D,B+A Flashcards

Question

What is the therapeutic range of lithium?

Answer 1

Therapeutic range; 0.4 mmol/L – 1.0 mmol/L Potentially fatal > 1.5mmol/L

Answer 2

Dose adjusted according to serum-lithium concentration and once daily administration is preferred when treatment is stabilised There are several key drug interactions including ACEI, diuretics and NSAIDs (including OTC preparations) Monitoring of adverse effects including renal and thyroid function are key A single daily dose regimen is associated with less polyuria, a reduction in permanent renal damage and better compliance Solid dose forms (lithium carbonate) and liquids (lithium citrate) need careful dose conversion if swapping between them Preparations vary in bioavailability by brand, stick to the same whenever possible Abrupt withdrawal is necessary in severe toxicity but if possible should otherwise be avoided – rebound mania can be severe and difficult to treat

Answer 3

Therapeutic serum-lithium concentrations should be taken 12hrs post-dose and the target range is usually 0.4–0.8 mmol/litre (may be as high as 1mmol/litre in specific cases) Weekly monitoring is required while treatment is established or re-started Monitoring of lithium levels and other key parameters including renal function should be undertake at least every 6-months for patients on a stable dose, more frequently (3-monthly) in higher risk groups several variability factors for PK profile including age, body weight, renal function and pregnancy The pharmacokinetic profile of lithium is linear within the dose regimen used in clinical practice

Answer 4

- Polyuria and polydipsia (renal problems) - Weight gain - Aggravation of skin disorders - Tremor, Muscle twitching, Dysarthria - Nausea, Vomiting, Appetite loss, Diarrhoea - Sluggishness, Languidness, Drowsiness - Coma - Hyper-reflexia, Fasiculations - Choreiform and Parkinsonian motor symptoms - Seizure and Convulsions

Answer 5

- Thyroid goitre - Nephrotoxicity - Hair loss

Answer 6

We don’t really know! Monovalent cation that permeates voltage-gated sodium channels, not removed by Na/K ATPase Depolarization of excitable cells Inhibition of phosphatidyl inositol pathway Prevents agonist stimulated IP3 formation Inhibition of glycogen synthase kinase 3 (GSK3) Involved in apoptosis and amyloid formation

Answer 7

Gastro-intestinal disturbances (vomiting, diarrhoea), Visual disturbances Polyuria Muscle weakness Fine to coarse tremor CNS disturbances (confusion and drowsiness increasing to lack of coordination, restlessness, stupor) Abnormal reflexes, myoclonus

Answer 8

Depression, anxiety, OCD, panic, social anxiety, phobias, and adapting to long-term health conditions.

Answer 9

Recommended to help families work together to support a loved one who has a severe mental health disorder

Answer 10

Subthreshold depressive symptoms, mild to moderate depression, and severe depression.

Answer 11

Recommended for borderline personality disorder.

Answer 12

Initiated by the patient - Respect the patient’s request – don’t be dismissive - Exploring reasons for the request Initiated by a healthcare professional - Don’t rush a patient into a decision to stop/reduce - Explain reasons - Be prepared for queries about prescribing decisions made previously. Explain that our understanding of the balance of risks and benefits of a medicine can change over time.

Answer 13

- Is the patient symptom-free, and if so, for how long? - What is the severity of adverse-effects (EPS, TD, sedation, obesity, etc.)? - What was the previous pattern of illness? - Has dosage reduction been attempted before, and, if so, what was the outcome? - Is the patient in a period of relative stability, or are stressful life events anticipated? - What is the social cost of relapse? (implications for family/work) - Is the patient/carer able to monitor symptoms, and, if so, will they seek help?

Answer 14

Approximately half of patients will experience withdrawal symptoms on reducing or stopping their antidepressant. Variation between patients. There is some evidence that tapering slowly can reduce the chance of intolerable withdrawal symptoms. Clinical experience suggests that most patients take between 3 months and 2 years to withdraw in a tolerable manner from long-term antidepressant treatment.

