Drugs, Anxiety & Schizophrenia

What is the lifetime incidence of MDD and Schiz?

• MDD = ~15-20%

• Schiz = 1%

Name 3 drugs that has been used historically?

1. Iproniazid - first MAOI introduced 1957 which was developed for TB in the early 1950's

2. Imipramine - first TCA introduced in 1957/8 first developed for schizophrenia

3. Reserpine (antihypertensive and antipsychotic): an indole alkaloid which depletes monoamines via its action on vesicular monoamine transporters (VMAT's)

   1. This therefore causes depression as it reduces amount of monoamines in the synapse

• Whole basis around treatment = monoamine transmission

What are the risk factors of depression?

• Gender - females, even higher during reproductive years

• Age - Younger onset, shorter duration. Oldies less prevalence but increasing

• Marital status - Highest in separated, then widowers, then divorced females

• Socio-economic factors: social class 3 has a higher incidence than social class 1 and 2. Higher in rented accommodation, highest in homeless.

• Ethnicity - Highest in asian females then white then black

  • Males - No difference between race

Depression definition

• Refers to a wide range of mental health problems characterised by:

1. The absence of positive effect (anhedonia: loss of interest and enjoyment in ordinary things and experiences.),

2. Low mood

3. A range of associated emotional, cognitive, physical and behavioural symptoms

What are 3 elements contributing to depression severity?

• 3 elements

1. Symptoms (which may vary in severity and frequency)

2. Duration of the disorder

3. The impact on personal and social functioning

   1. Personal functioning - when an individual is able to effectively engage in normal activities of daily living and can react to experiences

   2. Social functioning is the ability to interact with other people, develop relationships and gain from and develop these interactions.

Classification of Depression severity

• Sub-threshold - less than 5 symptoms

• Mild - Excess of 5 symptoms and minor functional impairment

• Moderate - Symptoms of functional impairment are between mild and severe

• Severe - Most symptoms and they interfere with functioning

How are new episodes of depression defined/scored?

1. Less severe - encompasses sub-threshold and mild depression (<16 on PHQ-9 scale)

2. More severe - encompasses moderate and severe depression (>16 on PHQ-9 scale)

What are 3 key symptoms?

• Lowered mood

• Anergia - lack of energy

• Anhedonia - No longer enjoys previously enjoyed

What are other symptoms? Sam Smith Sucks Willy For Anxiety, Praise Liam

• Sleep pattern interference

• Self-harm

• Sexual dysfunction

• Weight changes

• Feelings of guilt

• Anxiety

• Psychotic features

• Loss of self-confidence

3 things that can cause depression

• Physical

  • Causative or exacerbated from depression

  • Organic causes like chronic pain

• Latrogenic - Prescription drugs

  • BB

  • Opioids

  • Corticosteroids

• Loss and regret

  • Jobless, homeless, no bitches yute

Treatment considerations for depression:

• Carry out assessment of need

• Develop a treatment plan

• Take into account physical health problems and coexisting mental health problems

• Discuss what factors would make a person more likely to engage with treatment - positive/negative experiences

• Account for previous treatment history

• Address any barriers to the delivery of treatments because of any disabilities, language or communication difficulties

• Ensure regular liaison between healthcare professionals (as well as specialist support if the patient is receiving this)

When prescribing what info must be provided to pt.?

1. SE from first few doses and what they are

2. How long it takes to see an effect (~4 weeks)

3. When their first review will be (usually within first 2 weeks)

4. Importance of following instructions and how to take the medication

5. Why regular monitoring is required and how often they need to attend reviews on their medications

6. Treatment for 6 months after remission but reviewed regularly

7. Persisting SE throughout treatment

8. Withdrawal symptoms and how to minimise them

What is the stepped care for depression (NICE guidance)?

