Optimizing Outcomes for Patients With Depression

Transcription

1 Handout for the Neuroscience Education Institute (NEI) online activity: Optimizing Outcomes for Patients With Depression

2 Learning Objectives Employ strategies to assess treatment effectiveness and adherence over time Make evidence-based treatment adjustments to address residual symptoms and side effects Identify investigational treatment targets for depression

3 Pretest Question 1 A 34-year-old man has been taking mirtazapine for 12 months with good response; however, during that time, he has experienced a 20-pound weight gain, which he finds quite distressing (his BMI is now 27). He has not dramatically changed his exercise or diet habits, and he feels that the weight gain is related to his medication. Which of the following is a reasonable strategy to address the patient's weight gain? A. Reduce the dose of mirtazapine B. Augment with bupropion C. Switch to a tricyclic antidepressant D. All of these are reasonable E. None of these are reasonable

4 Pretest Question 2 A 44-year-old woman has been taking an SSRI for 3 months. At her follow-up visit, she informs you that she stopped taking her medication a few weeks ago because although her mood had improved with treatment, she experienced problems engaging in sexual activity with her husband. What is the main mechanism by which serotonergic antidepressants are thought to cause sexual dysfunction? A. Reduction in dopamine neurotransmission via stimulation of 5HT1A receptors B. Reduction in dopamine neurotransmission via stimulation of 5HT2A and 5HT2C receptors C. Reduction in nitric oxide synthesis via blockade of 5HT1A receptors D. Reduction in nitric oxide synthesis via blockade of 5HT2A and 5HT2C receptors Copyright 2011 Neuroscience Education Institute. All rights reserved.

5 Monitoring for Response, Adherence, and Side Effects 46% of patients stop medication before the chance of response A large portion who do respond discontinue once they "feel better" Use 10-minute phone calls to identify patients at risk of non-adherence (e.g., side effects, lack of response) Focus on tracking most troublesome symptoms rather than depressed mood per se Rost K. Nordic J Psychiatry 2009;63:17-21.

6 Monitoring for Response/Remission and Relapse: Markers Stahl SM. J Clin Psychiatry 2000;61(5):327-8.

7 Side Effects Options to Avoid or Address the Most Troublesome Side Effects

8 Most Troubling Antidepressant Side Effects receptor sensitivity amount of NT therapeutic effect antidepressant introduced nausea headache activation sedation sexual dysfunction weight gain Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press; Bostwick JM. Mayo Clin Proc 2010;85(6):538-50; Cascade E et al. Psychiatry (Edgmont) 2009;6(2):16-8.

9 Mechanisms Associated With Troubling Short-Term Side Effects Nausea Headache Activation 5HT reuptake inhibition X X X NE reuptake inhibition X X DA reuptake inhibition Psychomotor Morehouse R et al. J Affective Disord 2011;132:S14-20; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

10 Management of Nausea Consider divided doses Advise patient to take dose with food Recommend ginger Potential adjunct medications Histamine 2 antagonist Omeprazole Promethazine Prochlorperazine Ondansetron If nausea is truly intolerable, consider switching to a non- 5HT agent (e.g., bupropion) or an agent that blocks 5HT receptors (e.g., mirtazapine) Kelly K et al. Dialogues Clin Neurosci 2008;10(4):

11 Management of Activation Propensity for SSRIs to induce activation fluoxetine > sertraline > citalopram/escitalopram/paroxetine Activation usually subsides in the first few weeks of treatment Consider a temporary dose reduction or a more gradual uptitration Consider adding a benzodiazepine short term Consider adding a 5HT2A antagonist such as trazodone, mirtazapine, or an atypical antipsychotic Kelly K et al. Dialogues Clin Neurosci 2008;10(4):

12 Mechanisms Associated With Troubling 5HT reuptake inhibition 5HT2 antagonism Long-Term Side Effects Sedation Sexual dysfunction Alpha 1 antagonism X X X Histamine 1 antagonism X X Anticholinergic X X NOS inhibition Morehouse R et al. J Affective Disord 2011;132:S14-20; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press. X X Weight gain X

