Drugs used in Affective Disorders Flashcards
(48 cards)
What kind of disorder in depression ?
Affective Disorder - disorder of mood rather than thought or cognition.
What is the prevalence of depression ?
Lifetime prevalence of about 25% - primary mental disorder by 2030
What is the proportion of suicide attempts amongst depressed individuals ?
How effective is treatment ?
About 20% attempt suicide
About 5-10% succeed (5602 in UK: 1993 -2004)
Only 30% respond to 1st line of treatment
About 30% are non-responders (especially psychotic depression)
Failure to respond increases with each episode
How can the signs and symptoms of depression be classified ?
Which particular symptoms fall within each category ?
Psychological/Emotional - Depressed mood, misery, pessimism - Anhedonia - Low self-esteem, guilt, inadequacy - Poor concentration - Indecisiveness and lack of motivation - Feeling of ‘hopelessness’ and ‘helplessness’ - Suicidal thoughts - Hypochondria Somatic/Biological/Psychomotor - Retardation of thought and action – cognitive deficits - Fatigue - Loss of appetite (unintentional weight change) and sleep - disturbance - Aches and pains - Loss of libido Behavioural - Psychomotor agitation or retardation - Self-neglect
What are the 2 types of depressive syndromes ?
Unipolar and bipolar.
What are the 2 types of unipolar depression ?
What is the proportion of each ?
Reactive, non-familial —> association with stressful life-events/anxiety/agitation (75%)
Endogenous - familial pattern –> distinct symptomatology unrelated to stress (25%)
What is bipolar depression ?
Depression alternating with Mania over periods of weeks
Mania component – excessive exuberance/enthusiasm/ self-confidence coupled with impulsivity and occasionally combined with irritability/impatience/aggression.
In extreme cases, psychotic symptoms appear.
Early adult presence, strong hereditary tendency.
What differentiates bipolar depression type 1 and BP type 2 ?
BP1 – mania
BP2 – hypomania
What is the evidence supporting the monoamine hypothesis of depression (“antidepression”) ?
Reserpine depletes MAs : caused depression in some (c. 15%) patients
Iproniazid prevents MA metabolism: caused euphoria
Is the MA hypothesis of depression more useful in understanding the cause or the attenuation of depression (anti-depression) ?
Equivocal evidence for MA hypothesis in the aetiology of depression
Supportive evidence for MA hypothesis in palliation of depression –> Anti-Depression
According to the MA hypothesis of depression, what NT levels must be manipulated to attenuate symptoms ?
Augmentation of NA and 5-HT levels.
What are the symptoms of unipolar depression ?
With which kind of drugs can these be treated ?
Symptoms : Depressed Mood + Inhibited Psychomotor Drive
Thymoleptics = Drugs with pronounced property of re-elevating mood e.g. MA reuptake –TCAs
Thymeretics = Drugs that predominantly activate
psychomotor drive e.g. MA metabolism – MAOIs
Effective Therapeutics should have both.
Why is it dangerous to prescribe drugs that only increase psycho-motor (in the absence of mood elevation e.g. amphetamine) drive to a patient with unipolar depression ?
It increase suicide risk.
What are the main classes of anti-depressant treatments ?
Inhibitors of 5HT and NA Metabolism (MAOIs)
Inhibitors of 5HT and NA Transport (Reuptake Inhibitors)
- TCAs : block reuptake (mainly NA, in vivo)
- SSRIs
- NRIs
- 5-HT and NA Reuptake Inhibitors = SNRIs
Mixed action
- Blockade of inhibitory presynaptic receptors to increase release of NA and 5HT.
- Inhibition of 5HT and NA reuptake combined with blockade of postsynaptic receptors.
Drugs targeting intracellular messengers e.g. rolipram
(phosphodiesterase inhibitor)
Electroconvulsive therapy
How were the effects of MAOs first discovered ?
What is the effect of MAOs (e.g. iproniazid) on the nerve terminal and on the treatment of depression ?
Discovered: Anti-tuberculotic drug Iproniazid –> caused euphoria
Inhibition of nerve terminal MAO-A
Increase in cytoplasmic [5-HT] and [NA]
Efflux of NT via the reuptake transporter (not exocytotic release)
Increase of external [5-HT] and [NA] antidepressant effect especially for ‘Agitated depression’ (depression with anxiety)
What are the substrates for MAO-A Vs MAO-B ?
MAO-A : NA + 5-HT
MAO-B : phenylethylamine + benzylamine
Non-selective : tyramine, DA
Name reversible and irreversible inhibitors of MAO-A.
Irreversible : - Clogyline Reversible (RIMAs) : - Moclobemide - Brofaromine - Pirlindole - Toloxatone - Befloxatone
Name irreversible inhibitors of MAO-B.
Are these drugs used as anti-depressants ?
- Deprenyl/Selegiline
- Pargyline
No, these drugs are used to treat PD.
Name 4 non-selective irreversible MAO inhibitors.
Iproniazid
Isocarboxazid
Phenelzine
Tranylcypromine
What are the effects of MAO-A inhibition in the intestinal mucosa/liver ?
In Intestinal Mucosa and Liver - metabolises dietary amines to prevent passage into systemic circulation.
a) Inhibition of intestinal/liver MAO-A
Increase in systemic/plasma tyramine
Displacement of endogenous [NA] from sympathetic nerve
endings
(i) Major stimulation of alpha1-ARs on vasculature => hypertension
(ii) Major stimulation of beta1-ARs on heart => tachycardia
So called ‘Cheese Reaction’
Acute MDMA/Ecstasy toxicity equivalent to ‘Cheese Reaction’
b) Potentiation of Sympathometics, e.g. ephedrine, phenyephrine
c) Overdose => fatal respiratory depression especially with alcohol and barbiturates
d) Postural Hypotension
e) Increased Motor Activity and Excitability
PATIENTS need to carry treatment card
NOT first line antidepressant, but cf RIMAs in future
Which which reuptake transporter are targeted for the treatment of depression ?
SERT and NET
To what other drugs are TCA similar ?
Antipsychotic Phenothiazines
TCAs are used as 2ary or 3ary amines.
Which is more selective for SERT and for NET ?
Give examples for both.
Tertiary amine => SERT - imipramine - clomipramine - amitriptyline Secondary amine => NET - desipramine (=Imipramine biotransformed (demethylated) to desmethylimipramine)
How is [DA] affected by TCAs ?
[Dopamine] less affected by TCAs.
