Past, Present & Future of Pharmacotherapy of Affective Disorder

Introduction

Disorder of mood (affective disorder) are common in GP as well as in psychiatry.

Two main types of depression

Major Depression :- A depressed mood on daily basis for minimum peroid of 2 wk.

Incidence :- App 15 % of general population (major depression) 6 – 8 % are correctly diagnosed out of which only ½ - 1/3^rd are adequately t/ted.

10 – 15 % pt of (MD) are prone – suicide.

Manice (M) :- Opposite of depression – euphoria, HM, etc.

Unipolur depression :- Depression / mania with wa x s waning nature.

Bipolar depression :- Cyclically alternating manic & depressive phases.

Bipolar I – Mania predominates

Bipolur II – Depression predominaly

Biochemical changes in Depression

Post :- Older Humoral theories of (AD) affective D. Ancients belived that temprament and mood depended on (4) humours :- likely

1. Blood
2. Black bole
3. Choler
4. Phelgm

Transmitter Hypothesis :- 1960 have attracted supported by mood of action attension 1^st genration (AD) which NA S-H and less ofent (DA) in synapses. Conversly – Reserpic – deplition (MA) – depression

Hypothesis :- (NA) major (NT) in aff. Dis.

1^st coined by schildkraut 1965.

Schildkraut et al showed that meta of (NA) 3 – methoxy – 4 hydexyphengl gycol (MHPG) ed in urine D CSF samples in depression ed in munia and normal during remission in bipolur depression.

History of Antidepressent drug discovery

1. Lithium 1948 John Cade
2. ICAs :- In 1940 Hafliger and Schildler made > 40 comp. Dibenzazepine (imipramine)

In 1958 khun – imipramine effective in mood of depressed pt

1951 (INH) it's iscprepyl derivative iproniazid

3. MAOI :- 1952 Zeller and Co-workers found that iproniazid had a mood elevating effect in pt of TB and later condueled it was MAOL.

1^st MAOI used :- Hydrazine derivatives phenelzine and isocurboxuzide its less hepototixc congerers and nonhydrazine

MAOI – Tranglcypromine became popular in 1960's but their toxicity and interaction placed them to a minor role in psychiatry

Present Trends of affective disorder pharmachotherapy

Most important development of (AD) in 1990s are

1. Selective 5 – HT rut inhubitors SSRIs
2. Reversible and selective of MAO RIMAs
3. Selective serotonergic and (NA) nergic rut NASSRI
4. Selective (NA) nergic rut (SNRI)
5. Almost 40 years ago 1^st (An were introduced

These were

Both classes of drugs are effective in t/t of depression but both posses considerable disadvantage B/o. (AE) profile.

With drawn B/o. (AE) (a) clinical efficucy uncertain classified as (NA) and specific 5 – HT tnergic (AD)

1. (TCAs) rute of (NA) and 5 – HT potentiate their action they differ markedly in their potency

(NA) > 5.HT

1. Nortryptyline
2. Desipramine
3. Protryptegline
4. Amosapine

Mech of action + post synaptic recpt (AR) – ed responsineness – (AD)

Gaba ® - Unclear

P₂ presynaptic autorecptor – desensitization

(DA) in forebrain – (AD)

AE :- Anticholinergic action, post hypotension

• Sinus tachy cardia.
• Arrhythmics

(SSRIs) are free from this (AE)

Current status :- TCAs like

Are now "2^nd drug of choice" in (MD)

2. SSRIs. At present there are 5 marketed SSRIs

• Fluoxitine
• Fluvoxamine
• Paroxetine
• Sertraline
• Citalopram nes

1. Same mech of action, 2. Only differ in their ½ life (SSRIs)

SSRIs have same efficay

(AE)

1. Naused, vomitting are common (AE) of all SSRIs ranfoing (20 – 37 %)
2. Headache
3. Saxual dysfuntion

In comparision to (TCAs) all SSRIs have fuvorable (AE) profile ie : they lack

Anticholinengic of properties as sedating tree from HR arryth as in TCAs lesstoxic in suicidal overdose ed incid :- of suicide as to TCAs interaction

Plasma TCAs l;evel when used in combination – ppt. TCAs poisoning

TCAs are superior in efficacy to SSRIs used in resist depression.

Current status :- From 1960 – 1990 TCAs were more commoly used to t/t depression.

SSRIs posses a preferable (AE) profile.

Ie :- Free of sedation freedom from congnative and psychomotor SSRIs

Frequently used on (OPD) basis.

D.O.C also 1^st D.O.C.

1 – in medically ill pt

2 – Potentially saicidal pt.