13 Sedation bupropion citalopram amitriptyline mirtazapine escitalopram desvenlafaxine amoxapine nefazodone fluoxetine duloxetine clomipramine nortriptyline selegiline milnacipran desipramine paroxetine sertraline venlafaxine doxepin phenelzine vilazodone fluvoxamine protriptyline imipramine tranylcypromine isocarboxazid trazodone maprotiline trimipramine Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

14 Management of Sedation Dose at night or take larger dose at night Increase daytime exercise If patient is responding and otherwise tolerating current treatment Augment (modafinil/armodafinil, bupropion, atomoxetine, stimulant) If patient is not responding or if sedation is truly intolerable Switch to a non-sedating antidepressant Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed. 2011; Zajecka JM. J Clin Psychiatry 2007;68(suppl 10):23-7.

15 Sexual Dysfunction bupropion amitriptyline citalopram phenelzine mirtazapine amoxapine desvenlafaxine sertraline nefazodone clomipramine duloxetine tranylcypromine selegiline fluvoxamine escitalopram venlafaxine trazodone imipramine fluoxetine vilazodone maprotiline isocarboxazid nortriptyline milnacipran protriptyline paroxetine trimipramine Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed. 2011; Serretti A, Chiesa A. J Clin Psychopharmacol 2009;29:

16 Addressing Sexual Dysfunction: 5HT2 Receptors

17 Addressing Sexual Dysfunction: 5HT1A Receptors Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

18 Addressing Sexual Dysfunction: 5HT1A Receptors Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

19 Addressing Sexual Dysfunction: 5HT1A Receptors Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

20 Addressing Sexual Dysfunction: 5HT1A Receptors Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

21 Addressing Sexual Dysfunction: 5HT1A Receptors Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

22 Management of Sexual Dysfunction Assess sexual function before starting medication Arizona Sexual Experiences Scale (ASEX) Changes in Sexual Functioning Questionnaire (CSFQ) Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX) Sex Effects Scale (SexFx) Rizvi SJ et al. J Psychosom Res 2011;70:99-109; Serretti A, Chiesa A. Clin Pharmacol Ther 2011;89(1):142-7.

23 Management of Sexual Dysfunction Add 5HT2 antagonism Cyproheptadine, mirtazapine (add or switch), trazodone Add 5HT1A partial agonism Augment with high-dose (60 mg/day) buspirone Switch to vilazodone (5HT1A effects SERT effects) Add pro-dopaminergic effects Amantadine, bupropion, stimulant Add phosphodiesterase 5 (PDE-5) inhibitor Does not increase desire Add alpha 2 antagonism Mirtazapine For women, consider estrogen creams Rizvi SJ et al. J Psychosom Res 2011;70:99-109; Serretti A, Chiesa A. Clin Pharmacol Ther 2011;89(1):142-7.

24 Weight Gain bupropion paroxetine amitriptyline citalopram tranylcypromine amoxapine desvenlafaxine clomipramine duloxetine desipramine escitalopram imipramine fluoxetine isocarboxazid fluvoxamine maprotiline milnacipran mirtazapine nefazodone nortriptyline selegiline phenelzine sertraline protriptyline trazodone trimipramine venlafaxine vilazodone Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed. 2011; Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10): Copyright 2011 Neuroscience Education Institute. All rights reserved.

25 Short-Term Weight Gain: Meta-analysis imipramine, paroxetine, desipramine, clomipramine *Filled squares indicate a significant effect Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):

26 Long-Term Weight Gain: Meta-analysis imipramine, paroxetine, desipramine, clomipramine *Filled squares indicate a significant effect Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):

27 Management of Weight Gain In meta-analysis, average weight gain is small A few patients may experience large weight gain due to their own genetic predispositions and other factors Large weight gain typically occurs gradually over many months Monitor patients for weight gain, appetite changes, and metabolic parameters If significant weight gain occurs, consider switching to an agent with less risk of weight change Can also consider augmentation with bupropion, topiramate, or zonisamide Metformin, orlistat, phentermine/topamax combo, or lorcaserin may be helpful Diet and exercise Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed. 2011; Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):

28 Partial Response Options for Specific Residual Symptoms

29 Response Response Response Response When Does it Make Sense to Increase the Dose? TCAs venlafaxine Dose tranylcypromine Dose SSRIs Dose Dose Adli M et al. Eur Arch Psychiatry 2005;255(6): Copyright 2011 Neuroscience Education Institute. All rights reserved.