• Depending on the severity and duration of their depression, there is stepped treatment for increasing risk

1. All known and suspected presentations of depression

2. Treatment of persistent sub-threshold depressive symptoms, mild to moderate depression

3. Persistent sub-threshold or mild to moderate depression that has failed to respond to initial interventions;’ moderate or severe depression

4. Severe and complex depression; risk to life; severe self-neglect

Step 1

• Screen individuals for depression using validated assessment tools such as the Patient Health Questionnaire-9 (PHQ-9)

• Establish a diagnosis of depression based on clinical criteria and severity of symptoms

Step 2

• Mild patients: watchful waiting

  • Patient does not want treatment or may recover without further intervention, re-assess in two weeks

• CBT

• Encourage therapy

• Some Antidepressant use

  • Not recommended as SE likely but efficacy maybe = risk

Step 3

• AD routinely offered to all patients

• Key Medication counselling points

  • Addiction

  • Potential SE

  • Discontinuation symptoms

  • Delay in full benefit

  • Consider referral

• Monitoring risk

  • Pts. at high risk of suicide or younger than 30 - follow up weekly

  • Prescribe limited AD

  • Monitor for increased signs of anxiety, agitation and akathisia

Step 4

• HIGH RISK PTs.

• Assess symptoms, suicide risk, treatment history

• Refer to specialist mental health services

• STAR*D treatment for TRD patients

Treatment of depression 1st line and something not recommended by NICE

• First line - SSRIs (Citalopram, Sertraline and Fluoxetine)

  • similar effectiveness to TCA (Amitriptyline) and less chance of SE and toxicity

• St John’s Wort not recommended by NICE due to lack of evidence and efficacy in severe MDD

  • Induce CYP450 for toxicity of drugs like anticonvulsants

How to treat relapsing pts.?

• 50-80%

• Therefore medication should be continued for 2 years for people who have had 2 or more episodes in the recent past and have suffered functional impairment during these episodes

• Patients on maintenance treatment should then be revaluated after two years (taking into account age, co-morbidities and other risk factors)

• Maintenance dose = the dose that achieved remission

MOA of AD (In detail further down in anxiety)

• Almost all antidepressants increase either

1. Seratonin

2. Noradrenaline

• Reuptake inihibition in post-synapse

• So more to bind to receptors

Common side effects of SSRIs/SNRIs

• Nausea

• Vomiting

• Agitation

• Akathisia

• GI upset

• Hyponatraemia

• Sexual dysfunction

• Panic attacks

• Serotonin syndrome

Common side effects of TCAs

• Dry mouth

• Anticholinergic

• BP disturbances

• Hyponatraemia

• Discontinuation/serotonin syndrome

• Sedation

Common side effects of NARIs (Reboxetine)

• Dry mouth

• Constipation

• Sweating

• Insomnia

• Anxiety

• Agitation

MAOIs food interaction problem

Food and drug interactions which can result in HTN crisis

What to do when pt. fails to respond to initial AD?

• Ensure it was taken as prescribed

• If so and SE were tolerable, increase dose

• If no response after a month consider switch in AD

• Choices for second-line AD:

  • Another SSRI

  • SNRI - Duloxetine

  • MAOIs

  • TCAs

Other treatments due to limited pharmacological response

• Adding a group exercise intervention

• Switching to psychological therapy

• Changing to a combination of psychological therapy

  • CBT

  • Interpersonal psychotherapy (IPT)

  • Medication

What is treatment refractory depression?

• Diagnosis made when a patient is unresponsive to two or more medications, given sequentially

  • 70% will respond to the initial AD

  • 30% - half of these people will respond to a second AD

  • Treatment refractory sub-population = 15%

What are TRD treatment options?

MOA of Buspirone

• Neuromodulator of serotonin

• Presynaptically, buspirone's partial agonism at 5-HT1A receptors inhibits release of serotonin regulating serotonin levels in the brain, preventing excessive serotonin release

• Postsynaptically, buspirone's partial agonism at 5-HT1A receptors enhances serotonin neurotransmission in certain brain regions = antidepressant & anxiolytic effects

Why is the serotonin theory obsolete?

