Major Depressive Disorder: Bridging the Gap From Response to Remission

Transcription

1 Handout for the Neuroscience Education Institute (NEI) online activity: Major Depressive Disorder: Bridging the Gap From Response to Remission

2 Learning Objectives Make evidence-based treatment adjustments to address inadequate antidepressant response Implement evidence-based strategies for treatment-resistant depression Describe the molecular targets of novel antidepressant treatments

3 Pre-Poll Question I feel competent combining mechanisms for patients with depression who have inadequate response (strongly disagree) (strongly agree)

4 Pretest Question 1 A 25-year-old patient with first-episode major depressive disorder is being prescribed an antidepressant. The time course for therapeutic effects of antidepressants correlates with: 1. Increase in presynaptic neurotransmission 2. Increase in postsynaptic neurotransmission 3. Changes in receptor sensitivity and expression

5 Pretest Question 2 A 36-year-old patient with unipolar depression has only partially responded to his second monotherapy with a firstline antidepressant. Which of the following has the best evidence of efficacy in augmenting antidepressants in patients with inadequate response? 1. Adding buspirone 2. Adding lithium 3. Adding a stimulant

6 Pretest Question 3 The efficacy of ketamine in treatment-resistant depression is hypothesized to be due to: 1. Activation of the mtor pathway 2. Suppression of the mtor pathway 3. Upregulation of NMDA receptors 4. Downregulation of AMPA receptors

7 ispot: Remission Rates at 8 Weeks Remission: HRSD17 7 Response: 50% reduction in HRSD17 Remission: QID-SR16 5 Response: 50% reduction in QID-SR16 Saveanu R et al. J Psychiatr Res 2015;61:1-12.

8 Most Common Residual Symptoms in Nonremitters complete remission 33% Present 94% of the time 2 Persist 44% of the time 2 residual insomnia symptoms 67% most common: fatigue/pain concentration interest antidepressant severe anxiety at baseline predicts non-remission 1 Stahl SM. Stahl's essential psychopharmacology. 4 th ed Saveanu R, et al. J Psychiatr Res 2015;61: Conradi HJ, et al. Psychol Med 2011;41(6): Copyright 2014 Neuroscience Education Institute. All rights reserved.

9 relapse rate relapse rate Remission is Protective Remission after 1 treatment Response after 1 treatment 0% 0% 33% relapse 60% relapse 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months Rush AJ, et al. Am J Psychiatry 2006;163(11):

10 relapse rate relapse rate But It Also Matters How Fast One Gets There 0% Remission after 2 treatments 0% Response after 2 treatments 50% relapse 67% relapse 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months Rush AJ, et al. Am J Psychiatry 2006;163(11):

11 relapse rate relapse rate But It Also Matters How Fast One Gets There 0% Remission after 3 treatments 0% Response after 3 treatments 50% relapse 70% relapse 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months Rush AJ, et al. Am J Psychiatry 2006;163(11):

12 relapse rate relapse rate But It Also Matters How Fast One Gets There 0% Remission after 4 treatments 0% Response after 4 treatments 30% relapse 70% relapse 50% relapse 70% relapse 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months Rush AJ, et al. Am J Psychiatry 2006;163(11):

13 THERAPEUTIC EFFECTS OF MOST ANTIDEPRESSANTS ARE DUE TO DOWNSTREAM EFFECTS

14 Monoamines DA 5HT NE Dysregulated signaling cascades MAPK camp RSK PKC Wnt/Frz GSK-3 CaMK Inactivation of camp response element binding protein (CREB) The Neuroplasticity Hypothesis Genes turned on or off Decreased expression of AMPA receptor subunits Decreased proteins involved in neuroplasticity Upregulation of NMDA receptors Increased release of glutamate Decreased neuroplasticity Duman RS, Voleti B. Trends Neurosci 2012;35(1):47-56.

15 Acting on monoaminergic systems, current antidepressants may lead to downstream improvement in neuroplasticity and glutamatergic neurotransmission

16 DA 5HT NE Dysregulated Improved signaling signaling cascades MAPK camp RSK PKC Wnt/Frz GSK-3 CaMK Activation Inactivation of of camp response element binding protein (CREB) Genes turned on or off Decreased Increased expression of AMPA receptor subunits Decreased Increased proteins involved in neuroplasticity Downregulation Upregulation of of NMDA receptors Decreased Increased release of glutamate Increased neuroplasticity and reduced glutamatergic neurotransmission Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4): Barbon A, et al. Neurochem Int 2011;59(6):

17 GETTING TO REMISSION (FASTER) Combining Mechanisms

18 The Brain Is a Neuronal Network and Connectivity is Altered in Depression frontoparietal network default network dorsal attention network affective network ventral attention network Kaiser RH et al. JAMA Psychiatry 2015;72(6):

