance therapy: Lithium Valproic acid Lamotrigine Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine

114 Goals of treatment in BPAD Again, the goal is to treat to complete remission of all mood symptoms It has been theorized that under-treated discrete depressive and manic episodes may progress to mixed and dysphoric episodes, rapid cycling and treatment resistance The hope is that recognition and full treatment of mood episodes may prevent progression to more difficult mood states

115 Pre-test (true/false) All patients with symptoms of major depression should be treated with an antidepressant – FALSE Mirtazapine causes drowsiness through it’s effects on the benzodiazepine receptor – FALSE (antihistaminic) SNRIs such as Venlafaxine can cause diastolic hypertension - TRUE

116 Pre-test (true/false) Trazodone is rarely tolerated at full therapeutic dosages due to significant sedation side effects - TRUE Lithium is rarely tolerated due to multiple side effects and should be reserved only for treatment resistant bipolar patients - FALSE Atypical antipsychotics are indicated as first line monotherapies for bipolar depression, mania and maintenence treatments - TRUE

117 References CANMAT Clinical guidelines for the management of major depressive disorder in adults. III. Pharmacology CANMAT guidelines for the management of patients with bipolar disorder: update 2009 Stahl’s Essential Psychopharmacology, Third edition, Cambridge University Press, Ottawa Review Course of Psychiatry DSM5 Mnemonics are in part from mnemonics and more for psychiatry, P.I.E.C.E.S education Initiative & mnemonics in mnutshell, Current psychiatry, Oct 2008 The Hunter Serotonin Toxicity Criteria, QJ Med 2003 Current Concepts: The Serotonin Syndrome, NEJM, 352, 11, Special thanks to Dr. Michael Cheng for input on child content and to Perry Ng for preparing images 2008 Position Paper on Using SSRIs in Children and Adolescents. J Can Acad Adolesc Psychiatry 18:2 May 2009

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