Mood Stabilisers in Treatment of Bipolar Disorders

Types of Mood Stabilisers

1. Lithium

2. Sodium valproate

3. Carbamazepine

4. Lamotrigine

Lithium

Mechanism of action – unknown
     (possibly increase 5-HT function in the brain)

Pharmacokinetics

- onset: 5-7 days
- absorbed and excreted by kidney

- narrow therapeutic index (TI)

Caution!

1. conditions which raise lithium concentration

   - dehydration

   - sodium depletion, diarrhoea

   - thiazide therapy
2. conditions which is absolute/relatively contraindicated

   - CVS disease

   - acute infection

   - fever

   - pregnancy (teratogenicity)

Dosage

Acute mania: 0.8-1.5mmol/L

Prophylaxis/maintenance: 0.5-1.0mmol/L (or 1.2mmol/L)

Side Effects

Early
1. polyuria – dehydration (and risk of intoxication)

2. fine tremor (rx propranolol)

3. dry mouth

4. metallic taste

5. weakness and fatigue

Late

6. fine tremor

7. polydipsia (compensatory from polyuria)

8. hair loss

9. thyroid enlargement

10. hypothyroidism, cold intolerance

11. impaired concentration

12. weight gain

13. GI distress

14. sedation

15. acne

16. impaired memory

17. ECG changes (flattened T wave, widening of QRS)

Long Term

18. kidney failure – impaired concentrating ability

19. nephrogenic diabetes insipidus (interferes with ADH)

20. teratogenic (crosses placenta) – Ebsein’s anormaly

Toxicity Effect (>1.5mmol/L)

1. nausea, vomiting

2. diarrhea

3. coarse tremor

4. ataxia, dysarthria

5. muscle twitching, hyperreflexia

6. confusion, coma

7. convulsion

8. renal failure

9. cardiovascular collapse

Emergency Treatment of Lithium Toxicity

1. stop lithium immediately

2. high fluid intake

3. IV normal saline or hyperosmotic saline to stimulate osmotic diuresis

4. renal dialysis if necessary

Monitoring of Lithium Administration

1. baseline physical and laboratory assessment

2. hx and pe on CNS, GIT, metabolic, thyroid, renal

3. pregnancy test

4. ECG in patients >40yo

5. RP for BUN, serum creatinine, electrolyte, biannually

6. TFT – TSH biannually
7. serum lithium level measured after 4-7 days of administration

8. repeat weekly for x3/52

9. then repeat once every x3/12
10. repeat serum lithium when inefficacy or adverse effect

* timing of measurement must be 12 hours after last dose (at steady state level)

Drug Interactions

1. Increases lithium concentration in:

   - haloperidol

   - thiazide diuretics

   - muscle relaxants

   - antibiotics (metronidazole, spectinomycin)

   - anti-HT (ACEi, methyldopa)

2. Interactions with antipsychotics

   - potentiates extrapyramidal side effects

   - confusion, delirium

3. Interactions with SSRI or ECT

   - serotonin syndrome

Withdrawal Symptoms

1. irritability

2. emotional lability

3. relapse to mania

Indications

1. acute mania, classic features (rapid cycling ↓ efficacy)

2. bipolar maintenance

3. other mood disorder use

Sodium valproate

Mechanism of Action – increase GABA in CNS

Pharmacokinetics

- onset: 2-5 days

- metabolized in liver, excreted in kidney

Dosage

Starting: 250-500mg titrated upward by 250-500mg/day

Maintenance: 750-1250mg/day

Side Effects

1. sedation

2. tiredness, fatigue

3. tremor

4. GI disturbance

5. reversible hair loss (alopecia)

6. thrombocytopenia

7. weight gain

8. haemorrhagic pancreatitis

9. hepatotoxicity

10. teratogenic – neural tube defect
* monitor FBC and LFT for baseline and changes