30 Symptom-Specific Strategies for Common Residual Symptoms vasomotor anxiety fatigue concentration psychomotor sleep disturbance depressed mood interest/ pleasure guilt/ sexual worthlessness dysfunction pain suicidality appetite/ weight sleepiness/ hypersomnia Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

31 Residual Sleep Disturbances Symptom Insomnia Hypersomnia Neurotransmitter system involved NE GABA HA HA DA Treatment strategy Optimize sleep hygiene Cognitive behavioral therapy Use sedating antidepressant Stop activating antidepressant Add sedative hypnotic Chronotherapy Melatonin Dose at night Add modafinil, armodafinil, bupropion, atomoxetine, or stimulant Discontinue agent with antihistaminic, antimuscarinic, and/or alpha 1 blocking properties Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Watanabe N et al. J Clin Psychiatry 2011;72(12): Copyright 2011 Neuroscience Education Institute. All rights reserved.

32 Phase Delay in Depression due to Reduced Melatonin retinohypothalamic tract Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

33 Melatonin as Treatment for Depression Short half-life Prolonged-release melatonin improves sleep but not depression A preliminary study suggests that the melatonin agonist ramelteon has antidepressant effects For patients who can't fall asleep and wake up late Give melatonin in late afternoon/early evening Advances circadian clock earlier falling asleep and waking For patients who fall asleep early and wake up early Give melatonin in the morning Delays circadian clock later falling asleep and waking Quera Salva MA et al. Curr Pharm Des 2011;17(15): ; McElroy Sl et al. Int Clin Psychopharmacol 2011;26(1):48-53; Galecka E et al. Psychiatry Res 2011;Epub ahead of print.

34 Serotonin Inhibits Dopamine and Norepinephrine Release via 5HT2C Receptors NE DA prefrontal cortex NE GABA interneurons 5HT2C DA 5HT 5HT overactivation normal baseline hypoactivation 5HT brainstem neurotransmitter centers Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed Copyright 2011 Neuroscience Education Institute. All rights reserved.

35 5HT2C Antagonism Releases Norepinephrine and Dopamine in the Frontal Cortex NE release DA release prefrontal cortex NE GABA interneurons 5-HT2C DA overactivation normal baseline hypoactivation 5-HT brainstem neurotransmitter centers Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed. 2008; Millan MJ et al. J Pharmacol Exp Ther 2003;306(3): Copyright 2011 Neuroscience Education Institute. All rights reserved.

36 Agomelatine 5HT2C antagonist; melatonin 1 and 2 receptor agonist Demonstrated to decrease depression and prevent relapse Onset of efficacy as early as week 1 Usual dose: mg at bedtime Metabolized by CYP450 1A2 Relative lack of sexual dysfunction and weight gain Most common side effects are nausea and dizziness Usually mild and resolve within 2 weeks of treatment No discontinuation symptoms Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

37 Chronotherapies: Bright Light Therapy Exposure to light alters circadian rhythms and suppresses melatonin release 10,000 lux (bright light) for 30 min/day Must be timed with patient's circadian phase of melatonin secretion Administer light hrs after evening melatonin secretion Melatonin secretion can be determined using the Horne- Östberg Morningness-Eveningness Questionnaire (MEQ) Useful as a non-pharmacological intervention during pregnancy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Pail G et al. Neuropsychobiol 2009;64:

38 Bright Light Therapy for Depression Rapid onset of antidepressant action Hastens the effects of antidepressant drugs Antidepressant effects mediated through eyes Extraocular administration shows no antidepressant benefits Dawn simulation therapy Slow incremental light signal at end of sleep cycle Side effects are rare Headaches, eyestrain, nausea, and agitation Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Terman M et al. Biol Psychiatry 1989;25(7):

39 Chronotherapies: Sleep Deprivation Therapy 36 hrs of deprivation Antidepressant effects within hours Response rates are similar to those of antidepressants (50 80%) Improvement does not last unless combined with: Other chronotherapies Lithium Antidepressants Contraindicated for patients with epilepsy Sleep deprivation increases the risk of seizures in patients with epilepsy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):

40 Chronotherapies: Sleep Phase Advance Therapy Advances timing of sleep-wake cycle Synchronizes sleep with other biological rhythms Improves effects of antidepressants Also effective as monotherapy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):

