Prescribing psychotropics
Management of Psychosis in Primary Care
Learning Outcomes
• Pathophysiology• Mode of action of antipsychotics• Side‐effects• Management of some of the challenges
• Psychosis – Includes schizophrenia, schizoaffective disorder, delusional disorder
• 0.7% ‐ 1%• Reduced lifespan – metabolic disorder, suicide, • M:F• Lifelong• Suicide – 15%• Symptoms – +ve, ‐ve – quality of life• Cost >20 bn
Introduction
Aetiology
• Genetic• Structural• Biochemical• Social – low socioeconomic status, poor housing, social isolation, loss of cultural identity and discrimination
• Environmental• Psychological – stressful life events
Genetics of Schizophrenia
A heterogeneous disorder or set of disorders. Often triggered by stress at puberty / early adulthoodBehavioural effects of disordered brain development then become manifest
Neurodevelopmental structural changes
Symptoms
• Hallucination• Delusion• Thought disorder
• Social withdrawal• Avolition/Apathy• Blunted affect• Poverty of speech
NegativePositive
Dopamine hypothesis of schizophrenia
Hypoactivity in mesocortical pathway- Negative symptoms- Impaired learning and memory
Hyperactivity in the mesolimbic pathway-Positive symptoms
Normal dopamine activity in nigrostriatal pathway(involved in movement regulation)
Normal dopamine activity in tuberoinfundibularpathway(involved in prolactin regulation
Schizophrenia is associated with impaired dopaminergic neurotransmission in the brain
Dopamine hypothesis of schizophrenia
The Dopamine Theory
• DA‐ergic hyperactivity in Mesolimbic forebrain areasD‐amphetamine causes paranoia, delusions & auditory hallucinations at high dosesStimulants can exacerbate psychosisAll typical neuroleptics block D2receptors & alleviate positive symptoms
• Structural changes – limbic forebrain smaller and disorganised
• Risk factors –stress, alcohol, drugs, smoking cannabis
• Reduction in Mesocortical DA activity is known to be responsible for negative symptoms
Effects of Dopamine agonism and antagonism
Mesocorticalpathway
Mesolimbic pathway
Nigrostriatal pathway
Dopamine receptor agonism
Increased attention and concentration1
Positive mood1
Euphoria/mania Psychoses
Motor activity2
Dopamine receptor antagonism
Decreased attention and concentration1
Negative mood1 Extrapyramidal symptoms2
1. Nutt DJ et al. J Psychopharmacol 2007;21:461–71; 2. Shiloh R, et al. Atlas of Psychiatric Pharmacotherapy. Second edition. Oxford: Taylor & Francis; 2007.
More than dopamine!Effects of serotonin agonism and antagonism at main 5HT receptor subtypes in the brain
Effect at receptor
5HT1A 5HT2A 5HT2C
Agonist Anxiolytic effect1,2
Antidepressant effect1,2
Psychosis3
Hallucinations4
Insomnia5
Anxiety2
Satiety3
Antagonist Turns off autoreceptor activity3
Antidepressant effect2,6
Possible antipsychotic effect2,3
Can counteract EPS effect of D2blockade3
Possible increased appetite/weight4
1. Blier P et al. Biol Psychiatry 2003;53(3):193–236; 2. Hardman JG et al. (eds) Goodman and Gillman’s The Pharmacological Basis of Therapeutics. New York: McGraw Hill; 2001; 3. Correll C et al. J Clin Psych 2008; 69 (Suppl 4): 26–36; 4. Gouzoulis-Mayfrank, E. Neuropsychopharmacology. 2006 Feb;31(2):431–41; 5. Quintin P et al. Encephale 2004;30:583–9; 6. Mann N. Engl J Med 2005;353:1819–34.