Drug Interactions

1. Displacement of protein-bound drugs (antiepileptics)

   - increases plasma level

2. Inhibits metabolism of lamotrigine (give only 50% dose if combined treatment)

Indications

1. bipolar disorder, manic episode, rapid cycling

Lamotrigine

- effective in bipolar depression without inducing mania

- prevents depressive relapse in bipolar

Mechanism of Action – blocks sodium channel

Pharmacokinetics

- metabolized in liver, excreted in urine (65%), faeces (2%)

Dosage

Initial: 25mg/day for 2 weeks
Later: 50mg/day for next 2 weeks
Maximum dose: 100-300mg/day

Side Effects

1. skin reactions – rashes, SJ S, toxic epidermal necrolysis

2. nausea

3. headache, aseptic meningitis

4. tremor

5. dizziness

6. teratogenic (cleft palate)

Drug Interactions

1. Increases lamotrigine concentration in:

   - valproate

2. Combined lamotrigine-carbamazepine – Neurotoxicity

Carbamazepine

- fastest onset mood stabilizer (? citation needed)

- prevent recurrence of affective depression

- patients unresponsive to lithium

- rapidly recurring bipolar disorder

Mechanism of Action - blocks Na channels, inhibits AP

Pharmacokinetics

- onset: 5-7 days

- metabolized in liver

- excreted in urine (72%) and faeces (28%)

Dosage

Starting: 400mg/day, increased up to 800-1000mg/day

Side Effects

1. drowsiness

2. dizziness

3. nausea

4. diplopia (double vision)

5. skin rash

6. agranulocytosis, leukopenia, aplastic anaemia

7. hyponatraemia
8. elevated liver enzymes
9. teratogenic – neural tube defect

* monitor FBC, LFT for baseline and subsequent changes

Drug Interactions

1. increased metabolism of some drugs and OCP

Indications

1. bipolar disorder, mixed episode, rapid cycling

2. trigeminal neuralgia

The ABCs of Rapid Sequence Induction

Rapid Sequence Induction

Definition: a technique to safely secure the airway with an endotracheal tube. Used in patients who are at risk of regurgitation and aspiration of gastric contents on induction of anaesthesia.

Regurgitation: passive movement of gastric contents into the pharynx. This is normally prevented by the upper and lower oesophageal sphincters.

The lower oesophageal sphincter is formed by the lowest 2-4 cm of the oesophagus. The major component of the upper oesophageal sphincter is the cricopharyngeus muscle.
Protective laryngeal reflexes are also lost during GA.

Aspiration: regurgitation occurs and gastric contents then enter the trachea and lungs.

Indications 1. Full stomach or conditions considered as full stomach     eg: stress, delayed gastric emptying,       emergency cases 2. Obese 3. Pregnant 4. History of hiatal hernia 5. Intestinal obstruction

Checklist 1. Anaesthetic machine and breathing circuit 2. Routine patient monitoring applied 3. Airway equipment 4. Tipping trolley 5. Suction switched on and immediately to hand 6. Drugs – including emergency drugs 7. A trained assistant

Technique

1.     Preparation and echking of equipment, tilting trolley and suction

2.     Pre-oxygenation – delayed onset of muscle relaxant, avoid face mask ventilation

3.     Administration of intravenous pre-calculated dose of induction agent

4.     Administration of suxamethonium – depolarizing muscle relaxant onset faster 30s compared to non-depolarising muscle relaxant onset 2-3 minutes*

5.     Cricoid pressure (Sellick’s manoeuevre) – cricoid cartilage at level C6

6.     Intubate and confirm ETT placement

7.     Remove cricoid pressure

* bag mask technique during 2-3 minute period may insufflate the stomach and increase intra-gastric pressure and regurgitation

Pre-oxygenation

- high flow oxygen for 3 minutes of tidal breathing or four vital capacity breaths, target 85% O₂

- tight fitting face mask, ensure no leakage

Cricoid pressure

The cricoid cartilage is the only complete ring of cartilage in the larynx. Pressure on the cricoid cartilage compresses the oesophagus against the cervical vertebrae, thus preventing the passage of gastric and oesophageal contents, should passive regurgitation occur.