Answer 15

- Paresthesia/numbness - Shock-like sensations - Rushing noises - Palinopsia - Confusion/decreased concentration/amnesia - Hypersensitivity

Answer 16

Explain to people taking antidepressant medication that: withdrawal symptoms can be mild, may appear within a few days of reducing or stopping antidepressant medication, and usually go away within 1 to 2 weeks Withdrawal can sometimes be more difficult, with symptoms lasting longer Withdrawal symptoms can sometimes be severe if the antidepressant medication is stopped suddenly. Recognise that people may have concerns about stopping their antidepressant medication and may need support to withdraw successfully. Support: - details of online or written resources that may be helpful - increased support from a clinician or therapist (for example, regular check-in phone calls, seeing them more frequently, providing advice about sleep hygiene). When stopping a person's antidepressant medication: - take into account the pharmacokinetic profile (half-life) - slowly reduce the dose to zero in a step-wise fashion - consider using smaller reductions as the dose becomes lower and using liquid preparations if needed - ensure the speed and duration of withdrawal is led by and agreed with the person taking the prescribed medication - ensuring that any withdrawal symptoms have resolved or are tolerable before making the next dose reduction - recognise that withdrawal may take weeks or months to complete successfully Do not stop a medicine abruptly unless there are exceptional medical circumstances such as the occurrence of serious side effects

Answer 17

Inform patients of potential withdrawal symptoms, but don’t sensationalise Be realistic about timescales Discuss differences between relapse and withdrawal symptoms Be prepared for the plan to be flexible and responsive to the patient If symptoms become intolerable, either hold the current dose for longer or return to the last tolerated dose and then make the next reduction smaller Some patients gain access to tapering strips but these are not widely available Final reductions may need to be very small

Answer 18

Lifetime prevalence of unipolar depression 5% - ~1 in 38 adults in the UK at any one time Globally, more than 300 million people of all ages suffer from depression Suicide is the second leading cause of death in 15-29-year-olds. Co-morbidity is common 2/3 of those with MDD will also meet criteria for anxiety disorder at some point MDD twice as common in women than men Differences emerge in adolescence Episodic, recurrent can lead to suicide (0.04-0.08%)

Answer 19

EITHER Depressed mood most of the day, nearly every day OR Diminished interest/pleasure in everyday activities (anhedonia), nearly every day PLUS 4 or more of the following Significant weight loss/gain (>5% in a month) or change in appetite Insomnia/ hypersomnia Slowing down of thought and reduction of physical movement Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt Diminished concentration, or indecisiveness, nearly every day Recurrent thoughts of death or suicide

Answer 20

Clinician administered assessment scales Hamilton Depression Rating Scale (HAM-D or HDRS) Montgomery-Asberg Depression Rating Scale (MADRS) Self-rating assessment scales Beck Depression Inventory (BDI) Why? Assess severity of symptoms Evaluate response to treatment Promote self-management strategies

Answer 21

Episodic Symptoms tend to dissipate over time Once depression occurs, future episodes likely Average number of episodes is 4 (Judd, 1997) Subclinical depression Sadness plus 3 other symptoms for 10 days Significant impairments in functioning even though full diagnostic criteria are not met

Answer 22

Chronic depression Depressed mood for at least 2 years (not severe enough for a MD episode) PLUS 2 other symptoms: Poor appetite or overeating Sleeping too much or too little Psychomotor agitation or retardation Loss of energy Feelings of worthlessness Difficulty concentrating or indecisiveness Recurrent thoughts of death or suicide

Answer 23

Elevated, expansive, or irritable mood PLUS 3 of the following (4 if mood is irritable): Psychomotor agitation or increase in goal-directed behavior Excessive talking or pressured speech Flights of ideas; racing thoughts Reduced need for sleep Grandiosity or inflated self esteem Easily distractible Excessive involvement in pleasurable activities with negative consequences e.g. spending sprees For manic episode: Symptoms last for 1 week OR require hospitalization Symptoms cause significant distress or functional impairment For hypomanic episode: Symptoms last at least 4 days Clear changes in functioning but impairment is not marked

Answer 24

Bipolar I At least one episode or mania or mixed episode Bipolar II At least one major depressive episode with at least one episode of hypomania Cyclothymic disorder (Cyclothymia) Milder, chronic form of bipolar disorder Lasts at least 2 years Numerous periods with hypomanic and depressive symptoms

Answer 25

Prevalence rates for bipolar disorder lower than MDD 1% for Bipolar I Average age of onset in 20s No gender differences Tends to be recurrent Severe mental illness A third unemployed a year after hospitalization Suicide rates high

