New Trips in the Space of Antipsychotics TAREK

New Trips in the Space of Antipsychotics TAREK DESOKY AHMED LECTURER OF NEUROPSYCHIATRY QENA FACULTY OF MEDICINE SVU

Historical View of Antipsychotics Early 1900 s 1950 s 1960 s 1980 s-1990 s-2005

The conventional mechanism of antipsychotics

Modulation of Neurotransmission Serotonergic Noradrenergic Dopaminergic TCAs SNRI MAOI SSRI NDRI Lithium? NRI DA agonists SNDI ( 2 antagonist) Buspirone Stimulants T 3, T 4 ? ? Papakostas GI, 2006; European Neuropsychopharmacology; 16: 391 -402

TYPE OF AFFECT Loss of positive affect Loss of pleasure/enjoyment DA/NE agents Loss of motivation And energy Loss of Low mood interest Sadness Guilt Irritability Fear Depression with anxiety Anxiety Negative affect NE/5 HT agents Hypothetical model showing differential actions of antidepressant agents on symptoms of positive and negative affect Nutt D. et al. , 2006; J. Clinic. Psychiatry, 67: 46 -49

MONOAMINE DEFICIENCY SYNDROMES SEROTONIN NORADRENERGIC DEFICIENCY SYNDROME

Functional Roles of Brain Monoamines Norepinephrine Serotonin Anxiety Irritability Energy Interest Social function Memory Motivation Attention Mood, Emotion, Cognitive function Impulse Control Sex & appetite Aggression Drive Reward Executive function Dopamine Modified from Healy & Mc. Monagle. J Psychopharmacol 1997; 11 (suppl 4): S 25 -S 31. Stephen E. , 2005; Journal of Neuroscience Nursing; 37, 2; Health & Medical Complete

Neuroanatomical & Neurochemical Basis of Symptoms of Depression EMOTIONAL Loss of Sadness & pleasure, suicide interest & motivation SOMATIC COGNITIVE Fatigue loss of energy, Pain Sleep appetite Libido etc. Attention Concentration Problem solving Dorsolateral PFC Ventromedial PFC DA NE 5 HT Nucleus accumbens & hypothalamus Dorso-lateral PFC DA 5 HT NE DA DA (D 1) Ach. 5 HT NE GABA Histamine Malhi GS, et al. , (2005): Acta Psychiatr. Scand. ; 111: 94 -105 Holtzheimer P. E. et al. , (2006): The American Society for Experimental Neuro Therapeutic; Vol. 3, 42 -56

The Conventional Mechanisms of Antidepressants TCAs NRIs MAOIs SNDIs SSRIs SARIs SNRIs NDRIs

New Antipsychotics In Clinical Trials (Pipeline 2015) Drug Mechanism Phase Company ABT - 126 ᾳ 7 -n. ACh. R agonist II Abb. Vie ADX-1149 (JNJ 40411813) m. Glu 2 positive allosteric modulator (PAM). II Addex therapeutics / Janssen Pharmaceuticals ALKS 3831 D 1, D 2, 5 -HT 2 antagonist + mureceptor antagonist II Alkermes AQW 051 ᾳ 7 -n. ACh. R agonist II Novartis Pharmaceuticals Aripeprazole Lauroxil (ALKS 9072) D 2 partial agonist, 5 HT 1 A partial agonist, 5 -HT 2 A antagonist III Alkermes AVL- 3288 (type 1) ᾳ 7 -n. ACh. R positive allosteric modulator (PAM). I Anvyl Pharmaceuticals

New Antipsychotics In Clinical Trials (Pipeline 2015) Drug Mechanism Phase Company AVN- 211 5 -HT 6 receptor antagonist II Cariprazine D 2 & D 3 receptor partial agonist FDA approval pending CEP- 26401 (Irdabisant) H 3 receptor antagonist / inverse agonist Encenicline ᾳ 7 -n. ACh. R selective partial agonist III Forum Pharmaceuticals ITI- 007 5 -HT 2 A receptor antagonist III Intra-cellular therapies MIN- 101 5 -HT 2 A / SIGMA-2 receptor antagonist II Minerva Neurosciences Alla. Chem / Avineuro Pharmaceuticals Forest laboratories I (complete) Teva Pharmaceutical

New Antipsychotics In Clinical Trials (Pipeline 2015) Drug Mechanism Phase Company NW- 3509 Voltage gated sodium channel (VGSC) modulator I Newron Pharmaceuticals OMS- 824 PDE 10 inhibitor II Omeros Pimavanserin (Nuplazid) SSIA (selective serotonin inverse agonist) II ACADIA Pharmaceuticals RBP- 7000 D 2 & 5 -HT 2 A antagonist III Reckitt Benckiser Pharmaceutical RP 5063 Dopamine serotonin system stabilizer III Reviva Pharmaceuticals

