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Contents

Depression

Overview, objectives

  • Rationale for drug therapy
  • Current drug treatment ‐ mechanism of action, adverse effects
  • Efficacy
  • Influences on drug choice
  • Impact of therapy on the brain
  • A lot of the time, trial and error (some drugs not work on some people, do work on other people)
  • Depression is way different to feeling down for a little while (e.g. if a loved one dies)
  • Recall the symptoms of depression

Rationale for drug treatment of Major depression

  • Provide relief from symptoms
  • Enhance functional capacity
  • Reduce likelihood of self‐harm

Most prescribed drugs

  • Antidepressants (increasing rapidly)
  • Sedatives
  • Anxiolytics
  • Antipsychotics
  • Mood stabilisers

Treatment of Major depression

  • CBT, counselling
  • More than 60% respond to drug therapy
  • Drugs are equal in efficacy
    • But work differently in different people, have different mechanisms of action and adverse reactions
  • All drugs take at least 2 weeks to have an effect

Before starting Treatment

  • Exclude treatable causes (eg drug abuse, hypothyroid, steroid)
  • Measure BP (esp if TCA - affects levels of catecholamines)
  • Consider assessment tool to allow tracking of response
  • Review all current medications (DDI) (potential for drug‐drug interactions)

How do we know if a drug may have “antidepressant” actions?

Rats

  • Forced swim test (if antidepressant works, the rat will keep swimming; normally the rat just gives up before you take it out of the pool).
  • Learned helplessness
  • Social interaction
  • Social defeat
  • Intracranial self-stimulation

Testing them on rats indicates whether we should try on patients.

Then when you try them on patients, use a questionnaire e.g. PHQ9 to assess their level of depression.

Dispensing data for antidepressants in Australia

  1. SSRIs
  2. SNRIs
  3. TCAs
  4. Receptor antagonists (newer)
  5. MAOIs

Some drugs aren't being prescribed as much because of their side effects

Treatment of major depression

  1. Monoamine oxidase inhibitors
  2. Monoamine reuptake inhibitors
    • Nonselective
      • Tricyclics
      • Heterocyclics (SNRIs)
    • SSRIs
  • Other types - 5HT antagonists
  • These drugs increase levels of serotonin or NA in the synapse, or might block presynaptic receptors to prevent reuptake

Synapse diagram

  • Left = serotonergic, right = noradrenergic;
    • Shows biochemistry on both sides.
    • Learn synthesis pathways, release mechanisms, GPCRs on other side, and reuptake mechanism or presynaptic receptor.
    • Refer to lecture in AEB about this
    • Some drugs work better at serotonin, some work better at NA, based on the chemistry of the drug.
    • Note where SSRIs vs TCAs work
    • SNRIs (venlaxafine and duloxetine) block both NA and Serotonin (not shown in old diagram)
    • MAOI blocks MAO-A which metabolises both serotonin and NA

Biosynthesis - NA and A

Biosynthesis - serotonin

Treatment of major depression

  • Tricyclic antidepressants (older drugs, less used now due to side effects)
    • Mechanism of action: Block re‐uptake of NA, 5HT into nerve terminal
    • Antidepressant effects take weeks to develop, so inhibition of amine uptake per se insufficient to explain TCA action ‐
      • Receptor changes ?
      • Second messenger changes ?
      • Takes a while for mood effects to develop because, although chemical changes happen instantly, receptor changes and brain structure changes occur over time to reduce depression
      • When the person is depressed, to maintain the normal activity, the body makes more receptors to try to make more receptors. When we increase the [transmitter] (giving drug), the body reduces the number of receptors over time.

Treatment of Major depression

Tricyclic antidepressants

  • Kinetics:
    • Metabolised by liver (drug‐drug interactions)
    • Active metabolites ‐ eg Imipramine-->Desipramine

other effects

  • blockade of:
    • alpha adrenoceptors
    • muscarinic receptors
    • histamine H1 and H2 receptors
  • therefore you have many side effects (due to off-target stuff) of
    • alpha: postural hypertension
    • muscarinic: dry mouth, blurred vision
    • histamine: _____ ?

Learn pharmacology receptors and effect!