• Serotonergic projections to prefrontal cortex mediate cognitive effects
• Mediates inhibition of DA release from dopaminergic pre‐synaptic neurones
• Second generation antipsychotics have mixed 5‐HT profiles– Reduced extrapyramidal side profile– Some serotonergic side effects (weight gain‐5HT2C)
Other receptor activitites affected by antipsychotics and effects
Receptor typeEffect at receptor
NoradrenalineAlpha 1 (α1)
NoradrenalineAlpha 2 (α2)
HistamineH1
AChM1
(central)
AChM2-M4
(peripheral)
Agonism Anxiety1
Anti-depressant1
Memory2
Attention2
Arousal 3
Insomnia3
Arousal4
Memory4
Seizures
Nausea3
Diarrhoea3
Bradycardia5
Antagonism3
Postural hypotensionDizzinessTachycardiaSyncope
Anti-depressantIncreased alertnessIncreased blood pressure
SedationAnxiolyticWeight gain
AmnesiaDecreased cognitionDry mouthAnti-EPS
Blurred visionConstipationUrinary retentionTachycardiaHypertension
Antipsychotics
dopaminedopamine
5HT2
Typical pharmacology
Atypical pharmacology
Partial agonist
dopamine
HaloperidolZuclopenthixolFlupenthixolSulpiride
Clozapine AmisulprideOlanzapine LurasidoneQuetiapineRisperidone
Aripiprazole
First-generation (“typical”) AP Side Effect Profiles
DrugUsual daily dose
Sedation Movement problems
Weight gain
Anticho-linergic
Sexual problems
Chlorpromazine 75-300mg • • • • • • • • • • • •Haloperidol 5-20mg • • • • • • • • • •Levomepromazine 100-200mg • • • • • • • • • • • •Pericyazine
5-20mg • • • • • • • • • • • •Perphenazine 12-24mg • • • • • • • • • • •Sulpiride 400-
1,600mg • • • • • • • • •Trifluoperazine 5-15mg • • • • • • • • • •
Second-generation (“atypical”) AP Side Effect Profiles
Drug Usual daily dose
Sedation Movement problems
Weight gain
Anticholinergic
Sexual problems
Amisulpride(Solian®)
400-800mg • • • • • • • • •Aripiprazole(Abilify®)
15-30mg • • † † †Clozapine(Clozaril®, Denzapine®, Zaponex®)
Usually300-600mg
• • • • • • • • • • •Olanzapine(Zyprexa®)
10-20mg • • • • • • • • •Paliperidone(Invega®)
6mg • • • • • • • •Risperidone (Risperdal®)
4-6mg • • • • • • • •Quetiapine(Seroquel®)
Around 600mg • • • • • • • •
Zotepine(Zoleptil®)
Up to 300mg • • • • • • • • • • •
19 November, 2019
NICE CG187 guidancePrimary care
20
• Referral from primary care
• Monitoring and follow up
• Promote wellbeing and relapse prevention
Management of Challenges in Clinical Practice
Non‐adherence Shared decision, Reasons explored, Depot, Psychological intervention, Increased follow up, CBT
Physical monitoring(Intervention – smoking, diabetes, obesity, lipids)
Q‐RISKYearly – ECG, Lipids, Weight, BP, Pulse, HbA1c,
Side‐effect: GASS, clozapineGASS
Weight gain & Metabolic disorder
Diet & exercise, CBT
Movement disorders Dose adjustment, procyclidine, second generation AP
Sexual dysfunction Prolactin level, management of mental condition
Sedation Dose adjustment and time of administration
Constipation Laxatives prophylaxis, diet and lifestyle
19 November, 2019
Management of Challenges in Clinical Practice
22
Information PILs
Off label prescribing Information, discussion, consent, documentation
Interaction:
Smoking Smoking cessation, monitoring
Other medication ‐ carbamazepine Avoid with clozapine, dose adjustment
Management of Depression in Primary Care
Introduction
• Increasing prevalence• High risk of mortality• 21% suicide rate• F>M• Social, economic, ethnic factors
• Associated with increased comorbidity of psychiatric and medical conditions
• Worsens outcome of general medical conditions
Morbidity/mortality post‐myocardial infarction Risk of mortality in nursing home patients Morbidity post‐stroke May worsen outcomes in cancer and HIV
Pathophysiology
• Genetic – altered neurotransmitter and receptor activity in response to triggers.