Light cricoid pressure (10 Newtons [N]) is applied before intravenous induction. The force is increased (30 N) after loss of consciousness. It is the responsibility of the anaesthetist to ensure that cricoid pressure has been applied. The direction of the force is posterior. A force of 30 N is approximately equal to a 3 kg weight.

Two-finger technique – the index finger and thumb are placed on each side of the cricoid arch, with force applied by both.

Three-finger technique – the thumb and middle finger are placed on each side of the cricoid arch with force applied by the index finger in the midline.

A two-handed technique is used if a cervical spine fracture is suspected. The second hand is placed behind the neck to prevent posterior displacement of the spine on applying cricoid pressure. Manual in-line stabilization of the neck must also be used.

Muscle relaxant (Suxamethonium)

- Fast onset of action providing paralysis in approximately 30-45 s

- Short duration of action of 5-8 min

- dosage: 1.5mg/kg

- post-administration, face mask remained applied with airway held open until fasciculations ceased and jaw relaxed.

Contraindications to Suxamethonium

1. anaphylaxis

2. malignant hyperthermia

3. major burns

Gastric Aspiration

Tilt the trolley head down, suction the oropharynx, intubate immediately and inflate the cuff. Pass a suction catheter down the endotracheal tube (ETT) to clear any aspirate before starting ventilation with 100 % oxygen (to prevent contamination of the distal airways).

A higher FiO2, Positive End-Expiratory Pressure (PEEP) or bronchodilators may be needed to maintain oxygenation.

If significant pulmonary aspiration has occurred the patient should be transferred to a high dependency area post-operatively.

Mendelson Syndrome

syndrome of pneumonitis following aspiration of gastric contents was originally described by Mendelson in obstetric patients. Features include hypoxia, bronchospasm and pulmonary oedema. Treatment is mainly supportive including oxygen, bronchodilators, physiotherapy and assisted ventilation if required.

sourced from: RCoA and AAGBI 

Lychee Seeds - A Potential Anti-diabetic Agent?

Awhile ago I came across a news feed on a seller of lychee seeds claiming that the seeds could cure diabetes. Out of curiosity thinking that it could be another scam, I decided to do some research on it.

D.O. Gray (1962) analysed lychee seeds and found a toxin known as methylenecycloproprylglycine in lychee seeds. This compound caused significant blood glucose level reduction in lab rats. Thus it may possess hypoglycaemic properties.

Zhang He, Teng Yin (1986) experimented on lychee antidiabetic pill between 1982 to 1983 on 45 patients with DM. The experiment showed that lychee is effective against improving hyperglycaemic symptoms and could be potentially used as an anti-diabetic agent.

Guo. et al (2004) investigated the mechanisms of lychee water extract on antagonising insulin resistance in rats with type 2 DM. They concluded that lychee water extract is effective in antagonising insulin resistance and improve kidney and liver function in rats.

Throughout the years India has constantly being reported to have outbreaks of hypoglycaemic encephalopathy. In 2013, the CDC has linked the hypoglycaemic outbreaks to lychee consumption.

As there are still limited studies to prove the efficacy of lychee as an antidiabetic agent, it is inconclusive to determine its effectiveness in treating of diabetes mellitus. More studies on lychee could be done to strengthen the findings. However, lychee has demonstrated huge potential in controlling blood sugar level, or at least, caused many children who works in lychee orchards in India to suffer from hypoglycaemic encephalopathy. Lychee could be one of the key to advancement of diabetic treatment.

Principles of Management of ADHD

Principles of Management of ADHD include psychotherapy and pharmacological threatment.

Behavioural Therapy

Behavioural Therapy is the only psychotherapy intervention viable for management of ADHD patients. They serve to alter the social and physical environment to modify ADHD patient’s behaviour. Models of behavioural therapy include:

A. Parent Behaviour Training

Parents are trained to implement specific techniques based on behavioural principles when interacting with child. Parent training sessions are given weekly and usually include homework sessions to give parents the opportunity to learn reward systems and strategies for providing consequences to shape behaviour.