Answer 26

Seasonal (SAD) Episodes happen regularly at a particular time of year Rapid cycling (Bipolar I and II) At least 4 episodes within past year Postpartum onset Within 4 weeks of giving birth Catatonic features Extreme physical immobility or excessive peculiar physical movement Psychotic features Delusions or hallucinations Melancholic Inability to experience pleasure (anhedonia)

Answer 27

- Pulmonary disease (COPD, asthma) - Endocrine disorders (Hypo/hyperthyroidism, diabetes) - Cancer - Cardiovascular disease, especially MI - CNS (migraine, infection, tumour, stroke, head injury, hypoxia) - Neurological disorders (Alzheimer’s, Epilepsy, Parkinson's, Huntington's, Multiple Sclerosis) - B12, folate deficiency - Chronic pain, back problems - Sleep apnea

Answer 28

Genetic factors - Heritability estimates 93% Bipolar Disorder 37% Major depression Neurotransmitter dysfunction Monoamines – 5HT, noradrenaline, dopamine Neuroendocrine – disruption of the hypothalamic-pituitary-adrenal axis Neurogenesis – Decreased rate of newborn neurones in the adult hippocampus Neuroinflammation – any chronic inflammatory condition could produce cytokines/inflammatory markers that are able to cross blood-brain barrier and activate microglia Glutamate – glutamate antagonists e.g. ketamine (NMDAR antagonist) antidepressant Psychosocial/environmental factors Stressful life events e.g. marriage breakdown, loss of job Co-morbidity e.g. chronic pain, substance abuse Medication e.g. corticosteroids, oral contraceptives, interferon

Answer 29

Neurotransmitters most implicated in mood disorders are the monoamines: MDD Low levels of 5-hydroxytryptamine and/or noradrenaline (and/or dopamine) Mania High levels of noradrenaline and dopamine, low levels of 5-hydroxytryptamine Based largely on the ability of known antidepressant drugs to facilitate monoaminergic transmission = ‘the monoamine hypothesis of depression” Reserpine – inhibits 5-HT and NA storage – lowers mood Tryptophan depletion – lowers brain 5-HT synthesis – induces relapse in recovered patients

Answer 30

depression is a functional deficit of 5HT and/or noradrenaline in the brain

Answer 31

Interpersonal psychotherapy (IPT) Short term psychodynamic therapy Focus on current relationships Cognitive therapy Monitor and identify automatic thoughts Replace negative thoughts with more neutral or positive thoughts Behavioral activation Mindfulness based cognitive therapy (MBCT) Strategies, including meditation, to prevent relapse

Answer 32

Reserved for Severe depression with high risk of suicide Depression with psychotic features Treatment non-responders Induce brain seizure and momentary unconsciousness Unilateral ECT Side effects Memory loss

Answer 33

e.g. phenelzine, tranylcypromine, iproniazid Irreversible inhibitors of monoamine oxidase MAO is widely expressed Within nerve terminals regulates intraneuronal concentration of NA/5HT In the gut wall inactivates endogenous/ingested amines Enzyme exists in two forms MAOA and MAOB MAOA – substrate preference = 5HT MAOB – substrate preference = DA

Answer 34

Tyramine (diet) normally metabolised by MAO in the gut/ liver. During non-selective MAOI: Tyramine not metabolised but absorbed Tyramine has sympathomimetic effects Can result in acute hypertension, headache, angina, cardiac arrest, pulmonary oedema, intracranial haemorrhage.

Answer 35

- Hypotension (sympathetic block) - Atropine-like effects - Hepatocellular jaundice

Answer 36

e.g. moclobemide Reversible action allows MAOA inhibition to be partially overcome by high concentrations of substrate, e.g. tyramine Unlikely to result in ‘cheese reaction’ if tyramine or sympathetic amines ingested

Answer 37

e.g. imipramine, amitriptyline, clomipramine Block the uptake of amines by nerve terminals 5-HT=NA >> DA Competitive with endogenous substrate Relatively non-selective Receptor blockade e.g. mAChRs, HA, 5-HT Contributes to side effect profile Major metabolites also active

Answer 38

- Sedation - Atropine-like (muscarinic blockade) - Postural hypotension - Mania and convulsions (rare) - Dysrhythmia and heart block

