Effective approach in treatment of anxiety and depressionThe road to recovery

Mechanism of anxiety

• Overactivation of brain neurotransmission and neuronal firing (glutamate/calcium influx)• Underinhibition of brain neurotransmission and neuronal firing (GABA)• Both

• Generalized anxiety disorder • Obsessive-compulsive disorder • Panic disorder • Post-traumatic stress disorder • Social phobia (or social anxiety disorder)

Anxiety disorders - Types

Definition

• Depression is a common mental (mood) disorder, characterized by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration.

Epidemiology • Chances of developing a depressive illness are estimated to be 1 in 5 for women and 1 in 10 for men • The WHO estimated that within 20 years, recurrent depressive disorder will be the second most serious cause of morbidity and burden of disease in the world.• Depression affects approximately 350 million people worldwide; constituting a major portion of mental health disorders.• According to the World Mental Health Survey, approximately 6% people aged 18 years and above have had an episode of depression in the previous year.• Lifetime prevalence rates of depression range from 8 to 12% in most countries

Symptoms of depression Persistently sad, anxious, or "empty" mood. Feelings of hopelessness. Feelings of guilt, worthlessness, helplessness. Loss of interest (anhedonia) or pleasure in hobbies and activities that were once enjoyed. Insomnia, early-morning awakening, or oversleeping.

Symptoms of depression Decreased appetite and/or weight loss, or overeating & weight gain. Fatigue, decreased energy, being "slowed down." Thoughts of death or suicide, suicide attempts. Restlessness, irritability. Difficulty concentrating, remembering, making decisions. Persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain.

Mechanism of depression

The monoamine hypothesis states that depression is caused by a deficiency of monoamines, particularly noradrenaline and serotonin. (NA & 5-HT)

Positive and negatives of anti-anxiety drug options

SSRI- AS DRUG OF CHOICE • It is considered as first choice for depression, anxiety and co-morbid depression associated with anxiety.• Block presynaptic serotinin reuptake(5-HT), which increases serotinin levels in the synapse• SSRIs have little effect on the NE or dopamine transporters and a low affinity for the histaminic, muscarinic/cholinergic, and alpha receptors.• Hence adverse effects are less as compared to TCAs.

SSRI • Fluoxetine• Fluvoxamine• Paroxetine• Sertaline• Citalopram• Escitalopram

PAROXETINE

Paroxetine is US FDA approved

SSRI

No dependence or addiction

potential

Lowers intraplatelet serotonin

levels

Inhibits platelet plug formation

Does not activate coagulation

Paroxetine normalizes heart rate

variability

Paroxetine

Paroxetine blocks the uptake of serotonin, thus increasing serotonin concentration at synaptic cleft

Indication

• Major Depressive Episodes

• Obsessive Compulsive Disorder

• Panic Disorder with and without agoraphobia

• Social Anxiety Disorder/Social phobia

• Generalised Anxiety Disorder

• Post-traumatic Stress Disorder

Dosage recommendation of normal paroxetine tablet

• Administered once daily in the morning with food

dosage recommendation of paroxetine controlled release tablet

Adverse effects• Akathisia- restlessness and psychomotor agitation (such as an inability to

sit or stand)

• Serotonin syndrome/Neurolept malignant syndrome (characterised by

clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic

instability with possible rapid fluctuations of vital signs, mental status

changes including confusion, irritability, extreme agitation progressing to

delirium and coma)

• Withdrawal symptoms (Dizziness, sensory disturbances, sleep

disturbances, anxiety, nausea, tremor, confusion, sweating, headache,

diarrhoea, palpitations. Emotional instability, irritability, and visual

disturbances)

Warning & precautions

Paroxetine should not be used for the treatment of children

and adolescents (7-17 years) as controlled clinical trials have

found paroxetine to be associated with increased risk for

suicidal behaviour and hostility.

Increased plasma concentrations of paroxetine occur in

patients with severe renal impairment (creatinine clearance

less than 30 ml/min) or in those with hepatic impairment.

Therefore, dosage should be restricted to the lower end of the

dosage range.

Warning & precautions

At least two week should elapse between discontinuation of paroxetine

and initiation of therapy with any MAOI.

• As with all antidepressants, paroxetine should be used with caution in

patients with a history of mania. Paroxetine should be discontinued in any

patient entering a manic phase.

• Teratogenic Effects: Pregnancy Category D Epidemiological studies have

shown that infants exposed to paroxetine in the first trimester of pregnancy

have an increased risk of congenital malformations, particularly

cardiovascular malformations.

• Paroxetine is secreted in human milk, and caution should be exercised when

paroxetine hydrochloride is administered to a nursing woman.

ESCITALOPRAM

• US FDA approved since 2002

• S- enantiomer of citalopram.

