Difficult-to-treat Depression

Transcription

1 Difficult-to-treat Depression Stephen M. Stahl, MD, PhD Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine Sponsored by Neuroscience Education Institute Additionally sponsored by American Society for the Advancement of Pharmacotherapy This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP; Cephalon, Inc.; and Shire Pharmaceuticals Inc. with additional support from Alkermes, Inc.; Eli Lilly and Company; Jazz Pharmaceuticals, Inc.; and Sepracor Inc. Copyright 2007 Neuroscience Education Institute. All rights reserved.

2 Learning Objectives Upon completion of this lecture, you should be able to: Understand the rates of response, remission and treatment-resistant depression Evaluate evidence based selection of treatments versus symptom based selection of treatments Anticipate new treatments still in clinical development

3 Antidepressant Response Rates medication started 67 % responders 33 % non-responders 8 weeks Stahl, SM. Essential Psychopharmacology, third edition. In press

4 ancillary 5T1A Li T3/4 augmentation SSRI NDRI SNRI monotherapies 2nd line monotherapies 1st line depression pharmacy

5 cognitive therapy ECT IPT VNS ancillary augmentation SSRI NDRI SNRI monotherapies 2nd line monotherapies 1st line depression pharmacy

6 ancillary 2 antagonist NRI TCA SARI MAOI augmentation monotherapies 2nd line monotherapies 1st line depression pharmacy

7 Evidence-Based Algorithm for Antidepressants SSRI#1 option 2 doesn t matter SSRI#2 NDRI SNRI +NDRI +5T1A switch options augmentation options option 3 doesn t matter 2 antag TCA +Li +TY switch options augmentation options option 4 doesn t matter MAOI SNRI + 2 antag Stahl, SM. Essential Psychopharmacology, third edition. In press

8 ow well do antidepressants work? Antidepressant REMISSION Rates 33% 20% 6-7% 6-7% 67% remission after 4 treatments 67% 47% 40% 33% nonremitters after 4 treatments antidepressant treatment #1 antidepressant treatment #2 antidepressant treatment #3 antidepressant treatment #4

9 What Proportion of Major Depressive Disorders Relapse? after 1 treatment after 2 treatments 0% 0% in remission in remission relapse rate not in remission 33% 60% relapse rate not in remission 50% 67% 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months

10 What Proportion of Major Depressive Disorders Relapse? after 3 treatments after 4 treatments 0% 0% relapse rate not in remission in remission 50% 70% relapse rate 30% 50% not in remission in remission 70% 100% 100% 3 months 6 months 12 months 3 months 6 months 12 months

11 Atypical Antipsychotics as Augmenting Agents for Inadequate Response to One SSRI/SNRI Only FDA approved treatment for inadequate response to an antidepressant Based on 2 randomized, double-blind, controlled studies (total N = 743) 2-20mg daily dosage Mean change in MADRS Total Score Base Week Placebo Aripiprazole Adapted from Berman et al. J Clin Psyc 2007

12 Atypical Antipsychotic as Antidepressant: Risperidone Augmentation Mean Change in RSD-17 Total Score Base Week n = 268 Dose: mg/day Scale: RSD-17 Placebo Risperidone Results: significant difference in reduction of RSD-17, rate of response and remission Adapted from Mahmoud et al. Annals of Int Med. 2007

13 Atypical Antipsychotic as Antidepressant: Ziprasidone Augmentation 100 Proportion of Sample (%) n = 20 (intent to treat) 6-wk open-label trial 0 Remission Response Adapted from Papakostas. CNS Spect 2007;12(12)supp22:10-12

14 Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: Meta-Analysis of 10 Randomized Controlled Trials 100 Percent in Remission n = 1,500 p <.05 0 Atypical Antipsychotics Placebo Adapted from Papakostas. CNS Spect. 2007;12(12)supp22:10-12

15 Treating Insomnia in Depression depression with insomnia/ GAD with insomnia SSRI + Z drug 42% remission SSRI alone 33% remission treatment Stahl, SM. Essential Psychopharmacology, third edition. In press

16 What is a trimonoamine modulator (TMM)? An agent that boosts the action of the trimonoamines serotonin, dopamine and/or norepinephrine Works indirectly and in combination with agents that directly modulate trimonoamines, such as the antidepressants that block monoamine transporters If monoamine neurons do not synthesize monoamines adequately, there is nothing released during neurotransmission, and thus no neurotransmitter reuptake to block

17 What agents are trimonoamine modulators (TMMs)? Lithium Thyroid (T3/T4) Modafinil (Provigil)/Stimulants 5T1A partial agonist buspirone L-methyl folate Atypical antipsychotics ECT/VNS (vagal nerve stimulation) TMS (transcranial magnetic stimulation DBS (deep brain stimulation) Psychotherapy

