Biochemistry of Depression and Commonly Prescribed Antidepressants Tricia Hill Biochemistry 7 December 2006

Abraham Lincoln “I am now the most miserable man living. If what I feel were equally distributed to the whole human family, there would be not one cheerful face on earth. Whether I shall ever be better, I cannot tell. I awfully forebode I shall not. To remain as I am is impossible. I must die or be better it appears to me.”

Purpose of Research Recent issues regarding increased use of antidepressants Concern about long-term effects of antidepressants Previous rise in U.S. suicide rates More recent slight decline, except individuals age 10 to 45 Publications of books about mental illness and psychopharmacology

Depression Has been stated that antidepressants only control symptoms of depression Diagnosis of illness requires persistence of symptoms for Some symptoms include: –feelings of loneliness, sadness, hopelessness, or despair –changes in sleep or eating patterns –excessive irritability or anger –lack of confidence –physical exhaustion much of the time –suicidal thoughts or attempts

Causes of Depression Genetic predisposition Social learning factors Tendency to react negatively toward stress Serious loss or other unwelcome life-altering event ALL EVENTUALLY LEAD TO A CHEMICAL IMBALANCE IN THE BRAIN.

Chemical Imbalance Deals with three principle monoamines (neurotransmitters): –dopamine –norepinephrine (noradrenalin) –serotonin (5-HT) Abnormal levels create mood disturbance Sometimes results from enzyme-substrate interactions More frequently from abnormal reuptake during monoamine catabolism

Monoamine Oxidase Monoamine oxidase (MAO) is the enzyme ultimately responsible for the catabolism of the neurotransmitter into its respective metabolites

Catechol-O-methytransferase Abbreviated COMT Other party involved in the catabolism of monoamine Provides alternate pathway forming different metabolites than if compound went straight through MAO Follows same typical enzyme-substrate interaction Even if monoamine goes through COMT, it will also undergo further breakdown by MAO

Catabolism of Norepinephrine HO OH CH CHCH 2 NH 2 CH CHCH 2 NH 2 OH CH 3 0 HO CH 3 0 CHCOOHCHCH 2 OH CHCOOH OH CHO OH COMT ALDH MAO ALDH DHMA ALRED MHPGDHPGVMA

Catabolism of Dopamine OH CH CHCH 2 NH 2 OH CH 2 COOHCH 2 CH 2 OH CH 2 CHO OH H 3 CO CH 2 CH 2 NH 2 CHO OH COMT ALDH MAO ALDH DOPAC ALRED HVA OH CH 2 CHO CH 2 COOHCH 2 CH 2 OH H 3 CO

Catabolism of Serotonin HO NH 2 CH 2 HO CH 2 CH 2 0H CHO COOH NHNH NHNH NHNH NHNH 5-HIAA ALDH ALRED MAO

Metabolites The metabolites formed during the breakdown of each neurotransmitter enable physicians to determine the effectiveness of medications. DHMA and MHPG are the primary metabolites of norepinephrine and are measured most frequently. HVA and DOPAC are dopamine’s main metabolites. Serotonin’s predominant metabolite is 5-HIAA. Metabolites can be obtained through cerebrospinal fluid, blood plasma, saliva, and urine. Conjunctive measures help determine specific enzymatic abnormalities.

Psychopharmacology The study of the actions of drugs on the mind (Webster’s) Study of drugs that affect thinking, feeling, and action, emphasizing those drugs that affect abnormalities in thought, affect, and behavior (AccessScience) Concerned with four major classes of drugs linked to four major psychiatric disorders: anxiety, depression, mania, and schizophrenia

SSRI Selective Serotonin Reuptake Inhibitor Ex: Zoloft (sertraline hydrochloride) (cis-1S)-4-(3,4- dichlorophenyl)- 1,2,3,4-tetrahydro-N- methyl-1- napthalenamine hydrochloride

SSNRI Selective Serotonin and Norepinephrine Reuptake Inhibitor Ex: Cymbalta (duloxetine hydrochloride) (+)-(S)-N-methyl-γ-(1- naphthyloxy)-2- thiophenepropylamine hydrochloride

TCA Tricyclic antidepressant Ex: Tofranil (imipramine hydrochloride) 5-[3- (dimethylamino)propyl ]-10,11-dihydro-5H- dibenz [b,f]azepine monohydrochloride

MAOI Monoamine Oxidase Inhibitor Ex: Aurorix (moclobebide) p-chloro-N-(2-morpholinoethyl) benzamide

Conclusions These are the four most commonly prescribed classes of antidepressants We know that there is some action involved, but there is never 100% proof that antidepressants offer long-term effects on depression Therefore, we can only say that antidepressants alleviate the symptoms, not the disorder Depression is not a character flaw or caused by bad parenting as some might believe It is a chemical imbalance that has high rates of response to pharmacological intervention