• Tryptophan depletion does not cause/worsen depression

• Levels of HIAA do not correlate with depression

• Patients with depression do not have reduced levels of 5HT in plasma

• No. of post-synaptic 5HT-1a receptors is not increased in people with depression

• Genetic polymorphism with subjects having variations in SERT molecules has no effect on depression

Which is the best antidepressant?

• No singular AD is better than any other

• Best antidepressant is the one that works best for individual patient, differs from person to person

• Also depends on willingness

Which AD work the fastest?

• Esketamine

• Ketamine

• Dextromethorphan + Bupropion

  • DMX is an uncompetitive antagonist of the NMDAR and a sigma-1R agonist

  • Bupropion inhibits DMX metabolism as DMX alone is rapidly and extensively metabolised

How do AD’s work?

• Increase amount of certain chemicals that influence working of CNS

• This is monoamine theory of depression as chemicals involved are monoamine neurotransmitters

Are they AD’s addictive?

• Not addictive from a point of fixation or dose adjustment, however when patient stops they can experience withdrawal symptoms

• AD discontinuation syndrome

  • Flu like symptoms

  • Gastrointestinal effects

  • Anxiety

  • Sleep disturbance

  • Panic attacks

• Manage by reducing therapy gradually and reassure patients symptom won’t persist and not indicative of relapse

Can you drink alcohol on AD?

• Alcohol can potentiate sedative effects of certain AD

• CNS depressant

• Consumption strongly associated with suicide

How is libido affected in depression?

• Decrease in libido could be emergent symptom

• Need to get baseline to double check if this could have been caused by AD

What do you give to a patient with Closed angle glaucoma? What is contraindicated in CAG?

• Cannot give TCA as contradicated

• Give SSRI instead like citalopram as first line and safest

What can a lack of asthma control and steroid use lead to?

Depression

Name types of anxiety disorders and subtypes and lifetime prevalence of GAD

• Specific phobia - Marked fear or anxiety about something specific 6/12

  • Agoraphobia - Marked fear or anxiety about situations where escape is difficult

    • Leads to avoidance of situations like being alone in or outside home

• Social anxiety disorder - Persistent fear about 1 or more social situations 6/12

  • Selective mutism - consistent failure to speak in social situations when there is expectation to do so

• GAD - Excess worry about number of events or activities and difficulties controlling this 6/12

• Panic disorder - Recurrent unforeseen panic attacks

  • Repeated unpredictable attacks of severe anxiety occurring without warning unrelated to specificity

  • Can be combined with GAD

• Separation anxiety disorder - Excessive fear or anxiety focussed on separation from home or figures 1/12 children, 6/12 adult

• 5% lifetime incidence

Why is differentiation between disorders difficult?

• Can be a co-morbidity with other anxiety disorders or depression and other affective disorders

• Like depression, NICE adopts stepped care model

What is step 1 of the stepped care model?

• All known and suspected presentation of GAD, identification and assessment

  • Education about GAD

  • Treatment options

  • Active monitoring

What is step 2?

• Diagnosed GAD that has not improved after education and active monitoring in primary care

  • Individual non-facilitated self help

  • Individual guided self help

  • Psychoeducational groups

What is step 3?

• GAD with inadequate response to step 2 interventions or marked function impairment

  • Choice of high intensity psychological intervention

  • Drug treatment

What is step 4?

• Complex treatment refractory GAD and very marked functional impairment such as self neglect or high risk of self harm

  • Highly specialist treatment

  • Crisis services

  • Day hospitals

  • Inpatient care

What 3 groups of adults are likely to be affected by GAD?

1. Aged between 35-54

2. Divorced or separated

3. Living alone or as lone parent

Anxiety risk factors: Poor Cuban Families Find Young Children Personally Stressful

• Family history

• Childhood adversity

• Stressful life events

• Personality traits like excessive worrying

• Certain parenting styles

  • Over protectiveness

  • Lack emotional warmth

• Younger age

• Female, unmarried or unemployed

• Poor physical or mental health

What are 6 presenting symptoms? PPI Claims Are Annoying

1. Apprehension

2. Cued or spontaneous panic attacks

3. Irritability

4. Poor sleep

5. Poor concentration

6. Avoidance

What is Agoraphobia?

