Affective Disorders and their treatment.

Dr Trevor Bushell X2856 trevor.bushell@strath.ac.uk

Objectives
know the major forms of affective disorders be able to discuss the biogenic amine hypothesis of affective disorders know the mechanism of action of anti-depressant drugs

be familiar with the side effects and drug interaction of antidepressants

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.

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!!

Evidence supporting the hypothesis

Reserpine depletes stores of noradrenaline, dopamine and 5-HT, this leads to depressionlike 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 depressed patients.

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 of b-adrenoceptors usually transmission Down regulation of presynaptic a2-adrenoceptors - transmission Down regulation of 5-HT2 receptors usually transmission

Antidepressants: mechanism of action and side effects

Electroconvulsve Shock Treatment (ECT)

Monoamine Oxidase Inhibitors (MAOIs)

Tricyclic antidepressants (TCAs)

Atypical antidepressants and SSRIs

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 drug treatments.

2272 people were treated with ECT in the last survey conducted (Jan Mar 2002).

Film based on real-life experiences of Ken Casey in an Oregon mental hospital

The use of ECT is controversial, do you think it is a viable treatment for depression?

Overview of synaptic transmission.

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 of catecholamines (i.e. NA) along with catechol-O-methyl transferase (COMT).

 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
NB in non-depressed patients, MAOIs

depression
anxiety & agitation

MAOIs and the noradrenergic neurone (applies to 5-HT as well)

MAOIs Block Degradation Of NA & 5-HT

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.

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.

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

Ususally degraded by MAO in gut & liver

Large release of NA vasoconstriction

Can lead to severe headaches & even intracranial haemorrhage

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.

How does the action of MAOs fit with the monoamine hypothesis?

Tricyclic antidepressants (TCAs)

Closely related to phenothiazine compounds used to treat psychotic behaviour. 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) .

Structure of TCAs

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 Levels of NA & 5-HT depression

Note: secondary TCAs i.e. desipramine, are more selective for NA uptake than are tertiary amines i.e amitriptyline, which inhibit both NA & 5-HT uptake. Some TCAs also increase synaptic levels of amines by desensitising presynaptic a2 receptors i.e. inhibit autoinhibition of release

How will TCAs affect NA or 5-HT at the synaptic level?

TCAs and the noradrenergic neurone

TCAs inhibit presynaptic a 2 receptors

TCAs Block Reuptake of amines

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.

Drug interactions
TCAs bind strongly to plasma proteins, hence effects enhanced when 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

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 blockade of 5-HT reuptake. reuptake of 5-HT synaptic levels of 5-HT depression

Drugs include fluoxetine (prozac) fluvoxamine paroxetine setraline citalopram

Blockade of 5-HT reuptake.

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.

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.

Atypical antidepressants
Drug Maprotilline Mech of action selective NA reuptake blocker H1, 5-HT2 & a2 receptor antag. Weak 5-HT uptake blocker, H1 & 5-HT2 antag Non-selective 5-HT & NA uptake blocker Side effects atropine-like effects sedation agranulocytosis hypotension, sedation, as with SSRIs

Mianserin Trazodone

Venlafaxine

Use of lithium as a mood stabiliser

Lithium used to calm manic patients and prophylactically as 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 formation interference of cAMP formation accumulation of Li+ in cell, leading to sustained depolarisation Side effects: long half-life leads to commn side effects such as nausea, thirst, tremor, mental confusion

Clinical application of drugs to treat affective disorders. Anti-depressants: 1st line - SSRIs primarily fluoxetine and citalopram 2nd line venlafaxine 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 without an SSRI to treat depressive episodes.

Research is still ongoing!!!