Effective treatment in depression and anxiety

DEPRESSION AND ANXIETY-SSRI AS FIRST CHOICE

1. Effective approach in treatment of anxiety and depression The road to recovery

2. Mechanism of anxiety Overactivation of brain neurotransmission and neuronal firing (glutamate/calcium influx) Underinhibition of brain neurotransmission and neuronal firing (GABA) Both

3. Generalized anxiety disorder Obsessive-compulsive disorder Panic disorder Post-traumatic stress disorder Social phobia (or social anxiety disorder) Anxiety disorders - Types

4. 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.

5. 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

6. 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.

7. 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.

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

9. Positive and negatives of anti-anxiety drug options

10. 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.

11. SSRI Fluoxetine Fluvoxamine Paroxetine Sertaline Citalopram Escitalopram

12. 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

13. 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

14. Dosage recommendation of normal paroxetine tablet Administered once daily in the morning with food

15. dosage recommendation of paroxetine controlled release tablet

16. 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)

17. 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.

18. 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.

19. 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

20. DOSAGE RECOMMENDATION

21. 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

22. 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

23. 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.

24. 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.

25. 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.)

26. 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

27. 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.

28. Adverse reactions Nausea, Dizziness, Insomnia, Hyperhidrosis, Constipation, Somnolence, Decreased appetite, Anxiety, and specific male sexual function disorders

29. 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

30. 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.

31. 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.