(AE) reported during compurative controlled clinical trul of (Citalopram and {TCA}

(AE) interaction

Combination of SSR/s along with 5-H-T agonist should be aavoided

B / o may cause

B / o Serotonin sgndrome"

5-H-T_1A (R) Hyperwtimullllutⁿ

MAO / S

Substrate for type 'A' and type 'B'

Monoamine oxidase

MAO (A) MAO (B)

Preferred substrate : (NA)

5-H-T

Phenylethylamine

Benzylamines

Non specific subst :

Dopamine

Tyramine

Subs. For both MAO 'A'

MAO (B)

Irreversible

Specific inhibitors

Clorygyline (AD) action (A)

Selegiline used parkinsons dise (B)

Nonspecific inhibitors :

MAO 'A' and 'B'

Hypertensine crisis when tyramine rich food ingested chees reaction

Minor role as (AD)

Used only when other drugs fail

Pargyline Tranyl cypromine phenclzine

Specific inhibitors of MAOCA :-

In 1968 2 functional isoforms of MAO discovered development of new MAOI for t/t of depression focused on

1. With selective of MAO 'A' keeping MAO 'B' active to leaminate potentially hazardous tyramine.
2. Reversible and competitive property of this inhibition allowing other subs (Tyraramine) to displuce the inhibitor or (drug) from binding site k/as (RIMAs). Druggare

• MoClo Bemide
• Brofaromine
• Cimoxatone (only in france with weak MAOCA) action.

Moclobemide :- RIMAs isoengyme MAO'A' – only safer than older MSOIs.

• Recent clinical trials and meta analysis have confirmed the efficacy of moclobemide of good (AD) agent
• Moclobemide is of efficacy to – TCAs
• SSRI
• Older MAIL
• Some studies shows that

Moclobemide was less effective than clomipramine in t/t of severly depressed pt where clomipramine was also more effective than SSRIS like – citalopram and parotetine comparative studies show moclobemide better tolerated than.

1 – TCA

2 – nomselective MAOIs

Mochlobemide lacks follow (AE) like

• Anticholinegic effects
• Sedative
• CUS (AE)

Molocbemide vs SSRIs

• Efficaccy almost to SSRIs
• Tendency to cause fewer 91 T AE

91T (AE) SSRI > moclobemide.

• No sexual dysfuntion reported with modobemial of are common in SSRIs sexual dyfu SSRIs > moclo.

Current status

Moclo causes no cognative and psychomotor impairn used in elderly pt.

Or

400 – 600 mg

pt with curdiovascular disease

cost effective – cheeper than older (AD).

Venlafaxine :- Selective 5 – H tnergic (NA) rut pharmacodynamically venlafaxine is to TCAs venlafaxin posses both (5HT) and (NA) rut ing action

It has 5 times more (5 – HT) nergic rut tion action

It is only drug avialable from the group (SNRI)

Pharmucokinetic :-

Venlufaxine recemic mixture

Both enantiomers are active

Venlafaxin demethylatn

Metabolite

0, demethglvenlafaxin

(ODV)

elimination t/2

It also posses (AD) action

Venlufaxin – 5 hr and (ODV) = t/2 = 11 hr.

Plasmu protien binding is – 27% venlafaxin

(PPB) Fluoxetine – PPB – 94%

SSRLS like Paroxetine – PPB – 95%

PPB vcnlagaxin < PPB SSRIS

Compppured to (TCAS) / venlufaxin has less / no

• No anticholinery acit
• No anti histaminergic
• No x1 AK bloxking

Current status

1. Pt with suicidal temdancy

Clinical trials show

• Venlafaxin superior to placebo in (MD) for 6 wk.
• In comparative (OPD) trial (VS) imipramine

Efficacy of venlufaxin imipramine

Eff. Venlafaxin > Fluoxetine

• Venlufaxin has comparitiuely faster onset of action with 4-7 day of t/t (?)

Dose yes ponse velationship exist with BP.

75 mg OD (VLF) BP was / mm Hg; 225 mg of BP 2 mmg Hg 375 mg OD BP by 7.5 mm Hg.

Nefazodone : Congener of trazadone 5-H-T x. (Selective) 5HT rut X of fluoxetive with 5-H-T (R) blaking action very less x1 (AR) binding as comp to trazadone risk of priaapism less than trazadone efficacy of nefazodone imipramine for sever depression

Depression with anxity

Recurrent depression

(AE) Dry mouth

Weakness Rause

Consstipation

Blurredvision

(AE) likr that of SSRIs are absent may be B/o (5-H-T₂) antagonism onset.

Nefazodone REM sleep stage 3 and 4 sleep

Current status

Used in t/t of depression with insomnia recurrent depression.

