Affective Disorders DepressionII Oct 2011

8/3/2019 Affective Disorders DepressionII Oct 2011

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Affective Disorders

and their treatment.

Dr Trevor Bushell

X2856

[email protected]


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Objectives

know the major forms of affective disorders

be able to discuss the biogenic amine hypothesis ofaffective disorders

know the mechanism of action of anti-depressant drugs

be familiar with the side effects and drug interaction of

antidepressants


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Classification of affective disorders

Affective disorders are all characterised by a disturbance of mood.

Severely depressed subjects, symptoms include:

profound sadness, guilt and unworthiness, lack of motivation,suicidal thoughts

Mania, symptoms include:

hyperactivity and elation

Affective disorders are not solely extremes in mood, they are also

disproportionate and unresponsive to outside influence.


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Biogenic amine hypothesis of

depression Low levels of NA and/or 5-HT depression

Raised levels of NA and/or 5-HT mania

Hence, if return the levels of NA and/or 5-HT

to normal, reverse depression or mania.

Actual answer is not that simple!!


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Evidence supporting the hypothesis

Reserpine depletes stores of noradrenaline,

dopamine and 5-HT, this leads to depression-

like states in animal models. This can be reversed

by 5-HT precursor

Metabolite levels: Decreased metabolite levels

for NA and 5-HT in some clinically depressedpatients.


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Problems with the hypothesis

Drug action is relatively fast (hours) but relief of symptoms

takes longer (days)

Antidepressants have differing mode of action (i.e. 5-HT v NA)

but work similarly on symptoms.

Receptor adaptations following long term treatment do not

fit with the simple hypothesis:

Down regulation ofb-adrenoceptors usually transmission

Down regulation of presynaptic a2-adrenoceptors - transmission

Down regulation of 5-HT2 receptorsusually transmission


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Antidepressants:

mechanism of action and side effects

Electroconvulsve Shock Treatment (ECT)

Monoamine Oxidase Inhibitors (MAOIs)

Tricyclic antidepressants (TCAs)

Atypical antidepressants and SSRIs


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Electroconvulsve Shock Treatment (ECT)

Therapeutic potential discovered by Ugo

Cerletti in Rome in 1937.

Even most severe bouts of depression are

usually responsive to ECT.

Still used today in cases of very severe

depression with a high risk of suicide,

where there has been no response to drugtreatments.

2272 people were treated with ECT in the

last survey conducted (JanMar 2002). Film based on real-life experiences of

Ken Casey in an Oregon mental hospital


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The use of ECT is controversial, do

you think it is a viable treatment for

depression?


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Overview of synaptic transmission.


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Monoamine Oxidase Inhibitors (MAOIs)

First drugs found to have some efficacy in treating depression.

First found by accident when an antituberculosis drug was found

to improve the mood of the treated patients.

Compound was later discovered to be an inhibitor of

monoamine oxidase (MAO).

MAOs are one of two enzymes involved in the degradation ofcatecholamines (i.e. NA) along with catechol-O-methyl transferase

(COMT).


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MAOs exist in two forms:

MAO-A preferred substrate 5-HT but also NA

MAO-B preferred substrate benzylamine & phenylethylamine

Early MAOIs were irreversible, thus enzyme activity will return

only following the synthesis of new enzyme.

Theory: Inhibition of the degradation pathway leads to increased

levels of NA and 5-HT.

HENCE, FOLLOWING THE AMINE HYPOTHESIS

levels of 5-HT & NA depression

NB in non-depressed patients, MAOIs anxiety & agitation


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MAOIs and the noradrenergic neurone

(applies to 5-HT as well)

MAOIs

Block

DegradationOf

NA & 5-HT


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Clinically used MAOIs

Largely superceded by TCAs, as greater efficacy and less side

effects.

Advent of MAOIs selective for MAO-A have renewed the interest

in them.

Irreversible MAOIs include: phenelzine

tranylcypromine

iproniazid

pargylline

Reversible inhibitors for MAO-A: clorgilline

moclobemide

Reversible inhibitor for MAO-B, selegilline, is used in Parkinsons.


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Side effects associated with MAOIs

Hypotension (pargylline once used as an antihypertensive)

Weight gain (can lead to discontinued use of drug)

Some atropine-like side effects (dry mouth, blurred vision etc)

Less than with TCAs.

Extreme cases can lead to hepatotoxicity (phenelzine, iproniazid).

Overdose can leads to convulsions.


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Drug interactions(one of main reasons for their decline in use).

The cheese reaction.

Food containing high levels of tyramine acute hypertension

Tyramine enters nerve terminals and displaces

NA from vesicles

Large release of NA

vasoconstriction

Ususally degraded by

MAO in gut & liver

Can lead to severe headaches

& even intracranial haemorrhage


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Drug interactions (contd)

Interaction with indirectly acting sympathomimetics (amphetamines)also leads to severe hypertension.

Co-administration of MAOIs and TCAs has also been reported to

lead to severe hypertension.