• Enantiomer: non-superimposable mirror images of one another. This

property is known as “chirality”

• Escitalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for:

Acute and Maintenance Treatment of Major Depressive Disorder (MDD) in

adults and adolescents aged 12 -17 years

Acute Treatment of Generalized Anxiety Disorder (GAD) in adults

DOSAGE RECOMMENDATION

WARNING & PRECAUTIONS

• Clinical Worsening/Suicide Risk: Monitor for clinical worsening,

suicidality and unusual change in behaviour, especially, during the

initial few months of therapy or at times of dose changes

• Serotonin syndrome

• Seizures: Prescribe with care in patients with a history of seizure

• Activation of Mania/Hypomania: Use cautiously in patients with

a history of mania

• Hyponatremia: Can occur in association with SIADH

WARNING & PRECAUTIONS

• Abnormal Bleeding: Use caution in concomitant use with

NSAIDs, aspirin, warfarin or other drugs that affect

coagulation

• Pregnancy category C: Use only if the potential benefit

justifies the potential risk to the fetus

• Nursing Mothers: Caution should be exercised when

administered to a nursing woman

RATIONALITY OF L-METHYLFOLATE COMBINATION WITH ESCITALOPRAM

• Depression is linked with folate deficiency and that patients with insufficient folate are less

likely to respond to treatment and more likely to experience a relapse.

• One theory of depression is that the brain is not developing enough neurotransmitters. This

may be due to insufficient amounts of L-methylfolate in the brain.

• L-methylfolate is needed to regulate serotonin, norepinephrine and dopamine

production.

• Without enough L-methylfolate, it may be difficult to produce enough neurotransmitters for

antidepressants to work fully.

• L-methylfolate, is indicated for the distinct nutritional requirements of individuals

who have suboptimal L-methylfolate levels in the CSF, plasma, and/or red blood cells

and have major depressive disorder, with particular emphasis as adjunctive support

for patients taking antidepressant medications.

RATIONALITY OF COMBINATION

• ESCITALOPRAM being SSRI blocks reuptake of neurotransmitters, while

L-methylfolate augments the production of more neurotransmitters

• Clinical trials suggest that L-methylfolate augments antidepressant

effect of SSRI/SNRI.

• Combination is cost-effective option than second generation

antidepressants.

To conclude, Adjunctive L-methylfolate at 7.5 mg/day may constitute an

effective, safe, and relatively well tolerated treatment strategy for patients

with major depressive disorder who have a partial response or no response

to SSRIs. Hence it is rationale to combine it with ESCITALOPRAM.

desvenlafexine• Atypical antidepressant.

• It is serotonin and norepinephrine reuptake inhibitor

(SNRI)

• Desvenlafaxine : major active metabolite of

venlafaxine

• Desvenlafaxine lacks significant affinity for

numerous receptors, including muscarinic-

cholinergic, H1 -histaminergic, or α -adrenergic

receptors in vitro.

• Desvenlafaxine also lacks MAO inhibitory activity.

• Efficacy demonstrated against vasomotor

symptoms of menopause, physical symptoms

associated with depression (somatic pain,

fatigue, irritability etc.)

Desvenlafaxine vs. venlafaxine

• No dose titration required; starting dose is the target

dose; once-daily dosing.

• Efficacy demonstrated against painful symptoms

associated with depression.

• Minimal hepatic metabolism (no concerns about

CYP 2D6 slow and extensive metabolizers).

• Very small effect on pulse and BP at 50 mg/day.

• Efficacy demonstrated against vasomotor

symptoms of menopause

Dosage and administration • Recommended dose: 50 mg once daily with or without

food

• Discontinuation: Reduce dose gradually whenever possible

• Moderate renal impairment: Maximum dose 50 mg per

day

• Severe renal impairment and end-stage renal disease:

Maximum dose 50 mg every other day.

• Moderate to severe hepatic impairment: Maximum dose

100 mg per day.

Adverse reactions

• Nausea, • Dizziness, • Insomnia, • Hyperhidrosis, • Constipation, • Somnolence, • Decreased appetite, • Anxiety, and specific male sexual function

disorders

Warning & precautions

• Hyponatremia:Can occur in association with SIADH

• Interstitial Lung Disease and Eosinophilic Pneumonia

• Pregnancy category C: use only if the potential benefits

justify the potential risks to the fetus.

• Nursing Mothers: Discontinue drug or nursing taking into

consideration importance of drug to mother

• Geriatric Use: There is an increased incidence of orthostatic

hypotension in desvenlafaxine treated patients ≥ 65 years

Anxiety and Depression

• Depression often accompanies anxiety disorders and, when it does, it needs to be treated as well• Symptoms of depression include feelings of sadness, hopelessness, changes in appetite or sleep, low energy, and difficulty concentrating. • Most people with depression can be effectively treated with antidepressant medications, psychotherapy, or a combination of both.

Comorbid depression with anxiety

• It is recommended that anxiety symptoms should be taken into account when

assessing the most appropriate antidepressant agent for treating someone with

depression, to optimize treatment outcome and recovery rate

• Escitalopram/paroxetine/desvenlafexine is extensively prescribed medication

for major depression.

• Clonazepam is a high-potency, long-acting benzodiazepine with anxiolytic

property.

• Clonazepam's long half-life of 20 to 80 hours render this compound especially

promising for augmentation therapy in major depression, because interdose

fluctuation in mood state is less.

• Hence it is rationale to combine it with SSRI for comorbid depression with

anxiety.