Drugs used in Affective Disorders Flashcards
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.
What are the problems and adverse effects of TCAs ?
Antidepressant effect take 2-3 weeks to develop, but
acutely TCAs –> sedation, confusion, motor incoordination (effects desensitize)
Lack of Selectivity:
- α1-AR antagonism –> Postural Hypotension
- H1 R antagonism –> Sedation
- mAChR antagonism –> dry mouth, blurred vision,
constipation, etc.
- Acute Cardiotoxicity
- Overdose and Drug interactions (e.g. alcohol) –> life-threatening
Give examples of SSRIs.
Zimelidine : the first SSRI Fluoxetine (Prozac) : the most popular in the 199os (probably not an SSRI!) Citalopram most selective for SERT Paroxetine : the most potent for SERT Vortioxetine : the newest SSRI Others : Fluvoxamine, Sertraline
What are the problems and adverse effects of SSRIs ?
GI Rash / tremor / urticaria Loss of libido BUT...... No or less α1-AR/H1-R/mAChR antagonism, or acute cardiotoxicity + Safer in overdose
What are 3rd generation anti-depressants ?
NRIs + SNRIs
Give examples of NRIs and SNRIs
Maprotiline = a tetracyclic NRI selectively inhibits NET
Venlafaxine inhibits both SERT and NET (but no activity at DAT)
Concerning SNRI, which reuptake transporter is preferably targeted at :
- low therapeutic doses ?
- high therapeutic doses ?
Low Therapeutic Doses SERT > NET
High Therapeutic Doses SERT = NET
Which receptors can be antagonized to increase MA transmission ?
• Presynaptic α2-AR –> Gi/o Signalling –>
Inhibition of NT (NA and 5HT) release.
• Presynaptic 5HT-1A R –> Gi/o Signalling –> Inhibition NT (NA and 5HT) release.
What is mirtazepine ?
Mirtazapine = another tetracyclic (like maprotiline)
• NRI activity
AND
• α2-adrenoceptor antagonist –> decreased presynaptic feedback inhibition of NA and 5-HT release
No α1-AR/mAChR antagonism, but sedative (H1-receptor antagonism)
5HT-2A/ 5HT-3 R antagonist activity –> decreased non-selective serotonergic stimulation (insomnia, agitation, sexual dysfunction, nausea)
What is mianserin ?
Mianserin = another tetracyclic (like maprotiline)
• Not an MAO inhibitor
• Has weak MA (NA) uptake inhibitory
activity
INSTEAD
• Is an α2-AR antagonist –> decreased presynaptic feedback inhibition of NA release
AND
• 5HT-1D / 5HT-2A / 5HT-2C / 5HT-3 receptor inverse
agonist/antagonist activity –> decreased presynaptic feedback inhibition of 5-HT release and postsynaptic effects
What is trazodone ?
Trazodone = a 5-HT antagonist and reuptake inhibitor (SARI)
• SSRI activity
AND
• 5HT-2 AR antagonist
No mAChR antagonism, but sedative (H1-R antagonism) and orthostatic hypotension (α1-adrenoceptor antagonism)
Give an example of an atypical anti-depressant and explain why it is “atypical”.
Iprindole = no effect on repuptake or presynaptic receptors of any monoamine!
In what cases is electroconvulsive therapy used ?
How does this therapy work ?
Used for severely depressed, suicidal or manic patients –> non-responsive to medication
Electroconvulsive therapy increase CNS sensitivity to NA and 5-HT
What is the overall evidence supporting of the MA hypothesis of depression ?
- Reserpine –> Inhibition of NA& 5-HT storage –> causes depression
- alpha-Methyl-DOPA –> Inhibitionof NA Synthesis –> causes depression
- MAOIs –> Increase of [NA] & [5-HT] in cytoplasm and stimulus-independent release –> alleviate depression
- TCAs/ SSRI/ NRIs/ SNRIs –> Inhibition of NA & 5-HT reuptake –> Increase of [NA] & [5-HT] in synaptic cleft –> attenuates depression
What are the main arguments countering the MA hyp of depression ?
- Amphetamine, Cocaine & L-DOPA –> Increase
NA neurotransmission, but anti-depressant actions
debatable - Delayed therapeutic action of all drugs –> Suggests
change in receptor numbers, possibly in multiple
systems - Not all anti-depressantdrugs enhance MA transmission –> e.g. iprindole, a tricyclic, but no effect on NA and 5HT turnover.
- ‘Levels’ of NA and 5HT, and metabolites thereof, in CSF and urine respectively –> Equivocal and inconsistent data in depressed patients
- Biochemical changes associated with depression often similar to those associated with mania
What are the short and long term neuronal effects of SSRIs ?
Short term :
- SSRI –> Increased extraneuronal [5HT]
- Activation of 5HT-1A Rs –> decreased firing
- Activation of pre-/post-synaptic 5HT Rs increased
Long term :
- SSRI –> Increased extraneuronal [5HT]
- 5HT-1A Rs desensitized –> no feedback inhibition of NT release –> increased firing
- Activation of pre-/post-synaptic 5HT Rs increased
Also : other long-latency changes: e.g. stimulation of neurogenesis
What might be the downstream processes underlying 5-HT R up/down-reguluation ?
- Hippocampal neurogenesis (cognition or affect?)
- Synaptogenesis / remodeling
- Oscillatory synchrony
How is BPI different from BP2 ?
BPI : Manic episode with psychotic element requiring hospitalization cycling with major depression
BP2 : Hypomanic episodes (not ever psychotic), chronic cycling
Which mood stabilizer can be given to patients with BPI ?
What other anti-convulsants or anti-psychotics can be given ?
Lithium (~1-2mM) (used prophylactically to prevent switching) • Enter via VDSCs instead of Na+ • Decreased phosphatidyl inositol (PI) turnover • Decreased GPCR activity (Gs/cAMP) • Othermechanisms Anticonvulsants: - Lamotrigine - Carbemazepine - Valproate Anti-Psychotics --> with severe mania : - quetiapine, - olanzapine - risperidone
What drugs can be given to patients with BP2 ?
Lithium Anticonvulsants : - Lamotrigine - Carbemazepine Can be given w/ anti-depressants e.g. SSRIs (BUT NEVER ALONE!!!)
Why are SSRIs contraindicated for BP I ?
Because they might cause a switch to mania.
Why must anti-depressants never be given alone to patients w/ BP2 ?
Because it increases suicide ideation and risk.
What are the main point that need to be improved for anti-depressants ?
- Safety in overdose
- Greater efficacy
- Rapid onset
What is ketamine ?
How does it work ?
Dissociative anaesthetic (OFF-LABEL) - Blocks NMDA receptor activation - Enhances AMPA receptor activation - Disinhibits glutamate release (inhibition of GABA neurones) - Activation of proteins translation - Upregulation of BDNF pathway
Which affective disorder could ketamine potentially help treat ?
Acute and Rapid (no lag) effect in trials with Major
Depressive Disorder - drug/treatment resistant cases.