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How does the action of MAOs fit

with the monoamine hypothesis?


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Tricyclic antidepressants (TCAs)

Closely related to phenothiazine compounds used to treat psychoticbehaviour.

Initially produced as antipsychotic compunds. No use in

schizophrenia but elevated mood of depressed patients.

First drug introduced was IMIPRAMINE in the 1950s.

Other drugs such as CLOMIPRAMINE were developed from

this initial compound.

Development of other antipsychotic drugs lead to discovery of

AMITRIPTYLINE (tertiary amine) and its demethylated metabolites,

DESIPRAMINE & NORTRYPTILINE (secondary amines).


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Structure of TCAs


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Mechanism of action of TCAs

Primary effect is to block uptake of amines by competition at the

reuptake transporter protein (little effect on DA reuptake).

reuptake of amines

Some TCAs also increase synaptic levels of amines by desensitisingpresynaptic a2 receptors i.e. inhibit autoinhibition of release

Levels of

NA & 5-HTdepression

Note: secondary TCAs i.e. desipramine, are more selective forNA uptake than are tertiary amines i.e amitriptyline, which

inhibit both NA & 5-HT uptake.


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How will TCAs affect NA or

5-HT at the synaptic level?


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TCAs and the noradrenergic neurone

TCAs

Block

Reuptake

of

amines

TCAs

inhibitpresynaptic

2 receptorsa


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Side effects associated with TCAs

In non-depressed patients, some TCAs cause sedation and confusion.Similar effects seen in depressed patients for first few days but wear

off as antidepressant effects develop. Can be useful in agitated patients!!

Atropine-like side effects: blurred vision, dry mouth,

constipation, urinary retention

Ventricular dysrhythmias via K channels block (particularly in

overdose; caution in patients with cardiovascular problems).

Overdose can lead to in seizure threshold.

Ventricular dysrhythmias and in seizure threshold, main reasons

for death when TCAs used for suicide attempts.


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Drug interactions

TCAs bind strongly to plasma proteins, hence effects enhancedwhen given with competing drugs i.e. aspirin

Metabolised by liver enzymes, these are inhibited by potential

co-administered compounds such as steroids and some antipsychotics

Strongly potentiated by alcohol

l i 5 i k i hibi


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Selective 5-HT (serotonin) reuptake inhibitors

(SSRIs)

More recently developed drugs used to treat depression.

Not only used in depression, but also useful in treating anxiety,

panic attacks and obsessive-compulsive disorders.

As name suggests, mechanism of action is the selective blockadeof 5-HT reuptake.

reuptake of 5-HT

Drugs include fluoxetine (prozac)

fluvoxamine

paroxetine

setraline

citalopram

synaptic levels

of 5-HTdepression


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Blockade of 5-HT reuptake.


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Side effects

In general, less side effects than TCAs and MAOIs.

Compared to TCAs, less anticholinergic side effects and

less dangerous in overdose.

No cheese reaction as observed with MAOIs

Despite this, they do produce some nausea, anorexia, insomnia,

sexual dysfunction.

IN SPITE OF REDUCED SIDE EFFECTS, STUDIES

REVEALED NO PREFERENCE FOR SSRIs OVER TCAs

IN STUDIES OF PATIENT ACCEPTABILITY.


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Atypical antidepressants

Several atypical antidepressants are used clinically.

Appears to be no common mechanism of action.

No higher efficacy at treating depression but generally

have fewer side effects.

Show efficacy in patients not responding to other treatments.


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Atypical antidepressants

Drug Mech of action Side effectsMaprotilline selective NA reuptake atropine-like effects

blocker sedation

Mianserin H1, 5-HT2 & a2 agranulocytosis

Trazodone Weak 5-HT uptake hypotension,

blocker, H1 & 5-HT2 antag sedation,

Venlafaxine Non-selective 5-HT as with SSRIs

& NA uptake blocker

receptor antag.


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Use of lithium as a mood stabiliser

Lithium used to calm manic patients and prophylacticallyas a mood stabiliser.

Results observed quicker and are considered safer

(no overdose potential).

Mechansim of action is not well understood. Suggested

mechanisms are:

inhibition of inositol triphosphate formationinterference of cAMP formationaccumulation of Li+ in cell, leading to sustained depolarisation

Side effects: long half-life leads to commn side effects such asnausea, thirst, tremor, mental confusion


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Clinical application of drugs to treat affective disorders.

Anti-depressants:1st line - SSRIs primarily fluoxetine and citalopram

2nd linevenlafaxine but several options may need to be tried

in order to find a suitable treatment if the depression

is somewhat drug resistant.

Bipolar disorder: BZD ( i.e. lorazepam) may be useful in

intial stages but cannot be used over extended periods.

Lithium and sodium valproate are used as a mood stabiliser

over an extended period. These may be given with or withoutan SSRI to treat depressive episodes.


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Research is still ongoing!!!

Affective Disorders DepressionII Oct 2011

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