  • Most of these drugs cause weight gain, some cause cardiac effects, can overdose on them (dangerous). Also sedation, antiAch, hypotension, seizures

Heterocyclics

  • Acute effect of these and TCAs is to inhibit reuptake of NA or 5HT
  • Some newer heterocyclic compounds have been introduced ‐ also known as Atypical antidepressants, or 3rd generation
  • Heterogeneous group, (non TCA) short acting
  • No common mechanism of action
  • Generally fewer adverse effects than TCAs

*Venlafaxine blocks NA, 5HT uptake

  • Nefazodone 5HT2 antagonist; decrease NA, 5HT uptake

Selective Serotonin Reuptake Inhibitors

  • selective for 5HT uptake ‐
  • weak inhibition of NA, DA uptake
  • few adrenergic, histamine, muscarinic effects
  • Kinetics:
    • oral absorption long t 1/2 15‐96 h
    • liver metabolism (drug‐drug interactn)

NOTE some agents are selective for noradrenaline‐ noradrenaline reuptake inhibitors such as reboxitine

  • side effects:
    • Nausea, insomnia, agitation, weight change
    • Loss of libido
  • Advantage‐ much safer in overdose
  • Drug Interactions‐ numerous (P450 enzymes) With MAOI, TCA ‐‐> “wikipedia:serotonin syndrome

Drug that are increased by SSRI (P450 enzyme inhibn)

  • beta adrenoceptor antagonists
  • antipsychotics, eg. haloperidol
  • anticonvulsants, eg. carbamazepine, valproic acid, phenytoin
  • benzodiazepines, eg. diazepam, alprazolam, midazolam
  • warfarin
  • cyclosporin
  • calcium channel antagonists, eg. nifedipine, diltiazem
  • antiarrhythmics, eg. quinidine

MAO Inhibitors

Monoamine Oxidase ‐ a mitochondrial enzyme found in neural & other tissues

  • Inhibit monoamine oxidase A & B, increasing NA, 5HT, Adrenaline, Dopamine in presynaptic nerve terminals
  • Antidepressant activity (& side effects) are related to MAO A inhibition
  • Hepatic MAO inactivates circulating/ingested monoamines (eg tyramine - "cheese effect"); MAOI inhibit other enzymes, including those involved in drug metabolism, leading to interactions

NB: MAOB-I used for Parkinson's with dopamine

Mechanism of action

  • Similar in structure to MAO substrates
  • Bind covalently to enzyme ‐ long lasting inhibition [NB Moclobemide is reversible]
  • Increase monamine concn in cytoplasm, increased leak
  • Delayed antidepressant effect
  • Antidepressant action related to beta, 5HT receptor downregulation

Adverse effects

  • Orthostatic hypotension
  • Sleep disturbance, anxiety
  • Fatigue
  • Weight gain
  • Liver toxicity (rare)

Interactions

  • “cheese” reaction ‐ dietary advice necessary unopposed tyramine hypertension, headache
  • MAOI plus TCA hypertension, hyperactivity

Examples

  • TCAs, SSRI, venlafaxine (cumulative 5HT effects)
  • Antihypertensives
  • Drugs affecting catecholamines ‐ severe hypertension (even topical)
  • Sumatriptan
  • Pethidine (moclobemide)

Serotonin syndrome

  • High dose of single drug, or more than one serotonin drug (or inadequate washout between drugs)
  • Increased serotonin ‐ stimulates 5HT receptors ‐‐>
    • Confusion, agitation
    • Myoclonus/clonus
    • Sweating, fever
    • Diarrhoea
  • Associated with TCAs, MAOIs, SSRIs nefazodone, venlafaxine, St John’s Wort
  • Important to consider when switching between classes of drugs

Cellular changes induced by antidepressant therapy

Therapy induces structural modifications in brain, eg

  1. Stress ‐‐> degeneration, imipramine ‐‐> regeneration of NA axons in cortex
  2. Neurogenesis of hippocampal cells (glucocorticoids, chronic stress decreases, and antidepressants increased BDNF expression --> neurogenesis); BDNF infusion produces antidepressant effects
  3. May be related to cAMP changes

Antidepressants enhance trophic factors

  • In depressed patients, there aren't enough dendritic sprouts so cells can't communicate
  • Antidepressants --> more sprouting (due to monoamines, BDNF) --> more communication

Dysregulation of HPA axis occurs in depression

  • Antidepressants may restore HPA feedback
  • In depression‐
    • Increased cortisol
    • Anterior pituitary,adrenal cortex may be enlarged
    • Increased CRF
    • Hippocampus size/cell number reduced

SUMMARY: Pharmacotherapy of Major depression

  • Several drug options (& many under development)
  • Choice will depend on clinical situation
  • Factors influencing your drug choice:
    • Previous response to therapy
    • Concurrent medication
    • Adverse effect profile of drug class
    • Potential for drug drug interactions
    • Toxicity in overdose

How to treat

  • SSRI first line; fluoxetine, fluvoxamine
  • venlafaxine
  • moclobemide (MAOI)
  • TCA can be used
  • nefazodone
  • Nonselective MAOI where other drugs not tolerated


  • some combinations avoided due to toxicity
  • change of drug requires washout (try each drug for a couple of weeks). When you're taking them down, do it on a lower dose