19 The Theory of Multiple Mechanisms Symptoms are theoretically linked to abnormal communication in distinct brain circuits Multiple symptoms likely means multiple brain circuits involved Each circuit is regulated by multiple neurotransmitters, but not all neurotransmitters regulate all circuits Theoretically, it's possible that changing more than one neurotransmitter's release in more than one site can affect multiple symptoms linked to multiple circuits

20 Monotherapies That Target Multiple Monoamines MAOI 1 M1 H1 imipramine trimipramine NRI SRI Na+ channel blocker DAT DAT desvenlafaxine duloxetine levomilnacipran milnacipran venlafaxine NET SERT bupropion NET investigational triple reuptake inhibitors NET SERT

21 Monotherapies That Target Multiple Receptors 1 H1 SRI Na+ channel blocker 5HT3 2 mirtazapine trazodone M1 5HT 2C 5HT 2A NRI 5HT 2A 5HT 2C amitriptyline amoxapine (minimal SRI) clomipramine doxepin nortriptyline (minimal SRI) 1A vilazodone SERT 1D 1A 1B 3 vortioxetine 7

22 Remission Rate (%) Combining Reuptake Inhibitors ns ns <.04 <.04 At Last Visit Escitalopram (N=84) Bupropion (N=83) Dual therapy (N=78) HAM-D 17 HAM-D 29 MADRS QIDS ns ns ns ns Dual vs. bupropion: HAM-D 17: c 2 =4.39, df =1, p<.04; HAM-D 29: c 2 =4.39, df =1, p<.04. Stewart JW et al. J Psychiatr Res 2014;52:7-14.

23 Remission Rate (%) Combining Reuptake Inhibitors ns <.02 <.06 <.04 <.01 At Week 2 <.07 HAM-D 17 HAM-D 29 MADRS QIDS Escitalopram (N=84) Bupropion (N=83) Dual therapy (N=78) Dual vs. escitalopram: HAM-D 29: c 2 =5.26, df =1, p<.02; MADRS: c 2 =3.66, df =1, p<.06. Dual vs. bupropion: HAM-D 17: c 2 =4.21, df =1, p<.04; HAM-D 29: c 2 =6.74, df =1, p<.01; MADRS: c 2 =3.56, df =1, p<.07. Stewart JW et al. J Psychiatr Res 2014;52:7-14. ns ns

24 Combining Reuptake Inhibition With Receptor Actions: Positive Study Blier P et al. Am J Psychiatry 2010;167:281-8.

25 Combining Reuptake Inhibition With Receptor Actions (CO-MED): Negative Study Rush AJ et al. Am J Psychiatry 2011;168:

26 Combining Mechanisms: Adjunct Atypical Antipsychotics α2 atypical antipsychotic Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

27 Atypical Antipsychotics in Depression: ARP* ASN BRX* ILO LUR OLZ* PAL QUT* RSP Proposed Mechanisms 5HT2A 5HT1A 5HT1B/D 5HT2C 5HT7 D3 D2 NET α2 ZIP *Approved (olanzapine in combination with fluoxetine; quetiapine only for XR). Red: inhibition/antagonism. Yellow: partial agonism. ARP: aripiprazole; ASN: asenapine; BRX: brexpiprazole; ILO: iloperidone; LUR: lurasidone; OLZ: olanzapine; PAL: paliperidone; QUT: quetiapine; RSP: risperidone; ZIP: ziprasidone. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

28 Atypical Antipsychotic Augmentation Adjunct olanzapine, quetiapine, aripiprazole, or risperidone to SSRI/SNRI Meta-analysis 1 Significant benefit vs. placebo for remission rates; NNT=7 Significantly higher discontinuation rate due to adverse effects Meta-analysis 2 Greater effect sizes in patients with higher degree of treatment resistance (response) 1. Wen XJ et al. Braz J Med Biol Res 2014;47(7): Wang HR et al. Int J Neuropsychopharmacol 2015;Epub ahead of print.

29 Combining Mechanisms: Adjunct Lithium neurotrophin NT NT GSK-3 = lithium promotes neuroprotection long-term plasticity Chiu CT, Chuang DM. Pharmacol Ther 2010;128: ; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed Copyright 2014 Neuroscience Education Institute. All rights reserved.