• The two hypothesis are high level of cortisol and functional deficit of noradrenaline, serotonin, GABA and dopamine transmission in the central nervous system.
• Structural brain changes have been noted in severe depression: ventricular enlargement; reduced grey matter in left hippocampus, basal ganglia and thalamus.
Risk Factors:
• Family history, early life adverse experience, life events such as divorce, pregnancy, physical conditions e.g. Diabetes, CVD, other mental condition, changes in sleep patter, social isolation, abuse, medication e.g. isotretinoin, alcohol, personality traits, social circumstances.
Present in many mental and physical processes:
• Anxiety• Pain perception• Vasoconstriction• Urethral sphincter contraction• Bladder wall relaxation• Gastrointestinal motility• Pilomotor contraction
Role of Serotonin and Noradrenaline in Mental & Physical Processes
19 November, 2019
Symptom classification for depression –more than feeling sad!
27
Emotional Symptoms
Cognitive Symptoms
Behavioural Symptoms
Physical Symptoms
Low Mood
Guilt
Worthlessness
Suicidal Thoughts, Ideas or Actions
Reduced Confidence
Reduced Attention
Reduced Concentration
Anhedonia
Tearfulness
Irritability
Anxiety
Social Withdrawal
Low Energy
Reduced Sleep
Reduced Appetite
Reduced Libido
Painful Symptoms
19 November, 2019
Diagnosis
28
• NICE recommends PHQ‐9, BDl‐ll, HADS when examining mental state through observation and direct questioning, against the DSM‐5 or ICD11 criteria. Five or more of these symptoms must have been present during the same two‐week period and represent a change from previous functioning.
• Differential diagnosis such as hypothyroidism, low folate as well as other prescribed medication e.g steroids should be considered, investigated and managed.
• The severity of the depression is based on the number of symptoms the patient has in addition to the two core symptoms of low mood and lack of interest or enjoyment as well as loss of daily living functions
Symptoms:
• A: Depressed mood present most of day and almost every day
• B: Loss of interest or pleasure in usual activities
• C: Decreased energy or increased fatigability
• D: Loss of confidence or self‐esteem• E: Unreasonable feelings of guilt• F: Recurrent thoughts of death or suicide
• G: Complaints of diminished ability to think or concentrate
• H: Change in psychomotor activity, with agitation or retardation
• I: Sleep disturbance• J: Change in appetite
19 November, 2019
NICE CG90 Depression
29
19 November, 2019
Management:
30
Treatment AimThe aim of treatment is to eliminate symptoms, improve functioning and prevent risk of suicide (mortality).
• Recover• Remission• Response
• Pharmacological• Psychological• Lifestyle/Social/Environmental
19 November, 2019
Antidepressants
31
• Mechanism of action – increased level of serotonin and noradrenaline in the synaptic cleft.
• Cipriani 2018 – meta analysis – double blind RCTs – all antidepressants are equally effective v placebo.
• Up to 60‐70% respond to antidepressants at first trial, the remaining 25% with treatment failures require a switch to an alternative agent, optimisation of medication therapy or combination of psychological intervention.
• Antidepressants are licensed, recommended and effective in moderate to severe depression.
• Choice of antidepressant is guided by anticipated safety and tolerability, presenting symptoms (e.g in lack of energy – non‐sedative antidepressant), history of prior treatment, patients preference and prescriber experience. It also depends on patient factors: age, comorbid physical illness, pregnancy, breastfeeding, risk of suicide.
• In treatment resistant depression, augmentation strategies such as addition of another antidepressant, lithium, triiodothyronine, quetiapine have shown to be beneficial (NOT in Primary Care).
19 November, 2019 32
Antidepressant Mode of Action Side‐effect
SSRI (sertraline, citalopram, escitalopram, fluoxetine, paroxetine) is recommended as first choice due to a more favourable tolerability profile.