Answer 39

- Confusion, mania - Cardiac arrhythmias - Coma - Respiratory depression, hypoxia

Answer 40

e.g. fluoxetine (Prozac), paroxetine, citalopram Developed by Eli Lilly in 1980s on the concept that ‘biological’ components of depressive illness are sensitive to antidepressant effects on NA systems ‘emotional’ components of depressive illness are sensitive to antidepressant effects on 5-HT systems The most commonly prescribed class of antidepressants = 1st line Also used to treat anxiety disorders

Answer 41

Better side-effect profile? Safer in overdose No evidence of greater efficacy No evidence of more rapid onset

Answer 42

Mirtazapine – blocks a2 adrenoceptors/5HT2C receptors Enhanced NA/5HT release Trazodone - blocks 5HT2A/2C and 5HT reuptake Mianserin – blocks multiple 5HT receptors, a1/2 adrenoceptors Agomelatine – blocks melatonin receptors Useful for depression associated with sleep disturbance

Answer 43

Efficacy of antidepressants < 40% achieve remission from symptoms Robust effect in preventing relapse in recurrent MDD Tolerability side effect profile deters use e.g. emotional blunting/detachment with SSRIs Time to onset/discontinuation effects Typically 4-6 weeks to onset of therapeutic benefit Safety of antidepressants Risk of suicide Older drugs are cardiotoxic, dangerous in overdose

Answer 44

Immediate short-term pharmacological effects MAOIs increase 5-HT, NA by inhibiting metabolism TCAs increase 5-HT, NA by blocking reuptake SSRIs increase 5-HT by blocking reuptake Clinical effects appear to take weeks to onset Suggests chronic adaptive changes in response to antidepressants rather than acute

Answer 45

Aka “mood stabilizing drugs” Lithium Up to 80% receive at least some relief with this mood stabilizer Potentially serious side effect = Lithium toxicity Anticonvulsants (prevent relapse to depression?) e.g. valproate, lamotrigine Antipsychotics (co-prescribed, where mania predominates?) e.g. olanzapine, risperidone, quetiapine, aripiprazole

Answer 46

Anxiety is a normal, physiological response to threatening situations that serves a protective function Anxiety is pathological when there is a bias to interpret non-threatening situations as threatening The concern about the stressor is out of proportion to the realistic threat and can occur without exposure to an external stressor = pathological anxiety Negative cognition: Bias to interpret unthreatening situations as threatening Context/memory/reinforcement Physiological symptoms: autonomic activation Racing heart Palpitations Restlessness Sweating Increased blood pressure

Answer 47

- Simple/Specific phobias - Social phobia/ Social anxiety disorder (SAD) - Panic disorder (PD) - Posttraumatic stress disorder (PTSD) - Generalized anxiety disorder (GAD) - Obsessive compulsive disorder (OCD) - (Premenstrual dysphoric disorder (PMDD))

Answer 48

DSM criteria for generalized anxiety disorder include: - Excessive anxiety and worry about several events or activities most days of the week for at least six months - Difficulty controlling feelings of worry At least three of the following symptoms in adults - restlessness - fatigue - trouble concentrating - irritability - muscle tension - sleep problems

Answer 49

Largely unknown Abnormal regulation of brain areas involved in stress/fear Several neurotransmitter systems implicated: - Underactivity of 5HT system? - Overactivity of NA system? - Disruption in level of GABA inhibition? reduced expression of GABAA-receptors reduced function/regulation of GABAA-receptors by benzodiazepines reduced function/regulation of GABAA-receptors by neurosteroids Genetic and environmental factors play a role

Answer 50

Pharmacotherapy - b-blockers – target autonomic symptoms - Benzodiazepines - Antidepressants (SSRIs) - Buspirone (partial agonist at 5-HT1A receptors) Evidence-based psychological interventions - Low intensity interventions e.g. self-help approaches - High intensity interventions e.g. CBT for social anxiety disorder - Stepped-care approach

Answer 51

Treat the physiological symptoms of anxiety Reduce the sympathetic manifestations of stress/fear response No effect on affective components Useful in treating phobias Evidence for use in curing phobias Useful in treating PTSD Effects on memory consolidation