Topics for learning include:

1. Overview of ADHD, social learning theory and behaviour management principles.

2. Establish daily report cards and checklist for rewarding bahaviour

3. Attend to appropriate behaviour and ignoring minor, inappropriate behaviour

4. Effective reprimands and commands

5. Establish and enforcing rules

6. Time-out procedures

7. Incorporating reward and response cost with home point system

8. Enforcing contingencies and planning ahead for misbehaviour outside home setting

9. Problem-solving techniques

10. Generalisation and maintenance of program post-therapy

B. Psychosocial Therapy

Psychosocial Therapy allows trained therapist to speak with child and family members about handling behviours and emotions to improve social skills.

C. School-based Programs

Special education services are offered in school settings to create and individualized education program (IEP) to increase school success

Pharmacological Modality in Treatment of ADHD

Stimulants and non-stimulants can be given and has shown success in reducing the symptoms of ADHD.

Alternative treatments such as nutrition and exercises could improve ADHD conditions, however there has been lacking of evidence to suggest a direct benefit (Larzelere et al 2010)

Stimulants

Methylphenidate Formulations – Concert, Quillivant XR

Methylphenidate HCl blocks reuptake of norepinephrine and dopamine in presynaptic neuron to increase their availability into extraneuronal space. It is available in IR, SR, LA, XR, OROS and MTS form.

The common side effects include insomnia, decreased appetite, weight loss, depression, anxiety, increased blood pressure and pulse rate, skin irritation

Extended release liquid formulation has been approved by FDA. Liquid XR could avoid the medication compliance challenges of solid form. The onset of treatment is 45 minutes and duration of action is 12 hours. It is also safe and well tolerable and adverse effects were consistent with known effects of methylphenidate.

Amphetamine Formulations – Dextroamphetamine sulphate, Vyvanse (prodrug)

LDX (Vyvanse) is a prodrug stimulant approved for management of ADHD symptoms. LDX is hydrolysed by endogenous enzymes into L-lysine and D-amphetamine. Swanson et al noted LDX was effective in reducing ADHD symptoms compared to placebo.

Efficacy was demonstrated between 2-12 hours post-dose. It is also well tolerable and safe for usage.

Common side effects include insomnia, decreased appetite, weight loss, depression, anxiety, increased blood pressure and pulse rate. It is also known to inhibit MAO and CYP2D6. Drug elimination is influenced by urinary pH and flow rates.

Non-Stimulants

Selective Norepinephrine Reuptake Inhibitor – Atomoxetine (Strattera)

Atomoxetine could increase concentration of NE and dopamine by acting on presynaptic norepinephrine  transporter in prefrontal cortex

Common side effects include GI upset, nausea, sedation, insomnia, agitation. CYP2D6 inhibitors may increase atomoxetine SS concentrations.

Α2-Adrenergic Agonist - Clonidine (Kapvay), Guanfancine

Clonidine and Guanfacine are also non-stimulant treatments of ADHD. The extended release forms are approved by FDA for ADHD.

Side effects are low blood pressure (hypotension), low heart rate (bradycardia), constipation, dry mouth, increased appetitie, hypersomnolence, sedation. Guanfancine is less sedating than clonidine as it is thought that the side effect of guanfancine diminishes over time (Faraone et al 2010). Care should be taken for guanfacine not to be taken with fatty meals as it may cause increase in exposure.

If withdrawal is indicated, gradual dose reductions are recommended to reduce withdrawal symptoms such as rebound hypertension and lightheadedness.

Monitoring Side Effects of Treatment

1. Inquiry by open-ended questions, spontaneous patient reporting. Structured interview is also possible but there are weakness in terms of biasness.

2. Commonly observed side effects include appetite suppression, headache, insomnia, irritability, abdominal pain

3. ECG prior to treatment initiation + regular blood pressure and auscultation examintion as there are risk of sudden cardiac death secondary to cardiac abnormalities and cardiovascular effects of drugs. Thorough family history of cardiac events should also be taken.