Increase level of serotonin in the synapse by blocking the pre‐synaptic reuptake of serotonin
Side‐effects ‐ initial increase in anxiety, nausea and vomiting , headaches , sexual dysfunction not exclusive to SSRI’s but may be more prevalent , occasional movement disorders, risk of gastric bleeding Side‐effects can be managed by starting low and increasing the gradually to a minimum effective dose; switching to an alternative; or use of medication, e.ggastric bleed with a proton pump
SNRI (venlafaxine, duloxetine) Increase the level of serotonin, noradrenaline, dopamine by blocking the reuptake Inhibitor
Side‐effects – similar to SSRI, but more pronounced.
19 November, 2019 33
Antidepressant Mode of Action Side‐effect
NaSSa (Mirtazapine) Noradrenaline and specific serotonin antidepressant. Increases serotonin and noradrenaline transmission by blocking alpha2 adrenoreceptor
Side‐effects ‐ sedation, dry mouth, weightgain,
TCA (amitriptyline, Imipramine, lofepramine, clomipramine
Inhibit reuptake of nor‐adrenaline and serotonin from the synaptic cleft into the pre‐synaptic neurone, increasing the availability and enhances noradrenergic and serotonergic transmission
Dry mouth, sedation, constipation.
Should be avoided in suicide risk
Caution in cardiac disease and epilepsy.
Vortioxetine Inhibits the re‐uptake of serotonin
Abnormal dreams, constipation, nausea, vomiting, diarrhoea, dizziness
MAOI (phenelzine, moclobemide) Inhibition of monoamine oxydase, a major metabolising enzyme
Postural hypotension, dizziness, agitation, elevated liver enzymes
19 November, 2019
Mechanism of action:
34
All antidepressants increase availability of serotonin or noradrenaline in the synaptic cleft
19 November, 2019
Side‐effects of Antidepressants
35
Seda
tion
Insomnia
Parado
xical
anxiety
Heada
che
Nau
sea
Anticho
linergic
effects
Cardiac
cond
uctio
n
Hypoten
sion
Falls in
older
adults
Drug
Weight g
ain
Gastrointestin
al
bleed
Lethality
in
overdo
se
Selective serotonin reuptake inhibitors
Citalopram – – – – ++ – + – +++ +++ – ++ +
Escitalopram – – – – ++ – + – +++ +++ – ++ +Fluoxetine – – + – ++ – – – +++ +++ – ++ –Paroxetine + + + + ++ + – – +++ +++ + +++ –Sertraline – + + ++ ++ – – – +++ +++ – +++ –
Tricyclic antidepressants
Amitriptyline +++ – – – + +++ +++ +++ ++ +++ ++ + +++Clomipramine ++ + + – ++ ++ +++ +++ ++ +++ + +++ ++Nortriptyline + + + – + + ++ ++ ++ + – – +++
19 November, 2019 36
Seda
tion
Insomnia
Parado
xical
anxiety
Heada
che
Nau
sea
Anticho
linergic
effects
Cardiac
cond
uctio
n
Hypoten
sion
Falls in
older
adults
Drug
Weight g
ain
Gastrointestin
al
bleed
Lethality
in
overdo
se
Serotonin‐norepinephrine reuptake inhibitors
Duloxetine – + – – ++ – – – ++ ++ – + ++Venlafaxine – + + + +++ – + + ++ +++ + + ++
Other
Mirtazapine +++ – – – + + – + ++ – ++ + +Trazodone +++ – – – + + + + ++ + + +++ +Bupropion – ++ – – + + – – + – – – ++
19 November, 2019
Management of Challenges in Practice
37
• Starting antidepressant ‐ It usually takes 1‐2 weeks to achieve a therapeutic response, therefore patients should be reassured, advised to persevere with treatment and report any worsening symptoms or side‐effects. Some may need management of severe agitation with a low dose short‐term use of benzodiazepine.
• Adverse drug reaction.
• The risk of suicide associated with antidepressants may be increased in those below age 25 years, patients should be warned of this risk during the early weeks of treatment and advised to seek support.
• Continuation and prevention of relapse ‐ NICE recommends continuation of medication for 6‐9 months after resolution of symptoms, to prevent a relapse. In patients with recurrent depression treatment should be continued longer term.