Bipolar

Bipolar depression/disorder

  • Recurrent disabling illness
  • Lifetime prevalence 1.6%
  • Periods of mania or hypomania, or “mixed episodes”
  • Outcomes are poor:
    • increased suicide, substance abuse
  • While Bipolar shares clinical features with major depression, the episodes of hypomania/mania distinct
  • Thorough assessment/diagnosis is vital

Treatment of Bipolar depression

Lithium

  • Drug of choice in acute manic illness/prophylaxis; mood stabilisers (so highs don't go too high, lows don't go too low)
  • Narrow therapeutic index‐effective conc 0.5‐1 mM, toxic effects > 1.5 mM; have to monitor to make sure they don't have too many side effects
  • Therefore need to monitor plasma levels
  • Distributes through Total Body water (enters cells)
  • Mechanism? Unclear‐
    • effects observed on monoamine release (DA);
    • also reduces Inositol Phosphate hydrolysis (IP2 to IP1) depleting IP3 & DAG, reducing effects of transmitters
    • promotes GABA, inhibits dopamine/glutamate (so reduces excitation)

Side effects

  • Nausea
  • Tremor
  • Decreased thyroid function
  • Polyuria ‐ concentrating ability in collecting tubule
  • Interaction ‐ diuretics

Special considerations

  • Monitor thyroid, renal function at outset
  • Monitor blood levels of lithium
  • Avoid in 1st trimester of pregnancy

Other drugs

Other ‘mood stabilisers’

  • Valproate and Carbamazepine ‐
    • When lithium is poorly tolerated / ineffective
  • Lamotrigine
    • (all 3 affect Na channels and are used in epilepsy)
  • Antipsychotics
    • Used in Acute manic episode, eg olanzepine

Volume of prescription

  • Valproate increasing -- prescribe this
  • Lithium stable
  • Carbamazapine decreasing
  • Lamotrigine increasing

Guidelines

Optimize therapy by monitoring blood levels

  • Manic episode
    • Mood stabilizer ‐Lithium, valproate, lamotrigine, olanzepine combined with antipsychotic or benzodiazepine
  • Acute treatment of bipolar
    • Mood stabilizer ‐Lithium (or lamotrigine) ... valproate Alternative‐ Mood stabilizer plus antidepressant combined
  • Breakthrough depression
    • Add another mood stabilizer, or add antidepressant or try a different antidepressant
    • [note antidepressants should not be used alone ‐ may induce mania or rapid cycling]

Anxiety

  • See AEB in phase 1
  • Psychotherapy 1st line
  • Combined cognitive therapy & drug approach may be useful
  • Drug choice varies with the type of disorder

Treatment of Anxiety Panic disorder

  • SSRI 1st line (then TCAs, MAOIs, benzodiazepine)
  • Social phobia ‐ TCA, MAOI, SSRI effective
  • Obsessive compulsive disorder ‐ SSRI

GABAA receptor

  • Benzodiazepines
    • enhance response to GABA
    • facilitate opening of GABA
    • activated Cl‐ channel (GABAA Receptor) --> more Cl going into cell
  • Eg diazepam, clobazam (long acting)
    • Sedation
    • Tolerance & dependence
    • Decrease in REM sleep
  • Short acting = short-term sleep drug. Long term = chronic anxiety
    • Not a good idea to keep on benzo for a long time
    • Used to calm people in an acute anxiety attack

Other anti‐Anxiety drugs

  • Buspirone
    • similar efficacy to BZDs in GAD
    • less potential forsedation and psychomotor impairment
    • less effective than BZDs in acute attack
    • lower abuse potential than benzodiazepines
    • Partial agonist at 5HT1A (inhibits 5HT release)
    • Less effective in acute attacks (slow onset: 1-2 weeks)
    • Adverse effects: Dizziness, nausea, headache, drowsiness/insomnia, nervousness, fatigue
  • Others?? Can you think of any
    • beta blockers
    • SSRIs
    • alcohol, cannabis

Schizophrenia

  • Affects 1% of the population
    • early age of onset (15-30 yo)
    • often chronic
    • highly debilitating (can't keep a job without medication, or even with due to side effects)
    • genetic link (parent or sibling --> 10% chance. Both parents: 40-70% chance);
      • DA levels, neurodevelopmental genes
    • may involve early life (2 hit model)
      • eg hypoxia, nutrition during birth, then a later stress later on (drug abuse, physical abuse, psych stress)
  • Direct costs worldwide: $63 billion pa with $19 billion spent on treatment
  • Identified by symptoms, so people have to start having an episode before it's identified
  • Schizophrenia is caused by one or more neurodevelopmental ‘insults’ during lifespan
  • First disruption occurs early in development: genetic, early stress, pregnancy complications, viral infection
  • Early disturbances alone not sufficient
  • A second stressful event later in life ‘triggers’ disease: psychological stress, drug abuse