4. Consider drug holidays or dose alteration if there are significant side effects.

Assessment of Neurocognitive Domains

There are 6 Neurocognitive Domains:
Acronym: MAPLES
1. Learning and Memory
2. Complex Attention
5. Perceptual Motor
4. Language
2. Executive Function
6. Social Cognition

Learning and Memory Domain
Immediate Memory Span is the ability to repeat a list of words or digits. It is also sometimes subsumed under working memory in executive function. Usually tested in mini mental state examination by listing 3 mutually exclusive items and asking patients to recall them.

Recent Memory assesses the process of encoding new information. Various subsets of recent memory include:
- Free Recall as the ability to recall as many words, diagrams or elements in a story as possible
- Cued Recall as the ability to recall with semantic cues
- Recognition Memory as even more obvious cues such as "did you see this picture"
- Semantic Memory as the memory for facts
- Autobiographical Memory as the memory for personal events or people
- Implicit Learning as the procedural and unconscious learning of skills

Complex Attention Domain
Sustained Attention is the maintenance of attention over time

Selective Attention is the maintenance of attention despite competing stimuli or distractors

Divided Attention is the ability to attend to 2 tasks within the same period


Perceptual Motor Domain
Visual Perception tests line bisection tasks to detect visual defect or attentionl neglect

Visuoconstructional assessment assesses the assembly of items under hand-eye coordination

Perceptual Motor integrates perception with purposeful movement

Praxis is the integrity of learned movements

Gnosis is the perceptual integrity of awareness and recognition

Language Domain
Expressive language consists of confrontational naming (identification), fluency and phonemic

Grammar and Syntax is assessed by comparing the frequency of errors and normal slips of the tongue

Receptive language consists of comprehension, performance of actions according to verbal command

Executive Function Domain
Planning is the ability to find a solution or interpret something

Decision Making as the performance of tasks that assesses the process of deciding in the face of competing alternatives

Working Memory is the ability to hold information for brief period and to manipulate it

Feedback and Error Utilisation is the abilithy to benefit from feedback to infer rules for solving a problem

Overriding Habits/Inhibition is the ability to choose a more complex and effortful solution to be correct

Mental and Cognitive Flexibility is the ability to shift between 2 concepts, tasks or response rules

Social Cognition
Emotional Recognition is the identification of emotion in images of faces representing a variety of both positive and negative emotions

Theory of Mind is the ability to consider another person's mental state (such as thoughts, desires and intentions) or experience

National Suicide Prevention Strategic Action Plan for Malaysia

National Suicide Prevention Strategic Action Plan - A 5 Year Preventive Plan for Malaysia

Strategies proposed:
1. Establish Technical Working Group (TWG)
2. Promote awareness on suicide through schools, health institutions and media with the emphasis on recognition of risk of suicidal behaviour
3. Enhance accurate collection and monitoring of data on intentional self harm (non-fatal and fatal) at hospital level
4. Strengthen reporting system on fatal intentional self harm
5. Promote human resources development and training
6. Establish and strengthen counselling services at all level of healthcare facilities, schools (pre and post exam counselling) and other government and non-government agencies
7. Enhance and utilise existing outreach programs for suicide prevention
8. Promote responsible reporting by the media
9. Reduce access to pesticides by risk-risk individuals
10. Reduce the availability of lethal amounts of prescription and non-prescription drugs.

Management Approaches to Generalised Anxiety Disorder

Generalised Anxiety Disorder (GAD) is a chronic and highly comorbid illness characterised by excessive and uncontrollable worry. There is a low probability of recovery (32% - 58%) and high recurrence (45% - 52%). Its severity and pervasiveness warrants effective treatment measures to be planned.