30 Lithium Augmentation Augmenting response (meta-analysis) 1 10 studies (7 TCAs, 3 SSRIs) Significant benefit vs. placebo; NNT = 4 Augmenting remission (STAR*D) 2 Benefit not confirmed Accelerating response (meta-analysis) 1 5 studies, TCAs No benefit (trend) Overall: evidence strongest for augmenting TCAs 1. Crossley NA, Bauer M. J Clin Psychiatry 2007;68(6): Nierenberg AA et al. Am J Psychiatry 2006;163:

31 Combining Mechanisms: Adjunct Triiodothyronine (T3) blood-brain barrier T3/T4 Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

32 T3 Augmentation Augmenting remission (STAR*D) 1 Trend favoring T3 over lithium (methodological factors?) Augmenting response (meta-analysis) 2 8 studies, TCAs Significantly increased response rate; NNT = 5 Augmenting response to SSRIs (various studies) 3 Mixed results, placebo-controlled study showed no benefit Overall: evidence strongest for augmenting TCAs 1. Joffe RT et al. Can J Psychiatry 2006;51: Aronson R et al. Arch Gen Psychiatry 1996;53: Connolly RK, Thase ME. Drugs 2011;71(1): Copyright 2014 Neuroscience Education Institute. All rights reserved.

33 Meta-analysis Across Augmentation Options 48 trials (6,654 participants) Significantly more effective than placebo Quetiapine (OR=1.92; 95%CI ) Aripiprazole (OR=1.85; 95%CI ) Thyroid (OR=1.84; 95%CI ) Lithium (OR=1.56; 95%CI ) Aripiprazole and quetiapine efficacy estimates were more robust than thyroid and lithium Quetiapine, olanzapine, aripiprazole, and lithium were significantly less well tolerated than placebo Zhou X et al. J Clin Psychiatry 2015;76(4):e

34 Recommended Adjunct Doses in Unipolar Depression Drug Daily dose lithium meq/l (bipolar depression)* T mcg aripiprazole 2 10 mg brexpiprazole 2 mg olanzapine 5 20 mg olanzapine-fluoxetine combination 3/25 mg 12/50 mg quetiapine mg *Blood level listed due to narrow therapeutic index

35 Adjunct Medications: Side Effects Other LI tremor, GI, acne, thyroid, renal T hyperthyroidism ARIP nausea, akathisia BRX akathisia OLZ QUET Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011; Stahl SM. CNS Spectrums; in press.

36 Adjunct Medications: Monitoring Guidelines Parameter Baseline Monthly 3 Months 6 Months 12 Months Renal Li Li Thyroid* Li Li Calcium Li Li Serum levels** Li Weight AAP AAP AAP Li AAP, Li BP AAP AAP AAP Fasting lipids AAP AAP AAP Fasting glucose AAP AAP AAP AAP: atypical antipsychotic Li: lithium *Periodic for T3 **Stable patients For first 3 months of treatment For first year of treatment Malhi GS et al. Bipolar Disord 2012;14(suppl 2):1-21.

37 Combining Mechanisms: Transcranial Magnetic Stimulation (TMS) 1. Electromagnetic coil on scalp: magnetic field penetrates skull by a few cm 2. Depolarizes neurons in superficial cortex DLPFC VMPFC amygdala 3. Through neural pathways, this local stimulation causes functional changes in other brain regions Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

38 TMS Augmentation Change From Baseline in HAMD Scores Liu B et al. BMC Psychiatry 2014;14:342.

39 TMS: The Procedure Generally done on an outpatient basis No anesthesia, no loss of consciousness Pulses of magnetic field are delivered in 30-s intervals 4 s each, 26-s rest intervals, 10 pulses/s Feels/sounds like light tapping on the scalp (patient and staff should wear protective earplugs) Session length: typically min Treatment duration: usually 5 treatments/week, 4 6 weeks Therapeutic dose: % of motor threshold* *Motor threshold: magnetic field strength that results in movement of right thumb

40 TMS: Clinical Considerations Side Effects Headache, discomfort at stimulation site Rare risk of generalized seizure Contraindications Patients with ferromagnetic metal within 30 cm of the coil Caution Patients with an implantable device controlled by physiological signs Blumberger DM et al. Curr Psychiatry Rep 2013;15(7):368; Kalu UG et al. Psychol Med 2012;42(9):

41 Other Augmentation Options Option Data summary References Buspirone Makes sense mechanistically but data are mixed/weak Connolly and Thase, 2011; Trivedi et al., 2006; Appelberg et al., 2001 Stimulants Limited data show trend of benefit Trivedi et al., 2013 DA agonists Best evidence for modafinil/armodafinil Some evidence for pramipexole and ropinirole Goss et al., 2013; Aiken, 2007; Cassano et al., 2005; Calabrese et al., 2010; Fava et al., 2005 L-methylfolate Positive controlled studies Bottiglieri, 2013