41 Residual Fatigue and Concentration Problems Symptom Fatigue Concentration problems Neurotransmitter system involved NE DA Treatment strategy Add/switch to bupropion Add modafinil, armodafinil, atomoxetine, or stimulant Add atypical antipsychotic, lithium, thyroid hormone, l-methylfolate, or 5HT1A agonist Switch to SNRI or MAOI Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

42 Symptom-Specific Strategies for Common Residual Symptoms vasomotor anxiety fatigue concentration psychomotor sleep disturbance depressed mood interest/ pleasure guilt/ sexual worthlessness dysfunction pain suicidality appetite/ weight sleepiness/ hypersomnia Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

43 Residual Pain Symptom Neurotransmitter system involved Treatment strategy Pain NE Use SNRI Add alpha 2 delta ligand Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

44 Depressed Mood Disrupts Brain Deactivation and Enhances Pain Unpleasantness 20 healthy volunteers Red/green: activation vs. rest Blue: deactivation vs. rest Significant lack of deactivation during pain in the depressed mood state Patients reporting greatest increase in pain unpleasantness after sad mood induction showed greater inferior frontal gyrus and amygdala activation Plotted on the average MNI 152 brain; Z coordinates are on the MNI system Berna C et al. Biol Psychiatry 2010;67:

45 Pain in Depression: The Role of Norepinephrine back pain stomach pain muscle/ joint pain descending NE projections deficient NE release digestion back posture muscle/joint movement Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

46 Pain in Depression: The Role of Serotonin back pain stomach pain muscle/ joint pain descending 5HT projections deficient 5HT release digestion back posture muscle/joint movement Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

47 SNRI Action Boosts NE Inhibition of Pain back pain stomach pain muscle/ joint pain descending NE projections SNRI boosts NE digestion back posture muscle/joint movement Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

48 SNRI Action Boosts 5HT Inhibition of Pain back pain stomach pain muscle/ joint pain descending 5HT projections SNRI boosts 5HT digestion back posture muscle/joint movement Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

49 SNRIs for Painful Symptoms Duloxetine (approved for multiple neuropathic pain disorders) 60 mg once daily; higher doses increase side effects without increasing efficacy in pain disorders Milnacipran (approved for fibromyalgia) mg/day in 2 doses Venlafaxine XR mg once daily Desvenlafaxine 50 mg once daily Tricyclic antidepressants Cyclobenzaprine (muscle relaxant) 15 mg/day in 3 doses; mg/day in 1 dose (ER) Not recommended for long-term use

50 Relief of Painful Excessive Nociceptive Activity in Central Augmentation = alpha 2 delta ligand Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed neuropathic pain

51 Alpha 2 Delta Ligands for Painful Symptoms Pregabalin (approved for multiple neuropathic pain disorders) mg/day in 2 3 doses Gabapentin (approved for postherpetic neuralgia) mg/day in 3 doses

52 Residual Anxiety Symptom Anxiety Neurotransmitter system involved GABA Treatment strategy Use SSRI, SNRI, or MAOI Add: Benzodiazepine Alpha 2 antagonist (e.g. clonidine or guanfacine) Atypical antipsychotic especially one with antihistaminergic properties Alpha 2 delta ligand Hydroxyzine Beta blockers (e.g. propranolol or atenolol Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

53 Non-Pharmacological Treatments to Address Partial Response Electroconvulsive therapy (ECT) Repetitive transcranial magnetic stimulation (rtms) Deep brain stimulation (DBS) Psychotherapy Augmentation may decrease depressive symptoms as much as pharmacological augmentation Family therapy Coping skills including assertiveness training and problem solving strategies Keitner GI, Mansfield AK. Psychiatr Clin N Am 2012;35:

54 The Future of Depression Treatment

55 Glutamate, Mood Disorders, and New Drug Treatments Possible glutamate excess in depression Unipolar, treatment-resistant, bipolar, and suicidal Improvement by anti-glutamate treatments Lamotrigine (bipolar maintenance) Inhibits glutamate release by interfering with sodium channels Beneficial effects in bipolar depression Riluzole (ALS) Inhibits glutamate release Reports of benefit in TRD, OCD Memantine (dementia) Depresses glutamate release Machado-Vieira R et al. Pharmacol Biochem Behav 2012;100:

