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Psychopharmacology and Pharmacology (The synapse - junction between two…

- - - - Antipsychotics
        
        Aims of antipsychotic treatment
        Leucht et al., 2012
        
        Short term
        
        Treat acute symptoms of psychosis
        
        Reduce the risk of patient to themselves/others
        
        Long term
        
        Prevent against relapse in short, medium and long term[1]
        
        Treat residual symptoms of psychosis
        
        All effective antipsychotics block D2 receptors
        Seeman, 2011
        The closer/tighter the drug binds to the D2 receptor the lower the dose can be (with the same effect) ... strong correlation shown
        .
        .
        Multiple dopamine pathways in the brain, not all related to pathophysiology of schizophrenia. Believed that the mesolimbic system is the target of antipsychotics - therefore need to block D2 receptors in the mesolimbic system. However, drugs diffuse aroud the brain and can bind anywhere (also possibly blooking other regions)
        
        Blocking the D2 receptor
        Different dopamine pathways; (.effects of antipsychotic drugs on different sites in the brain)
        
        Mesolimbic D2 blockade – antipsychotic
        
        Mesocortical D2 blockade – negative symptoms (might induce them, since dopamine is involved in the maintenance of drive, motivation and revard…)
        
        Nigrostriatal D2 blockade – EPSEs (extraprimital side effects, e.g. stiffness and motor symptoms)
        
        Tuberofundibular D2 blockade – prolactin (might increase levels of the hormone proactine in the blod, which dopamine normally inhibits)
        
        Antipsychotics - classification
        
        Typical antipsychotics
        
        Mainly Dopamine D2 antagonists
        
        Causing more EPSEs than atypicals
        
        E.g. haloperidol
        
        Atypical antipsychotics
        
        Serotonin 5HT2a and dopamine D2 antagonists
        
        Less EPSE but overall more metabolic side effects/weight gain
        
        Wider range of neural targets = more variable side effects
        
        E.g. olanzapine
        
        Typical antipsychotics
        Kapur et al., 1996
        
        First generation of antipsychotics discovered
        
        Chlorpromazine
        
        Higher incidence of EPSEs
        
        Historically been given in too high doses
        
        E.g. Haloperidol maximum doses
        
        1980’s = 60mg/day
        
        2014 = 20mg/day
        
        Need 65%≤ of D2 blocked for therapeutic effect = less than 5mg/day
        
        Types of EPSEs
        
        parkinsonism's
        
        dystonia
        
        akathisia
        
        tardive dyskinesia
        .
        
        Anticholinergic drugs used to stop EPSEs e.g. procyclidine (.however, they have side effects themselves)
        
        Side effects: dry mouth, constipation, confusion, blurred vision
        
        Atypical antipsychotics
        
        Dopamine & serotonin antagonists
        
        Bind more loosely to D2 receptor
        
        Less EPSEs
        
        Overall more metabolic side effects (e.g. weight gain)
        
        CATIE landmark study
        
        Efficacy of FGAs = SGAs (except for clozapine, which is shown to have a superiority to others)
        
        FGAs =First generation antipsychotics (typical ones) SGAs = Second generation antipsychotics (atypical ones)
        
        Leucht et al., (2013)
        Atypical antipsychotics - choice
        
        Big differences in side effect profile
        
        Involve the patient in choosing drug
        
        Clozapine
        Meltzer et al., (2003)
        
        Only effective drug for treatment-resistant schizophrenia
        
        Treatment-resisting schizophrenia being defined as: Failure to respond to 2 antipsychotic trials, including an atypical
        
        Clozapine having a high success rate
        
        30% respond at 6 weeks
        
        60% respond at 6 months[1]
        
        Reduces risk of suicide (in schizophrenia 50% attempt; 10% succeed)[2]
        
        Requires blood monitoring for agranulocytosis (which is a reduction in white blood cells)
        
        Potentially fatal side effect
        
        Mortality rate 0.01% with monitoring (0.3% without)[3]
        
        Receptor blockade and side effects
        
        D2 (dopamine receptor) = EPSEs
        
        M1 (acetylcholine receptor) = dry mouth, constipation, blurred vision
        
        H1 (histamine receptor) = sedation, weight gain, dizziness
        
        5HT2c (serotonin receptor) = satiety blockade
        .
        Side effects can be predicted: involve patient in choice
        
        Long-acting injectable antipsychotics (depots)
        Leucht et al., 2012
        
        Strong evidence to suggest reduced risk of relapse & rehospitalisation[1-3]
        
        Recommended when patient prefers or when covert poor compliance
        
        Typical depots are broadly similar; newer atypical depots offer choice
        
        Risperidone depot
        
        Paliperidone depot
        
        Olanzapine depot
        
        Aripiprazole depot
      - Antidepressants
        
        Antidepressants
        First drugs discovered accidentally
        
        Iproniazid for tuberculosis
        
        Made patients: “Cheerful, optimistic and more active”
        .
        Most antidepressants work by increasing neurotransmitters (.since most patients with depression have a lack of certain neurotransmitters)
        
        Usually serotonin/noradrenalin
        
        Antidepressant classification
        
        Selective serotonin reuptake inhibitors (SSRI) – e.g. sertraline
        
        Serotonin noradrenaline reuptake inhibitors (SNRI) – e.g. venlafaxine
        
        Noradrenergic & specific serotonergic AD (NaSSA) – mirtazapine
        .
        