• Anxiety about being in places or situations from which escape may be difficult or embarrassing, or where help may not be available in the event of a panic attack.

• This type of anxiety usually leads to a pervasive avoidance of a verity of situations

  • Being alone outside the home

  • Being home alone

  • Being in a crowd full of people

  • Travelling by car, bus or plane

  • Being on a bridge or in a lift.

What is Panic disorder?

• Repeated unpredictable attacks of severe anxiety occurring without warning, unrelated to a specific situation

• Can peak within 10 minutes with many somatic or physical symptoms

• Can be combined with GAD or phobic disorders

What is GAD?

• A persistent, excessive anxiety, apprehension or worry present for at least 6 months

• Chronic condition with acute episodes

• Often begins in early adulthood

• Twice as common in women than men

Explain Phobic disorders

• Irrational fear out of all proportion to situation or object

• Recognised as excessive but cannot be reasoned away

• Sub-divided into agoraphobia, social phobia

What is OCD?

• Obsessive compulsive disorder

• Time consuming obsession and compulsion

• Males and females equally effected

• Prevalence = 2%

What is PTSD?

• Intense and prolonged, can be delayed response to specific traumas

• Characterised by emotional numbness, flashbacks, recurring memories and vivid dreams

Symptoms in anxiety

• Symptoms in anxiety

  • Dry mouth

  • Hyperventilation

  • Palpitations

  • Difficulty breathing

  • Thoughts of worry

  • Fatigue

  • Dizziness

  • Sweating

  • Sleep disturbances

  • GI discomfort

Anxiety relationship with stress

• Anxiety naturally exists as means of overcoming or responding to stress

• An optimal level of anxiety allows us to perform at high level

• In disorders, anxiety remains after stress has ceased

2 brain systems involved in fear and anxiety

1. Defence system: responds to both learned and unlearned threats, initiates fear, fight, flight, freeze behaviour

2. Behavioural inhibition system: Responsible for avoidance behaviour, a neurobehavioral system thought to regulate negative affect and avoidance behaviour in response to threats or punishment

Neuro aspects of anxiety

• Techniques such as PET-scanning have demonstrated altered neuronal pathways especially in limbic regions

  • E.g. increased activity in the amygdala (fear response)

  • Hippocampus (memory regulation including stressful memories)

• Note also that there is a dense concentration of serotonergic and noradrenergic synapses and systems within limbic regions.

What happens in the brain with patients with GAD?

Exhibit increased metabolic rates in occipital, temporal and frontal lobes as well as cerebellum and thalamus compared with healthy individuals

What is the general management of anxiety disorders?

• Shared decision making between patient and HCP helps promote concordance and optimises outcomes

• Appropriate and usable information should be given to patients, carers and family - including med info

• Patients family should be informed of all appropriate self-help

What are 3 treatment options?

1. Self help

2. Psychological therapy

3. Pharmacological therapy

What is the pharmacological treatment?

• SSRI

• Consider giving sertraline first as cost effective

• Informed consent must be obtained and documented

• Monitor closely for adverse reactions

What is Sertraline licensed and indicated for the treatment of?

1. MDD

2. Panic disorder

3. OCD in adults

4. Social anxiety

5. PTSD

What if Sertraline is ineffective?

• Offer alternative SSRI/ SNRI

  • Can produce withdrawal syndrome e.g. venlafaxine

  • SE profile and potential for drug interactions

  • Increases risk of suicide and likelihood of toxicity in overdose e.g. venlafaxine

  • Persons prior experience of treatment with individual drugs

What pharmacological treatment options are there?

1. BDZ

2. SSRIs

3. Pregabalin

4. Antipsychotics

5. Beta-blockers

6. Antihistamines

How do BDZ work and how they are used responsibly ?

• Act on GABA-A receptors

• Short term relief (2-4 weeks) for anxiety that is severe, disabling or causing extreme distress NOT PRIMARY CARE

• Used as immediate care for patients awaiting other treatments

How do SSRIs work?