New Antipsychotics In Clinical Trials (Pipeline 2015) Drug Mechanism Phase Company Syntocinon (nasal spray) Synthetic oxytocin II Retrophin TAK- 063 PDE 10 A inhibitor I Takeda Pharmaceuticals LU AF 35700 D 1 receptor antagonist I lundbeck

Off-Label Use of Atypical Antipsychotics

The new mechanisms of antidepressants NMDA receptor modulators Opioid receptor modulators Antiglucocorticoid Neurogenesis Antiprogestogen SNDRI SDRI NOC-1 antagonist OX 2 antagonist Botox

THE OLD AND THE NOVEL ANTIDEPRESSANTS Are the new antidepressants better than the old? Are the new mechanisms much more clever than the conventional. Is the better side effect profile and the rapid onset of action will be on the expense of potency?

THE NEED FOR !!! THE MAGIC ANTIDEPRESSANT Can a novel antidepressant give an effect in hours, rather than weeks or months? The need for rapidly treating people with suicidal thoughts.

THE ADDICTIVE SUBSTANCES AS ANTIDEPRESSANTS !!! Esketamine (Murrough’s trial, 2013) (Pipeline 2015). ALKS 5461 (Mu receptor partial agonist / kappa receptor antagonist) (Pipeline 2015). AVP-786 (dextromethorphan) (Pipeline 2015).

Depression as a chemical imbalance? It is a bit more complex. RNAi for depression. Gene therapy for depression. Nanotechnology for depression.

Sertraline

Sertraline & Sigma-1 Receptor Affinity of antidepressants for sigma-1 receptor chaperone. Drugs Ki (n. M) Action at sigma-1 receptor Fluvoxamine (SSRI) 17. 0 Agonist Sertraline (SSRI) 31. 6 Antagonist? Fluoxetine (SSRI) 191. 2 Agonist Escitalopram (SSRI) 288. 3 Agonist Citalopram (SSRI) 403. 8 Agonist Paroxetine (SSRI) 2041 Duoxetine (SNRI) 3533 Venlafaxine (SNRI) >10, 000 Milnacipran (SNRI) >10, 000 Mirtazapine (Na. SSA) >10, 000 Ishima T. , et al. , Eur J Pharmacol, 727 (2014), pp. 167– 173

Sertraline for Retarded Depression Fatigue Cognitive slowing Pseudodementia Psychomotor retardation Sertraline Fluxetine Venlafaxine Bupropion Anxiety Agitation Panic Motor restlessness TCAs Paroxetine Fluvoxamine Mirtazapine Trazodone

Sertraline for Atypical Depression Typical TCAs Paroxetine Fluvoxamine Mirtazapine Trazodone Atypical sertraline Fluxetine Venlafaxine Bupropion Citalopram Escitalopram

Sertraline for Psychotic Depression Psychotogenic TCAs Bupropion Non psychotogenic “especially preferred” SSRIs (sertraline – fluvoxamine*). Trazodon. Mirtazapine.

Sertraline for Children FDA-Approved Pediatric Age Ranges and Indications for Antidepressant Medications: Depression: Fluxetine 7 y Escitalopram 12 y OCD: Sertraline 6 y Fluxetine 7 y Fluvoxamine 8 y Clomipramine 10 y NE: Imipramine 6 y

Sertraline for Elderly - SSRIs: Recommended: Citalopram. Escitalopram. Sertraline. …. . the lowest DDI. Not highly recommended: Fluxetine. …. long half-life and prolonged side effects & DDI. Paroxetine: …. anticholinergic side effects & DDI. Fluvoxamine: …. DDI

Sertraline and Cardiac Safety SERTRALINE Is the drug of choice in post MI and angina. FDA Drug Safety Communication, 2012

Sertraline and Drug–Drug Interactions 3 A 4 2 D 6 1 A 2 2 C 19 2 C 9 Fluoxetine ++ ++ Paroxetine + +++ + Fluvoxamine ++ + +++ ++ Citalopram 0 + + 0 0 Escitalopram 0 + 0 0 0 Sertraline + ++ + Venlafaxine 0 0/+ 0 0 0 Ca+ antagonists, erythromycin, ketoconazole, lidocaine, cancer therapies. Antiarrhythmic, bblockers, haloperidol, neuroleptics. caffeine, ciprofloxacin, theophylline, verapamil. diazepam, propranolol, moclobemide, imipramine miconazole, phenytoin, Swarfarin, NSAIDs Substrate Greenblatt et al. , 1998; Alberts et al. , 2000; Von Moltke et al. , 2001).

Sertraline and prolactin elevation

SERTRALINE SILVER PEARLS The highest cardiac safety The least DDI The lowest prolactin elevation Sigma 1 receptor affinity