Symptoms

  • Positive (easy to see/measure)
    • delusions (often paranoia)
    • hallucinations (voices)
    • disordered thought
  • Negative
    • withdrawal from society
    • flattened emotional response
    • respond poorly to medication
  • Disorganisation ‐ thought, speech, behaviour [diagnosis complicated in cross‐cultural setting]

Pathology of Schizophrenia

  • Altered structure of brain
  • Enlarged ventricles
  • Smaller temporal and frontal lobes
  • Abnormal brain blood flow
  • Reduced number of neurons and dendritic spines in the hippocampus and prefrontal cortex
    • some changes might actually be related to medications they take
    • people with schizophrenia may self-medicate, which may also affect this aspect
  • Uncertain mechanism
  • Consistent with overactivity of dopaminergic nerves:
    • D2 activation induce/worsen symptoms
    • Dopamine depletion (eg reserpine) controls positive symptoms
  • May also involve serotonin (5‐HT) & glutamate

Antipsychotic drugs and dopamine

  • All are dopamine D2 receptor blockers
    • No correlation with serotonin, alpha adrenergic, histamine, etc
  • Why are Dopamine antagonists useful in treating schizophrenia??
    • Inhibit actions of dopamine in mesocortical and mesolimbic pathways
    • Psychomotor slowing
    • Emotional quietening
    • Affective indifference
    • Inhibition of aggression
  • NB: patients with schizophrenia have a difficulty in blocking out extraneous information. Drugs can help these symptoms.
  • Strong correlation between dopamine D2 receptor affinity and clinical efficacy
  • Newer “atypical” drugs characterised by high affinity for 5HT2 receptors as well
  • Antagonism of many other receptors --> Side effects:

Side effects

Typical (old)

  • chlorpromazine
  • haloperidol

Atypical / novel (new)

  • clozapine
  • risperidone
  • olanzepine
  • quetiapine
  • sulpiride
  • Atypical vs typical ?
    • Better tolerated, fewer motor side effects
    • Atypical can block 5HT receptors
  • some available as depot preparations; easier than taking medication repeatedly

Mechanisms of Action

  • Antagonism of D2 receptors
  • Antagonists of other monoamine receptors, especially 5‐HT2
  • Delayed onset of activity ‐ Delayed increase in D2 receptor number

Dispensing data for antipsychotics

  • Typical less often prescribed than the atypical
  • haloperidol most common typical, decreasing.
  • olanz____ most common atypical, increasing.

Receptor binding profile of antispsychotic

  • Small number = stronger binding to that receptor
  • Note that although haloperidol focuses D2, it also hits A1, so side effects
  • Olanzapine: D2, but also 5HT2
    • Hence why new drugs affect negative symptoms (because they get serotonin etc)

Adverse effects

Because we're blocking dopamine in niagrostriatal pathway (motor disturbances, extrapyramidal problems), and tuberohypophyseal pathway (increase PRL release)

  • Motor disturbances
    • Parkinson‐like syndrome
    • Antagonism of D2 receptors in other parts of brain ‐ Reduce with time, reversible
  • Endocrine
    • increase prolactin secretion
    • breast swelling, pain, lactation
      • in both men & women
    • affects honadotrophin secretion
    • amenorrhea

*Sedation

  • Postural hypotension
    • α1‐antagonist effect
  • Antimuscarinic effects [clozapine chlorpromazine] ‐ Blurred vision, dry mouth, constipation, etc.
  • Weight gain, insulin resistance and diabetes [major limitation of atypical drugs]
    • 5‐HT antagonism
    • (measure weight & BMI at start)
  • Agranulocytosis (clozapine ‐ 1%)
  • Tardive dyskinesia
    • Develops after months to years
    • Involuntary movements (often of face & tongue)
    • Often irreversible
    • Less with atypical drugs
    • After long-term treatment

Drug ‐ drug Interactions

These drugs are CNS depressants

  • Alcohol and other CNS Depressants
    • e.g., opioids, antihistamines, anticonvulsants
  • Anticholinergic drugs
  • Dopamine‐like agents
  • Hypotensive drugs (e.g., beta‐blockers)

Recommendations

  • Early detection, treatment of 1st case a priority
  • Antipsychotic medication is cornerstone of treatment
  • Treatment of choice ‐ atypical antipsychotics
  • Careful monitoring required (inc. metabolic effects; eg T2DM)
  • Clozapine early in course (if resistant) - note clozapine can cause agranulocytosis
  • Psychosocial interventions should be available

Overall summary

  • Major disease burden
  • Cognitive, behavioural therapy, psychosocial support also critical
  • Sometimes may need to test multiple drugs to optimise therapy in individual patients
  • All have potential for adverse effects, also need to monitor success