• Non‐responders ‐ severe or treatment resistant cases referred to secondary care which often require hospital admission, adherence, review diagnosis.
• Switching – consider half life, cross taper, washout period.
• Stopping/discontinuation syndrome/deprescribing – hyperbolic dose withdrawal.
Management of Bipolar Disorder in Primary Care
19 November, 2019
Learning Outcome
39
• Pathophysiology of Bipolar disorder• Symptoms and clinical presentation• Recognition in Primary Care• Medication Management – mode of action, SE, monitoring• Management of some of the challenges
19 November, 2019
Introduction
40
• Common, chronic, recurrent, disabling, complex condition, characterised by extreme changes in level of mood and energy.
• Manifests as episodes of mania or hypomania (a mild form of mania) and depression or euthymia (stable mood).
• 1.4 %• M:F = 1:1• Average age of onset is 21 years • 10‐15% suicide rate
19 November, 2019
Pathophysiology
41
• Structural brain changes ‐Enlarged ventricles reported , Enlarged amygdala
• Family members of individuals with bipolar disorder have 5‐10 times increased risk of developing the illness, which is usually precipitated by psychosocial factors such as stress or major negative life events.
• Neuro‐hormonal and monoamine neurotransmission abnormalities with raised levels of dopamine, glutamate, noradrenaline, serotonin and low level of GABA implicated.
• Other e.g. organic brain disease, and medication such as corticosteroids, stimulants, antidepressants are well known for causing mania, hypomania or depression
19 November, 2019
Symptoms & Clinical presentation
42
Symptoms of Mania Symptoms of Hypomania Depression
Elation, unfounded excessive cheerfulness, optimism and irritability or outbursts of anger
Increased energy and psychomotor activity‐ rapid, loud speech, reduced sleep
Increased sexual desires, disinhibition
Expansive over valued ideas
Flight of ideas
Grandiose delusions
Poor judgement
Other delusions e.g. Persecutory
Less severe form of mania,without significant disruptionto functioning
No features of psychosis
Persistent low mood
Loss of interest
Low energy
Disturbed sleep
Poor memory or concentration
Suicidal thoughts
Agitation
More severe, frequent, shorter in duration compared to unipolar depression
19 November, 2019
Diagnosis
43
• ICD11 classificationSymptoms for at least one weekSevere enough to disrupt ordinary work and social lifeMood change with increased energyPressure of speechGrandiosityExcessive optimism• Schizophrenia / Schizoaffective disorder• Acute stages mania resemble schizophrenia• Both disorders can involve psychotic symptoms• Psychotic symptoms in mania are usually less stable, mood congruent and auditory hallucinations are likely to be second person
• Substance misuse• Stimulant drugs, e.g. cocaine, khat, ecstasy or amphetamines, can produce mania‐like symptoms
• Symptoms will resolve within a week of drug withdrawal• Urine screening may be useful in diagnosing the presence of illicit substances
19 November, 2019
NICE CG185: Bipolar disorderPrimacy care
44
19 November, 2019
NICE CG185; 2014 Secondary care
45
• Assessment – baseline physical monitoring, MSE, intensive psychiatric hx, differential diagnosis, substance misuse – ICD11, DSM5
• Physical monitoring
• Medication Management: Acute, maintenance
• Medicine optimisation
19 November, 2019
Management
46
Aim: Safety, rapid resolution of symptoms
• Acute mania or hypomania – Consider short term benzodiazepine for behavioural disturbance or agitation, e.g. lorazepam
• Stop Antidepressant if taking• Commence antipsychotic medication or optimise current treatment• Acute depression – Optimise mood stabiliser, consider antidepressant short‐term with mood stabiliser
• Maintenance ‐ BAD I – Mood stabiliser, Antipsychotic • Maintenance ‐ BAD ll – Mood stabiliser
19 November, 2019
Antipsychotics in Bipolar
47
• Olanzapine, Quetiapine, Aripiprazole, Risperidone, Haloperidol.