Treatment of GAD is split into 2 broad categories:
A) Psychotherapy
B) Pharmacotherapy

Psychotherapy Approach to GAD
1. Traditional Cognitive Behavioural Therapy (CBT)
2. Integrative Therapy
3. Psychodynamic Psychotherapy - Supportive Expressive Therapy (SET)

Cognitive Behavioural Therapy as The Best Modality for Treating GAD
CBT has currently being established as the best psychotherapy treatment for GAD. In the CBT framework, change in behaviour is promoted through: (Newman et al 2006)
i. identification of early anxiety triggers
ii. challenging and disrupting individual misconceptions and worries
iii. testing the validity of his erroneous beliefs
iv. reducing avoidance behaviours
v. improving skills for management of worry and anxiety
vi. developing adaptive ways of response to neutral and ambiguous situations

Initiation: psychoeducation on symptoms and treatment goals, engagement in self-monitoring and identification of maladaptive patterns, maintain present focus and develop cognitive, imagery, relaxation and behavioural intervention. Pt is given homework in between sessions.

Cognitive Restructuring: learning of association between thoughts and emotions, identifying cognitive errors and replacing with more accurate thoughts

Relaxation Technique: relaxation of muscles and breathing exercises

Self-Control Desensitisation: imagine encountering worry trigger then focus or relaxing away the stress response

CBT has significantly reduced anxiety symptoms posttreatment, with gains maintained for up to 2 years. (Borkovec and Ruscio 2001)

Integrative Therapy as Modification to CBT
Rationality: interpersonal and emotional processing deficits are noted in GAD patients. Pt may use worry not to avoid emotion but rather to brace themselves for a potential negative outcome.

Integrated treatment protocol incorporates CBT, interpersonal and emotional-based interventions to identify dysfunctional relationship patterns and enhancing emotional processing.

Acceptance and Commitment Therapy (ACT) helps to reduce reliance on emotional avoidance strategies as well as decrease individuals negative interpretation of thoughts, increase ability to enact behavioural changes that conforms to their values and to focus on here and now.

Supportive Expressive Therapy (SET) as Short Term Psychodynamic Psychotherapy
Delineation of core conflictual relatonship theme (CCRT) which comprises of:
1. wishes and needs of pt
2. response of others
3. subsequent response of pt

SET helps pt to identify CCRT across the areas of lives and understand its relation to the anxiety they are facing. Pt is able to learn improved ways of coping with feelings, expressing needs, and responding to others.

Treatment significantly reduced participants anxiety, worry andi nterpersonal problems (Crits Christopher et al 1996), but however 6-month follow up favoured CBT over SET, and CBT was superior to set on many measures. (Leichsenring et al 2009)

Pharmacotherapy Approach to GAD
1. Benzodiazepines
2. SSRI and SNRI
3. Pregabalin

Benzodiazepines as Short Term Control Measures
Alprazolam, diazepam and lorazepam are shown to be rapidly effective in short-term use. Thus they are most effective in treatment of acute anxiety symptoms.

Long term usage is controversial because of the adverse effects:
i. tolerance and dependence
ii. withdrawal
iii. sedative effect
iv. motor and cognitive impairment

SSRI and SNRI as First Line Pharmacological Treatment
SSRIs and SNRIs were efficacious in treatment of GAD.

Fluoxetine is best in terms of response and remission, while
Sertraline is best in terms of tolerability

TCA class imipramine in earlier studies (Rickels et al 1982) are also demonstrated to be effective in treating GAD but TCA prominent side effects and narrow therapeutic index has made it as second line treatment.

However while taking SSRIs, patient may experience side effects such as:
i. nervousness
ii. sexual dysfunction
iii. weight gain
iv. drowsiness
v. sleep disturbances

Conclusion
CBT and pharmacotherapy showed no significant differences in effectiveness for anxiety reduction, however CBT is better tolerated and more cost-saving than pharmacotherapy, making CBT the best modality for treatment.

In Child Adolescent Anxiety Multimodal Study, combination treatment of CBT plus sertraline had significant high rates of remission than other conditions, thus combination therapy may seem provide better outcomes for child and adolescent patients, and could be extrapolated to adults. There has not been any trials of combintion treatment in adults yet.