56 Possible Sites of Action of Lamotrigine and Riluzole on Glutamate Release Glutamate neuron Lamotrigine Riluzole Riluzole Lamotrigine Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

57 NMDA Blockade Ketamine (anesthetic) Blocks NMDA receptors, evokes glutamate release Like phencyclidine, induces schizophrenia-like symptoms in normal volunteers and exacerbates them in patients Short-term, low-dose intravenous ketamine does not induce full range of psychotic symptoms in experimental setting Dextromethorphan (cough, pseudobulbar affect) Blocks NMDA receptors

58 Site of Action of Ketamine: Binds to Open Channel at PCP Site to Block NMDA Receptor PCP site (in the ion channel) Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

59 Site of Action of Ketamine: Binds to Open Channel at PCP Site to Block NMDA Receptor Ketamine Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

60 PCP-Ketamine: Model of Schizophrenia or Novel Antidepressant? Ketamine blockade of NMDA receptors

61 PCP-Ketamine: Model of Schizophrenia or Novel Antidepressant? Ketamine blockade of NMDA receptors

62 Ketamine Rapidly Increases the Density and Function of the Dendritic Spines of Layer V Pyramidal Neurons in the Prefrontal Cortex Bottom slide shows regeneration of synaptic connections in group receiving ketamine compared to control group (Courtesy of Yale University)

63 Other Glutamatergic Strategies: NMDA Receptor Subtypes =

64 Other Glutamatergic Strategies: NR2B Selective NMDA Antagonists Traxoprodil CP101,606 Positive proof of concept Pfizer AstraZeneca compound In Phase II EVT101/103 In Phase II Evotec/Roche Radiprodil In Phase II RGH 896 Gedeon Richter/Forest MK 0657 In Phase II Merck/NIMH

65 NR2B Selective NMDA Antagonists: Some Key Questions Why would a mechanism associated with a human model of schizophrenia cause improvement in depression? "Rebooting" the system? 1 dose? Sustaining the effect over time? Treatment-resistant depression? Consequence of downstream actions: although this blocks glutamate at 1 receptor, the release of glutamate results in the stimulation of all the other glutamate receptor subtypes What is the desired action?

66 Other Rapid-Onset Strategies Sleep deprivation Widely investigated 40 60% response rate within 48 hours Short duration as monotherapy Scopolamine Intravenous 4.0 μg/kg rapidly alleviated depression in a mixed group of bipolar depressed and unipolar depressed patients (superior to placebo) Data were replicated in a unipolar sample Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15: ; Furey ML, Drevets WC. Arch Gen Psychiatry 2006;63:1121-9; Janowsky D. Curr Psychiatry Rep 2011;13:443-5.

67 Other Investigational Strategies Neutroceuticals such as L-methylfolate, SAMe, N-acetyl cysteine Glucocorticoid antagonists CRF1 antagonists Vasopressin 1B antagonists TC 5214 (active enantiomer of the nicotinic cholinergic agent mecamylamine) FAILED TRIALS / DEVELOPMENT DROPPED Triple reuptake inhibitors Too much DRI can lead to abuse potential; too little is not different than an SNRI Vortioxetine: multimodal (SRI, 5HT1A and 1B/D partial agonist, 5HT7 antagonist, 5HT3 antagonist)

68 Vortioxetine (LuAA21004) Multimodal 5HT1A SRI

69 Vortioxetine: Multimodal Antidepressant Transporter mode: SERT inhibitor Ion channel mode: 5HT3 antagonist G-protein receptor mode: 5HT1A partial agonist 5HT1B/D partial agonist 5HT7 antagonist Raises 5 neurotransmitters in preclinical models 5HT, NA, DA Plus histamine and acetylcholine

70 Summary Patient education and slower titration can often be sufficient to address early, short-term side effects Long-term side effects do not often spontaneously disappear and may require switching or augmentation to avoid patient discontinuation of medication Establishing markers and using rating scales can aid in the detection of troubling residual symptoms Common residual symptoms can be targeted by using augmentation strategies that apply mechanistic rationale Investigational drugs for mood disorders target hypothetically overactive glutamate functioning, the stress system, and multi-modal agents