        Less commonly used…
        
        Monoamine oxidase inhibitors (MAOI)
        
        Tricyclic antidepressants (TCA)
        
        MAOIs
        
        First class of antidepressant discovered
        
        Block the enzyme that breaks down 5HT, NA & DA
        
        Increases levels of all three in the brain
        
        Types
        
        Irreversible: phenelzine, tranylcypromine
        
        Reversible: moclobemide
        
        Side effects: cheese reaction / tyramine crises (.interacts with diet)
        
        Stroke/death
        
        Drug interactions: serotonin syndrome (.having too much serotonin in the synaptic clefts/brain general – if e.g. drugs are combined)
        
        Tricyclic antidepressants
        
        Less favourable side effect profile than SSRIs
        
        Weight gain, sedation
        
        Anticholinergic
        
        dry mouth, constipation, blurred vision
        
        Lethal in overdose!
        
        Good efficacy
        
        Still used in refractory / resistant cases
        
        MOA: block the reuptake of both 5HT + NA
        
        Examples: imipramine, amitriptyline
        
        SSRIs
        
        Fluoxetine (Prozac) 1988
        
        First rational target led design
        
        Block SERT increasing levels of serotonin in synapse
        
        More favourable side effect profile than earlier drugs (e.g. TCAs)
        
        GI upset, sexual dysfunction, anxiety
        
        First line antidepressants
        
        Efficacy, safety, tolerability
        
        How do SSRIs work then?
        
        Almost immediate increase in synaptic 5HT concentrations…
        
        Full therapeutic response is not immediate
        
        block SERT
        
        down-regulate 5HT1a auto receptors
        
        increased 5HT release
        
        down-regulate post-synaptic receptors
        
        Antidepressants work via downstream neuro-adaptive changes
        
        Mirtazapine – NaSSA
        Watanabe et al., 2011
        Not working on transporters, but working on receptors
        
        Mechanism of action
        
        5-HT2a antagonist
        
        Alpha-2 antagonist (auto-receptor)
        
        Works differently to SSRIs – good alternative / augmenting drug
        
        No nausea/GI upset
        
        No sexual dysfunction
        
        Works quicker than SSRIs[1]
        
        Side effects
        
        Sedation: potent antihistamine
        
        Weight gain: antihistamine, 5HT2c antagonist
        
        Depression – A Chemical Imbalance?
        
        No measurable deficits in 5HT, NA or DA
        
        “Chemical imbalance” of a neurotransmitter is an over simplification
        
        True pathophysiology much more complex
        
        Pharmacological strategies for MDD
        NICE, 2009
        
        SSRIs/Mirtazapine first line[1]
        
        Some evidence that switching within drug class is effective[2]
        
        Switching between different drug classes in case of poor tolerability has strong theoretical basis but little evidence
        
        How long to work?
        Mitchell, 2006
        
        General advice “it may take up to 4 weeks”
        
        BUT 90% cases = improvement by week 2
        
        Facts vs. Fiction
        
        Antidepressants don't work
        
        Antidepressants causse suicide
      - Mood Stabilisers
        
        Mood stabilisers
        
        Used mainly for bipolar affective disorder
        
        Reduce risk of relapse
        
        To treat acute manic episodes
        
        Examples
        
        Lithium
        
        Valproate
        
        Carbamazepine
        
        Lithium
        Kessing et al., 2011
        
        Gold standard drug for BPAD
        
        For prophylaxis and mania
        
        Superior to valproate alone in preventing relapse[1]
        
        Can reduce risk of suicide in BPAD by 80%[2-3]
        
        Complex mechanism of action
        
        Reduces excitatory neurotransmission (dopamine & glutamate)
        
        Reduces intracellular calcium & sodium
        
        Lithium monitoring considerations
        
        Levels need to be kept within a fine range
        
        The “therapeutic window”
        
        Side effects: tremor, nausea, GI upset
        
        Need patient to be on board (with the treatment plan)
        
        Regular blood tests for lithium level, renal function, thyroid function
        
        Intermittent treatment worsens outcomes significantly (manic relapse)
        
        Valproate
        
        Complex mechanism of action
        
        Inhibits GABA breakdown
        
        Generally works better treating mania, rather than the depression
        
        When given alongside lithium, works better than either drug alone[1]
        
        Teratogenic
        
        NOT first line for women of childbearing
        
        Give folic acid to women at risk
        
        Side effects: GI irritation, weight gain, liver toxicity
      - Anxiolytics and Hypnotics
        
        Anxiolytics & Hypnotics
        
        Low dose = reduction in anxiety
        
        High dose = hypnotic effect (.sleep)
        Examples
        
        Benzodiazepines
        
        Augment action of GABA – major inhibitory neurotransmitter
        
        Z-drugs e.g. zopiclone
        
        Similar actions to benzodiazepines
        
        Sedative antihistamines – e.g. promethazine
        
        Benzodiazepines & Z-drugs
        
        All BZD bind to sub-unit of GABA receptor, causing increased GABA-A receptor activity
        
        Reduce anxiety, tension and agitation
        
        Use determined by half life
        
        Long acting – diazepam
        
        Medium acting – lorazepam
        
        Short acting – midazolam
        
        Z-drugs
        
        Structurally different, similar mechanism of action
        
        Used in insomnia
        
        Benzodiazepines & Z-drugs - Problems
        
        Tolerance to hypnotic effects of benzodiazepines occurs rapidly
        
        Long term use can be associated with a withdrawal syndrome
        
        Side effects: cognitive, falls in the elderly, driving accidents
        
        Recommended for maximum of 4 weeks in severe, disabling anxiety or insomnia