18 Reversal of Trimonoamine Neurotransmitter Deficiency with Thyroid? overactivation normal baseline hypoactivation blood-brain barrier T3/T4 improved depressed mood mood B

19 Reversal of Trimonoamine Neurotransmitter Deficiency with Lithium? overactivation normal baseline hypoactivation blood-brain barrier Li improved mood

20 Vagus Nerve Stimulation: A Trimonoamine Booster? vagus nerve neck VNS heart gut

21 Transcranial Magnetic Stimulation (TMS): A Trimonoamine Booster? DLPFC VMPFC amygdala overactivation normal baseline hypoactivation

22 Deep Brain Stimulation (DBS): A Trimonoamine Booster? electrode DLPFC VMPFC OFC overactivation normal baseline hypoactivation amygdala

23 B4 Cofactor for Synthesis of DA and NE from Tyrosine ydroxylase And for the Synthesis of 5T from Tryptophan B B DA NE tyrosine

24 L-methylfolate (MTF) Regulates B4 Production C 3 MTF C 2 methylene TF MTFR qb 2 B 4 neurotransmitter synthesis

25 ow does Deplin increase trimonoamine synthesis? B4 (tetrahydrobiopterin) Tryptophan Tyrosine Tryp T 5-TP L-Dopa methylenetf MTFR 5-MTF qb2 (quinonoid dihydrobiopterin) 5T DA NE

26 Formation of L-methylfolate (MTF) from Folic Acid (F) folic acid (synthetic) F DFR (dihydrofolate reductase) *Inhibited by lamotrigine* DF dihydrofolate (dietary) C 3 MTF TF tetrahydrofolate C 2 methylene TF MTFR (methylene tetrahydrofolate reductase) *genetically regulated*

27 MTFR Enzyme Genotype Prevalence of MTFR C T Polymorphism by Genotype Genotype % Residual Enzyme Activity C/C 100 C/T 71 C/C 47% T/T 10% omozygous Polymorphism C/T 43% T/T 34 Normal eterozygous Polymorphism *Individuals with C/T polymorphism have reduced MTFR enzyme activity, resulting in an approximate 20% increase of homocysteine levels

28 MTFR Polymorphism and Depression Prevalence of C T Polymorphism in General Population 1 Prevalence of T/T Polymorphism in depressed patients 5 Patients who have the MTFR C T genotypes have a 1.36 times greater chance of developing depression (and reported to be as high as 4X the general population) 3,4 The frequency of the T/T mutation has been shown to be about 10 to 12 % in the general population and reported to be as high as 22% in ispanic and Mediterranean populations. 2 The odds of having the T/T genotype is almost 3X as great in depressed patients verses the normal population. 5,6 1. Popakostas, J. Clinical Psychiatry; 2004, Procopciuc L.M., Presented at Biological Psychiatry, Poster P86 2. Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, Arinami T, AM J. Medical Genetics Bjelland, I., et. al;. Arch. Gen. Psychiatry 2003, Kelly B., Journal of Psychopharmacology 18(4) (2004)

29 Clinical Trial for L-Methylfolate in Depression Clinical Outcome Score Time (Months) Placebo MTF 24 outpatients with depression Scales: Clinical outcome score (Likert scale 1-6) AM-D Beck L-Methylfolate (MTF) (n = 13) vs. placebo (n = 11), 15 mg/day for 6 mos Augmentation to continued drug regimen Results: significantly improved scores in methylfolate group Folate deficiency and methylation disturbances implicated in depression Godfrey et al. Lancet. 1990;336:392-95

30 Folic Acid vs. L-methyl folate Dosing Facts L-methyl folate more readily crosses the blood-brain barrier 1 mg l-methyl folate may equal 7 mg folic acid Most studies indicate lowest dose of 7.5 mg L- methyl folate, equivalent to 52 mg folic acid L-methyl folate is less likely to mask vitamin B12 deficiency L-methyl folate has few side effects, is less expensive than augmenting with second antidepressant Stahl, SM. CNS Spect 2007;12(10: Stahl, SM. Essential Psychopharmacology, third edition. In press

31 TMM Actions of MTF and SAMe: Methylation and Neurotransmitter Synthesis SAMe SA methylation methionine homocysteine C 3 B12 MTF MTFR C 2 neurotransmitter synthesis methylene TF

32 Reversal of Trimonoamine Synthesis Deficiency by L- methylfolate (MTF): Possible Boost to Actions of Antidepressants C3 blood-brain barrier F blocked overactivation normal baseline hypoactivation A