42 Other Augmentation Options Option Data summary References Bright light therapy Meta-analysis in non-seasonal depression suggests possible efficacy SAMe Positive controlled study; dosed mg/day oral or mg/day IM; best absorbed if taken 20 min before a meal; not recommended in first trimester Omega-3 Exercise Multiple meta-analyses suggest modest efficacy; 60% EPA (of total EPA+DHA) needed; 1 3 g/day is generally safe (including dietary intake) 5 times/wk, min/session was best in studies Golden et al., 2005; Pail et al., 2011 Papakostas et al., 2010 Lin et al., 2012; Martins et al., 2012; Freeman et al., 2006; McNamara and Shawn, 2013; Grosso et al., 2014 Rethorst et al., 2009; Rimer et al., 2012; Josefsson et al., 2015

43 GETTING TO REMISSION (FASTER) Glutamate

44 Ketamine NMDA receptor Ca2+ Directly targeting glutamatergic neurotransmission or neuroplasticity may lead to faster treatment response and may improve response and remission rates Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:

45 Ketamine Increases Synaptic Plasticity mtor AMPARs Increased synaptic plasticity Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15: Copyright 2014 Neuroscience Education Institute. All rights reserved.

46 glu AMPA receptor NMDA receptor blocked by ketamine ERK, AKT mtor Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

47 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)

48 Prospects for Glutamatergic Strategies Alternative delivery for ketamine Preliminary case studies and open-label trials for: Oral (20% bioavailability) Intramuscular (similar bioavailability) Sublingual (~30% bioavailability) Double-blind trial Intranasal Other promising glutamatergic strategies? Not yet Iadarola NI et al. Ther Adv Chronic Dis 2015;6(3):97-114; Irwin S, Iglewicz A. J Palliative Med 2010;2:903-8; Chilukuri H et al. Indian J Psychol Med 2014;36:71-6; Lara D et al. Int J Neuropsychopharmacol 2013;16:2111-7; Lapidus K et al. Biol Psychiatry 2014;76:970-6.

49 GETTING TO REMISSION (FASTER) Personalized Treatment

50 Evolving Disease Models in Depression Inflammatory Neuroplastic Excitotoxic Cellularmetabolic Can collections of biomarkers help stratify patients based on their underlying pathogenesis?

51 Effect Size (HDRS-28 Change from Baseline) Favors l-methylfolate Plasma Biomarkers Involved in L-methylfolate Treatment Response SAM/SAH ratio hscrp (mg/l) 4-HNE (ug/ml) < < < 3.28 Papakostas GI et al. J Clin Psychiatry 2014;75(8):

52 Preliminary Data: CRP Level Affects Differential Treatment Response Uher R et al. Am J Psychiatry 2014;171(12):

53 Targeting "Inflammatory Depression" Several studies and meta-analysis show that NSAIDs and cytokine inhibitors can reduce depressive symptoms, BUT With few exceptions, the studies have not pre-selected or stratified patients based on baseline inflammation Drugs studied (e.g., celecoxib) have additional, noninflammatory effects Standardized subset of inflammatory markers is needed C-reactive protein, tumor necrosis factor, and interleukin-6 Mendlewicz J et al. Int Clin Psychopharmacol 2006;21:227-31; Akhondzadeh S et al. Depression Anxiety 2009;26(7):607-11; Muller N et al. Mol Psychiatry 2006;11:680-4; Tyring S et al. Lancet 2006;367:29-35; Raison CL et al. JAMA Psychiatry 2013;70(1):31-41; Kohler O et al. JAMA Psychiatry 2014;71(12): ; Miller AH, Raison CL. JAMA Psychiatry 2015;72(5):527-8.

54 Other Potential Biomarkers Growth factors: BDNF, insulin-like growth factor 1, vascular endothelial growth factor, interferon regulatory factor 7 Endocrine factors: dexamethasone (dex) suppression test, CRF stimulation test, Dex-CRF test, sleep EEG (CRF) Genetic: serotonin transporter, 5HT2A, COMT, MTHFR Metabolic: BMI, leptin, ghrelin, others? Gene expression: histone deacetylase 5, CREB, histone deacetylase 2 Scarr E et al. Int J Neuropsychopharmacol 2015;Epub ahead of print. Schmidt HD et al. Neuropsychopharmacol 2011;36: Horstmann S et al. Harvard Rev Psychiatry 2011;19:

55 Summary Depression is likely a result of several underlying pathogeneses that lead to overlapping symptoms Likely due to their downstream effects, monoaminergic agents are effective for many patients Goal of treatment is to get patients to remission as fast as possible and keep them there Theoretical strategies to enhance/hasten remission Combining mechanisms Directly targeting glutamate and neuroplasticity Personalized strategies