• Substantial evidence for the benefit of antipsychotics in mania.
• Some evidence for benefit in maintenance treatment.
• Less confidence in benefit of antipsychotics in depressive phase of illness.
• Some are available as long acting injection (depot).
19 November, 2019
Lithium
48
• Reduces frequency of mood cycling and smoothens the extreme peaks of mood.
• Li+ alters Na+ transport.
• Inhibits second messenger systems (G‐proteins) and reduces responsiveness to neurotransmitters.
• Increases glutamate uptake.
• Pharmacokientic parameters: t1/2 = 22 hrs, 0.6‐1mmol, 5‐7 days to reach steady state.
• Brands and formulations are not bioequivalent.
19 November, 2019
Lithium toxicity and interaction
49
• Lithium clearance exclusively renal
• Body handles Li in the same way as Na
• If patient becomes dehydrated or prescribed diuretic, Li level increases as Na retained
• NSAIDs and ACE inhibitors (ACE I and ACE II e.g. candesartan / irbesartan) increase Li level by reducing renal clearance
If Patient is dehydrated or prescribed diuretic, NSAID or ACE (I or II) then additional blood tests are required
19 November, 2019
Lithium – side‐effects
50
Common:
• Thirst, polyuria, fine tremor, weight gain?
Rarely:
• Hypothyroidism
Signs of Toxicity:
Blurred Vision, Increasing Vomiting, Confusion, Ataxia, Coarse tremor, Lack of Co‐ordination, Impaired Consciousness
If any of the above toxic signs seen then URGENT BLOOD LEVEL Is necessary
19 November, 2019
Valproate
51
Pharmacological action• Increase GABA neurotransmission• Enhances synthesis, turnover & release of GABA• Inhibits Ca 2+influx through NMDA receptors• Enhances brain serotonergic function ( ↓ DA function) indirectly via GABA‐ergic means
Common side‐effect:• Gastric, weight gain,
Less Common:• Hair loss, polycystic ovary disease?
Rare:• Hepatic toxicity
• Women of childbearing age, Pregnancy Prevention Programme
19 November, 2019
Carbamazepine
52
Pharmacological action:
• Inhibitory effects on second messenger systems (as Li+)
• Also inhibits Ca 2+influx through the NMDA & GABA‐B receptors
• Na+channel mediated membrane stabilisation
• Potentiation of α2 adrenoceptors: Reduced release of NAPotent liver enzyme inducer: Changes plasma levels of many co‐administered drugs ‐ interaction
19 November, 2019
Lamotrigine
53
• Limited evidence in the treatment / prophylaxis of manic episodes.
• Reasonable evidence in prevention of depressive episodes.
• Particularly useful as can avoid need for antidepressants – reduced risk of switching into mania.
• Care needed with initiation – slow dose titration.
• Particular care needed if patient concurrently receiving valproate
19 November, 2019
Antidepressants
54
• Risk of ‘switching’ patients from depression into mania.
• Nor‐adrenergic antidepressants might induce more switching – SSRI’s thought to pose less risk.
• Cover with antimanic medication.
• Recommended stopping antidepressant therapy in bipolar depression after 8 weeks.
• Lamotrigine might have some benefit in managing bipolar depression.
19 November, 2019
Management of Challenges in Practice
55
• Management of bipolar depression
‐ Risk of antidepressant drugs ‘switching’ patients into mania‐ Risk possibly greater with nor‐adrenergic antidepressants‐Mood stabiliser cover, short duration, review
• Management of bipolar illness in women of child‐bearing age
‐ Increased risk of relapse in key reproductive stages‐ Valproate, lithium and carbamazepine all pose teratogenic / developmental risks‐ Valproate associated with increased risk of polycystic ovary disease – link with weight gain can not be separated‐ Antipsychotics may be an alternative option
19 November, 2019
Management of Challenges in Practice
56
• Lithium Monitoring
• Adherence
• Shared decision, information, CBT, education, long acting injection.
• Stopping treatment.
• Reduce over 4 weeks – 3 months, monitor closely for relapse sign.
Thank you