• Inhibits reuptake of serotonin at post-synaptic membrane

• Increases central serotonergic activity

• Onset of action may not appear for 6 weeks and full response from drug may take 12 weeks

How do ADs work in anxiety?

• Serotonin facilitates defensive responses to potential threat which is related to presentation of anxiety - basal forebrain (amygdala)

• Desensitises 5-HT2c receptors and increased stim of 5-HT1a receptors resulting in less activation of amygdala, medial PFC and insula

Other treatments for anxiety

1. Beta blockers - only to treat somatic or physical symptoms

2. Buspirone - complex MOA (partial 5HT 1A agonist, acts on both Noradrenergic and Dopaminergic pathways)

   1. takes time to work (1/12 minimum)

   2. better than placebo, worse than BDZ in terms of efficacy and tolerability (drug interactions with CYP450 3A4 inducers + inhibitors)

3. Sedating antihistamines - e.g. high dose hydroxyzine (not recommended)

4. Antipsychotics - specifically used in PTSD and occasionally OCD

   1. E.g. olanzapine, risperidone, quetiapine (not used routinely in GAD)

5. Social anxiety disorder and PTSD - valproate and carbamazepine (rarely used)

How does Pregabalin work?

• Binds to a2-∂2 protein of v-g Ca channels in CNS, causing conformational changes and reducing excitatory transmission

• Rapid onset of action

• Reduced dose in renal impairment

• Use when SSRI/SNRIs aren’t tolerated

• Monitor for misuse

How to diagnose Serotonin syndrome

What is Schizophrenia

• Signs and symptoms can include disorders of perception(hallucinatation), inferential thinking(Deluluuu), goal-directed behaviour and emotional expression

• No single symptoms or signs can be considered as specifically characteristic or indicative of schizo

• All pts. experience different symptoms

• Chronic illness that may progress through several phases

Aetiology of Schizophrenia

• Alteration in brain structure

  • Enlarged cerebral ventricles

  • Cortical thinning

  • Decreases size of anterior Hippocampus

• Changes in neurochemistry - change in neurotransmitter activity

• Recently demonstrated genetic risk factors

Explain neurodevelopmental vulnerability and its relation to schizophrenia

• Schizophrenia occurs more often in patients with changes/ difficulties in their cognitive/ memory/ social/ focus skills and the combination of these with environmental stressors can cause schizophrenia.

What childhood factors can influence disease onset in adulthood?

• Genetic predisposition

• Intrauterine, birth or postnatal complications

• Viral CNS infections

• Childhood trauma and neglect

Genetic predisposition (chances)

• First degree relative with schizo have 10-12% risk of developing schizo

• Monozygotic twins = ~45%

Environmental Stressors

• Can trigger emergence or recurrence of psychotic symptoms in vulnerable people

• May be mainly pharmacologic

• Can be social

• Environmental events can initiate epigenetic change that could influence gene transcription and disease onset

Types of protective factors

• Strong psychosocial support

• Well-developed coping skills

• Antipsychotic medication

When do patients display psychotic symptoms

• 8-15 months before presentation in medical care

  • Can be recognised earlier now

What do symptoms of schiz impair

• Ability to perform complex and difficult cognitive and motor functions.

  • This means they usually interfere with work, social relationships and self-care

• Common outcomes can include:

  • Unemployment

  • Isolation

  • Deteriorated relationships

  • Diminished quality of life

5 Phases of Schizophrenia

1. Prodromal phase

2. Advanced prodromal phase

3. Early psychosis

4. Middle phase

5. Late illness phase

Prodromal Phase

• Individuals may show no symptoms or may have

  • Impaired social competence

  • Mild cognitive disorganisation

  • Perceptual distortion

  • Anhedonia

  • Other general coping difficulties

Advanced prodromal phase

• Subclinical symptoms may emerge

  • Withdrawal or isolation

  • Irritability

  • Suspiciousness

  • Unusual thoughts

  • Perceptual distortions

  • Disorganisation

• Onset can be sudden or very slow

• Here <40% pts. convert to full schizo

Early psychosis

Symptoms are usually active and at their worst

Middle phase

• Symptomatic periods may be episodic

• Can also be continuous where functional deficits tend to worsen

Late Illness Phase

• Illness pattern becomes more established but there is considerable variability

• Disability may stabilise, worsen or diminish

Symptom categories in schizophrenia

• Positive: Hallucinations and delusions

• Negative: Diminution or loss of normal function and affect

• Disorganised: Thought disorder and bizarre behaviour

• Cognitive: Deficit in memory, info processing and problem solving

Positive Symptoms of schizophrenia

• Delusions: Erroneous beliefs that are maintained despite clear contradictory evidence

  • Persecutory: Tormented or followed, tricked or being spied on

  • Delusions of reference: patients believe that passages from books, on-line posts, TV, radio, newspapers, song lyrics or other environmental cues are directed at them

  • Delusions of thought withdrawal or thought insertion: patients believe that others can read their mind, that their thoughts are transmitted to others

• Hallucinations

  • Sensory perceptions that are not perceived by anyone else

  • Auditory, visual, olfactory, gustatory or tactile

  • Auditory hallucinations are most common

Negative symptoms of schizophrenia

• Blunted affect: patients face appears immobile, poor eye contact and lack of expressiveness

• Poverty of speech: patient speaks little and gives terse replies to questions, creating impression of inner emptiness

• Anhedonia: Lack of interest in activities and increased purposeless activity

• Asociality: lack of interest in relationships

Disorganised symptoms

• Thinking is disorganised with rambling, non-goal directed speech that shifts from one topic to another

• Speech can be incoherent and incomprehensible

• Bizarre behaviour may include childlike silliness, agitation and inappropriate appearance, hygiene or conduct

• Catatonia

Cognitive Symptoms

• Attention

• Processing speed

• Working and declarative memory

• Abstract thinking

• Problem solving

• Understanding of social interactions

Subtypes of schizo

• Classified into

  • Deficit

  • Non-deficit

• Based on presence and severity of negative symptoms such as:

  • Blunted affect

  • Lack of motivation

  • Diminished sense of purpose

Deficit of schizo

• Negative symptoms unaccounted for by other factors e.g

  • Depression

  • Anxiety

  • Under-stimulating environment

  • Drug adverse effects

Non-deficit of schizo

• May have delusions, hallucinations and thought disorders

• Relatively free of negative symptoms

How is schizo diagnosed

• Clinical criteria (ICD-11, DSM-5)

• Earlier diagnosis = better outcome

• No definitive test for schizophrenia

  • Combination of history, symptoms and signs

  • Info collected from close sources

During what time period and under what conditions for diagnoosis

• For 1 month, one of the below:

  • Positive symptoms (hallucinations, delusions, thought disorders)

  • Negative symptoms (reduced self-care, motivation, anhedonia, alogia, affective blunting)

  • Reduced social functioning

• There should be an absence of mood disorder ~mania/depression

Clinical aspects of schizophrenia in terms of prognosis

• For first year after diagnosis, Prognosis is closely related to adherence to prescribed psychoactive drugs and avoiding recreational drug use

• 15% of all patients fully return to pre-illness level of functioning

• 1/3 of patients achieve significant improvement

• 1/3 improve somewhat but have relapses and residual disability

• 1/3 severely incapacitated

Factors associated with GOOD and BAD prognosis:

GOOD	BAD
Good premorbid functioning	Young age at onset
Late and/or sudden onset of illness	Poor premorbid functioning
Family history of mood disorders other than schizophrenia	Family history of schizophrenia
Minimal cognitive impairment	Many negative symptoms
Few negative symptoms	Longer duration of untreated psychosis
Short duration of untreated psychosis

Age and Sex

• Women respond better to treatment with antipsychotic drugs

• Peak incidence of onset in

  • Males = 15-25yrs

  • Females = 25-35yrs

How do we manage schiz?

• Address psychological, social and emotional components for best prognosis

• Pharmacological treatment is 1st line in ALL CASES