33 Who are candidates for L-methyl folate augmentation? Documented MTFR enzyme reductions (CT/TT) - igh risk populations for CT/TT (ispanic, Mediterranean) Documented high homocysteine and/or low folate - igh risk populations for low folate (alcoholism, anorexia, pregnancy, atrophic gastritis/crohn s) igh risk populations on drugs that interfere with folate (lamotrigine, anticonvulsants) Those who fail to tolerate previous augmentation trials Patients/prescribers who prefer a natural product approach Stahl, SM. CNS Spetr 2007;12(10):423-28

34 Lamotrigine Stahl, SM. Essential Psychopharmcology, third edition. In press

35 Lamotrigine as a Mood Stabilizer Stahl, SM. Essential Psychopharmacology, third edition. In press

36 ancillary augmentation SSRI NDRI SNRI lamotrigine BP monotherapies 2nd line monotherapies 1st line depression pharmacy

37 ancillary hypnotic modafinil aripip DPA MTF C3 augmentation SSRI NDRI SNRI lamotrigine BP monotherapies 2nd line monotherapies 1st line depression pharmacy

38 ancillary hypnotic 5T1A Li BZ modafinil SDA UP DPA UP MTF C3 T3/4 stimulant augmentation SSRI NDRI SNRI lamotrigine BP monotherapies 2nd line monotherapies 1st line depression pharmacy

39 cognitive therapy ECT IPT VNS ancillary hypnotic 5T1A Li BZ modafinil SDA UP DPA UP MTF C3 T3/4 stimulant 2 antagonist NRI TCA SARI MAOI augmentation SSRI NDRI SNRI lamotrigine BP monotherapies 2nd line monotherapies 1st line depression pharmacy

40 Agomelatine Strong agonist at melatonin (MT1 and MT2) receptor sites Affinity similar to melatonin Antagonist properties at serotonin 5T2C receptors Increases NE and DA in frontal cortex of rats Active as 5T2C antagonist in stress tests of animal models; melatonin did not produce antidepressant effects Anxiolytic activity in Vogel conflict and social interaction tests in rats 5 mg dose effective and tolerated in approximately 6-week study of depressed patients Decreased MADRS score of 30.7 to 14.8 (n = 22) Studies indicate dosing of 5 to 100 mg for efficacy Minimal side effects Norman. Aust and NZ J of Psyc 2006;40:

41 Mechanism of 5T2C Antagonist NDDIs: Serotonin Inhibits DA and NE Release at 5T2C receptors NE DA overactivation normal baseline hypoactivation prefrontal cortex NE LC VTA GABA interneurons 5T2C DA 5T 5T 5T raphe Stahl, SM. Essential Psychopharmacology third edition. In press brainstem neurotransmitter centers

42 Mechanism of 5T2C Antagonist NDDIs: Serotonin Antagonism at 5T2C Receptors Disinhibits NE and DA NE release DA release overactivation normal baseline hypoactivation prefrontal cortex NE LC VTA GABA interneurons 5T2C DA agomelatine agomelatine 5T raphe Stahl, SM. Essential Psychopharmacology third edition. In press brainstem neurotransmitter centers

43 Drugs that Interact at 5T 2C Receptors: Future Treatments for Depression Fluoxetine (SSRI) Trazodone (SARI) Agomelatine (NDDI) Flibanserin (NDDI) Mirtazapine (alpha 2 antagonist, NaSSA) Nefazodone (SARI) Clozapine (AAP) Olanzapine (AAP) Ziprasidone (AAP) Stahl, SM. Essential Psychopharmacology, third edition. In press

44 Ketamine Stahl, SM. Essential Psychopharmacology, third edition. In press

45 Possible Actions of Anti-Glutamatergic Agents in Treatment of Depressed Bipolar Phase Stahl, SM. Essential Psychopharmacology, third edition. In press

46 Additional Emerging Treatment Options for Depression Beta 3 agonists (amibegron) Beta 3 receptors located in amygdala where they regulate neuronal activity in VMPFC Neuropeptides (nemifitide) Pentapeptide analog of tripeptide MIF-1, tripeptide tail of vasopressin Administered via subcutaneous injection Efficacy with rapid onset, treatment-resistant patients NK2 antagonists (saredutant) Excessive release of endogenous NKA in cases of stress or MDD may benefit from blocking NK2 receptors Stahl, SM. Essential Psychopharmacology, third edition. In press

47 SUMMARY Treatment response to various antidepressants may depend more upon when in the sequence of treatments a given agent is used rather than its specific mechanism of action Symptom based treatments, targeting residual symptoms such as fatigue or insomnia, or considering prior medication intolerance may influence intuitive sequencing of treatment selection in the absence of evidence determining a better strategy Several treatments with novel mechanisms of action are in late clinical development