Mianserin : Presynaptic x2 AR bloxk

(NA) release (AD) effect.

Not inhibiting (NA) and (5HT) rut.

H1 block by mainserin sedution releves anxity with depression

(AE) blood dyscrasis – Hepatotoxic

Use restricted

Currently not popular AD.

New drug

Noradrenaline

Serotonin

Mirtazapine

Mirtazapine enchaces NA nergic and 5 – 1 + T, mediate (NT)

Mirtazapine is a (NA) nergic and specific (5 tnergic (AD) (NaSSA) used in (MD).

A newer (AD) drug with unique mode of action efficacy of mirtazapine + to that of TCAs

= to Trazadone in modrate – sever depression and with Anxity and insomnia

evidence for faster onset of action tht (SSRIs) but tolerability profile of (Mtz) = (SSRIs)

(AE) seen of in (TCSa)

Apetite and wtgain common with (mtz) > to other (AD)

Mirtuzapine (mtz) low affinity for cholinergic (R)

• (DA)
• Muscarine (R)

High affinity for (H1R) sedation

(mtz) more cost effective than Fluoxetine or amitryptgline

For t/t of (MD)

Conclusion :- nely developed (AD) seem to posses certain advantage (TCAS).

2 major medical need – for t/t of depressedpt have not been met.

1. Superior officacy to (TCAs)
2. Faster on set of action.

Newer (AD) have some advantages over (TCA)s are

1. No sedation (expt. Mirtazapine)
2. No anticholinergic and cardiotoxic effect
3. Headache and insomnia with RIMA (Moclo).

Bipolar ddisorder

Morden t/t of (BP) disorder was revolutionized with Li⁺ in 1949. Lt⁺ was gradullay accepted world wide 1960 – 705.

At present Li⁺ is use prophylactically for t/t of (BP) disorder. But requires serum levels assesment frequently for (AE)

• Antiepileptics lide carbazmazepine

Valproate

Also have mood stabilizing property

And they are used as alternatives to Li⁺

In acute manice :- as Li⁺ has slow onset of action

Pts are 1^st controlled by

Low compliance in pt on Li⁺ - 10 razepam

Or

• Clonazepan.

Than gradually Li⁺ is introduced for long term mood stabilization.

Clinical trial show.

Carbamazipine = Li⁺ for protection rates efficacy. Combination of Li+ earbazi has in short term trials better efficacy.

• Valproate is better toleruted clinically.

Future :- GABA nergic agents like – Clobazam

Gabapentin

Lamotrigine

Vigabatrin

• Ca²⁺ channel Blocker need further evaluation as moodstabilizing agents

Atgpical Antiphychotics like – "Clozapine" should be considerd (Doc) for (BPD)

Future in )VD) t/t

• New pharmacological mech should be found to overcome the efficacy disadvartage of exsisting (AD).

1. Modulatⁿ of Neuropeptides :- As (NP) play key role in regulatocy CNS function.
2. Direct influence on 2^nd messenger system Via :- IC AMP

Or

Zphosphatidly inositol system

1^st step in this direction was Rolipram

3. Another intresting approch would be to dwelop CNS selective MAADDI with no effect on peripheral and hepatic MAO.

Drig is – MDL – 72394 (prodruy)

Irreversible central MAO – A Inhibitor

4. Very diff. Approch to (AD) t/t which might fullfil some of stated fzatuas of AN I deal AD is S – adenosy L – L – Methionine k/of (Same, ademetionine)

Same – Causes ed conversion phosphatidyl ethunolamine SAMe

Phosphutiiasl choline (ptc)

This – (ptc) Fluidity of (CM)

(NT) sion by No receptors

efficacy of receptor – effector coupliny

Uptill now no major progress has be made dixovery of imipramine – 1950s.

References

1. Goodman Gillman
2. Harrison's priciples of Internal medicine
3. Lewis's phormacology.
4. Principles of clinical psychiatry
5. Drugs :- 1996, 51 No. 3
6. Drugs :- 1992 43 supp. 2
7. Drugs :- 1999 57 (4)
8. Drugs :- 1996 52 (5)
9. Rang and Dale pharmacology

Summary

Major limitation of efforts to develop new (AD) is lack of exact pathophsiological mech of major depression and bipolr disorder despite decades of research work.

Most important development of (AD) in 1990s

Were – SSRI

• RIMAs
• (NA) ut
• SNRI

These compounds have very low binding capacities at other receptors not linked to their (AD) action – Tolerability improved.

But still no one of them fullfil critearum

• Superior efficacy to TCAs.
• Faster on set of action.
• Effectiveness in t/t of Resistant dep.