Answer 52

Functional GABAA receptors are pentameric combinations of different subunits arranged to form the integral chloride ion channel Most prevalent receptor in mammalian brain consists of two α, two β and one γ-subunit GABA binds between α and β-subunits – so 2 molecules to activate receptor Benzodiazepines bind at the interface between α/γ-subunits and affect chloride ion conductance to regulate GABAergic inhibition

Answer 53

Developed in the 1950’s for their tranquilizing properties First trials in monkeys noted “loss of fear, hostility, and aggressiveness; increased friendliness; still fully in touch with environment” In the early 1970s more potent BZs such as chlordiazepoxide (Librium) and diazepam (Valium) accounted for 50% of all US psychoactive drug prescriptions Fast acting and effective relief of anxiety and safer than barbiturates e.g. pentobarbital

Answer 54

The core of all BZ ligands is a benzene ring joined to a 7-membered 1,4-diazepine ring R side groups influence the AFFINITY of the BZ to bind the receptor INTRINSIC EFFICACY of BZ to produce a functional effect BZ AGONISTS have 100% intrinsic efficacy BZ INVERSE AGONISTS bind to the site but produce the opposite effect and are said to have negative intrinsic efficacy. BZ ANTAGONISTS bind to the BZ site but are unable to activate the receptor (intrinsic efficacy = 0) other properties such as lipophilicity, water solubility etc.

Answer 55

- Memory loss - Sedation - Abuse potential (?) - Addictive (?) - Withdrawal syndrome

Answer 56

A readily reversible state of reduced responsiveness to, and interaction with, the environment What is it for? - Cortical recovery - Organizing/storing memories - Metabolism/weight homeostasis - Sleep deprivation may provide clues

Answer 57

EEG like that of an active waking brain (“paradoxical sleep”) Oxygen consumption of brain is high Vivid dreaming Loss of skeletal muscle tone (atonia) Bursts of rapid eye movements Sympathetic activity predominates

Answer 58

Non-REM sleep is a rest period Muscle tension reduced Body temperature lowered Energy consumption lowered Increase in parasympathetic activity Brain rhythms slow (“slow wave sleep”)

Answer 59

Ascending reticular activating system (RAS) Locus coeruleus – noradenaline Raphe nuclei – serotonin Brainstem/forebrain – acetylcholine Midbrain – histamine Firing of these neurons = awakening Firing of these neurons = falling asleep

Answer 60

Interleukins immune mediators Melatonin derived from 5-HT in endocrine pineal gland cure for jet lag? Hypocretin-orexin Hypothalamic neuropeptide regulates appetite, metabolism Stimulants e.g. caffeine, cocaine, amphetamine

Answer 61

Transient insomnia e.g. noise, shift work, jet lag Short-term insomnia (“primary insomnia”) e.g. emotional problems, stress, anxiety Chronic insomnia (“secondary insomnia”) e.g. pain, depression, anxiety, alcohol abuse, dyspnoea Fatal familial insomnia – very rare

Answer 62

- regular sleep hours - restful environment - move more - be awake if awake - write worries - less caffeine

Answer 63

Good sleep hygiene = behavioural, environmental & temporal factors? Hypnotic = a drug used to induce and maintain sleep Use should be - intermittent - short term (< 2 weeks) if daytime impairment is severe (tolerance/withdrawal syndromes can occur) Treatment aims to shorten time to sleep, increase total duration of sleep, without suppressing sleep cycle and REM sleep

Answer 64

Long acting e.g. flurazepam/ Dalmane (2-keto) May give rise to “hangover” effect Short acting e.g. temazepam/ Restoril (3-OH), triazolam/ Halcion little or no “hangover” effect Rohypnol (flunitrazepam) – “date rape” Little to distinguish between BZs in terms of efficacy, adverse effects or risk of dependency Next-day residual effects common with diazepam, nitrazepam and flurazepam

Answer 65

Zaleplon, zolpidem, zopiclone (“Z drugs”) Non-benzodiazepines that bind to GABAA receptor Short duration of action Less likely to cause rebound insomnia than BZs Dependence may be a problem

Answer 66

Antihistamines - Promethazine (Phenergan) - Diphenhydramine (Nytol) ‘Natural remedies’ - Melatonin (Circadin) - Chamomile tea/Lavender/Evening primrose oil/Valerian