Depression Therapeutics Flashcards
Depression male or female
Affects more females than males.
Effective treatments for Depression
Effective treatments are available:
– Psychosocial treatments should be the first line treatment for mild depression.
– Pharmacological & psychological treatments are effective in cases of moderate and severe depression.
Risk of mortality
Schizophrenia, major depression, and alcohol-use disorders significantly increase the risk of early mortality
Best predictors of suicide
3 independent best predictors of suicide:
(a) history of attempted suicide using highly lethal means;
(b) coexisting significant physical illness;
(c) and delusions.
Pathophysiology of Depression
1) Biological (neuroendocrine theories)
– Hormonal influences:
• INCREASE secretion of cortisol (major stress hormone) – Monoamine Hypothesis:
• DECREASE neurotransmitters in brain
– Norepinephrine (NE), Serotonin (5-HT), dopamine (DA)
2) Psychological
– Loss; Negative self-evaluation
3) Psychosocial
– Isolation; Lack of social support
4) Genetics
– 1st degree relatives of patients with depression
• 1.5 – 3 times more likely to develop depression than normal controls.
–Twin study:
• 39% heritability, 61% environmental
– Polymorphism in the 5-HTT gene
• SLC64A on Chromosome 17q11.2-12
• Individuals with the “S” allele of the promoter region of the SERT gene are more vulnerable to the depressive effects of early life stress
– Those with “S/S” genotype most vulnerable to depression
– Those with “L/L” genotype more immune to depressive effects of early life trauma
5) Medical (eg DM, CVA, Cancer )
6) Pharmacological
Secondary Causes for Depression
(A) Medical Disorders
• Endocrine disorders:
Hypothyroidism, Cushing Syndrome; Bidirectional association between depression and Type 2 DM in women
• Deficiency States:
Anemia, Wernicke’s encephalopathy
• Infections:
CNS infections, STDs, TB
• Metabolic disorders: electrolyte imbalance ( decrease K+, decrease Na+), hepatic encephalopathy
• Cardiovascular:
CAD, CHF, MI (Depression as a risk factor for poor diagnosis among patients with ACS.)
• Neurological:
Alzheimer’s, Epilepsy, Pain, Parkinson’s, Stroke
• Malignancy
(B) Psychiatric Disorders • Alcoholism • Anxiety disorders • Eating disorders • Schizophrenia
(C) Drug-Induced • Lipid-soluble beta blockers • Psychotropics: Hypnotics, anxiolytics, anticonvulsants • Withdrawal from alcohol, stimulants • Steroids • Isotretinoin • Interferon- ß-1a
Clinical Presentation of depression and criteria
DSM-5 Diagnostic Criteria for Major Depressive Disorder
A.
At least 5 symptoms have been present during the same 2-week period and represent a change from previous functioning.
NB: One of the symptoms MUST be DEPRESSED MOOD or LOSS OF INTEREST*
Acronym: In.SAD.CAGES
(1) In terest:
DECREASE INTEREST and pleasure in normal activities (2) S leep: INSOMIA or HYPERSOMIA
(3) A ppetite: DECREASED appetite, weight loss
(4) D epressed: Depressed mood (adults); NB: may be irritable mood in children
(5) C oncentration:
Impaired concentration and decision making
(6) A ctivity:
Psychomotor retardation or agitation
(7) G uilt: Feelings of guilt or worthlessness
(8) E nergy: Decreased energy or fatigue
(9) S uicidal thoughts or attempts
B.
Symptoms cause significant DISTRESS or IMPAIRMENT in social, occupational, or other important areas of functioning.
C.
Symptoms are not caused by an underlying medical condition or substance
Major Depressive DIsorder (MDD)
MDD “with mixed features”:
- If co-existence within a major depressive episode of at least 3 manic symptoms (but insufficient to satisfy criteria for a manic or hypomanic episode)
General Assessment for Depression
General Evaluations prior to Treatment
1) Mental State Exam (MSE) for accurate diagnosis
• Assess for suicidal/homicidal ideations and risks
• Assess for history of manic/ hypomanic episode.
• Reassess MSE on every subsequent interview/ visit to evaluate efficacy (and side effects)
2) Physical & Neurological exam
3) Complete family & social history
• Review patient’s psychosocial circumstances on every visit
4) Complete medical and medication history
• Any current or history of drug/alcohol abuse? Tobacco Use?
• Drug allergy? History of medication response?
• Using medications from other clinics/ hospitals? Regularly?
• Compliance? Reassess adherence to medications on every visit
5) Lab and other investigations
• Vital signs, FBC, U/E/Cr, LFTs, TFTs, ECG, Folate & Vit B12, fasting blood glucose and lipid panel, urine toxicology.
• To exclude general medical conditions or substance-induced symptoms, e.g. psychosis/ depression/ mania/ anxiety/ insomnia
6) Psychiatric Rating Scales
– Clinician-rated
• Hamilton Rating Scale for Depression (HAM-D) – “Gold Standard”
– Remission = HAM-D score <= 7 (Therapy Goal)
– Response = “50% improvement”
• Clinical Global Impression - Severity Scale (CGI-S)
• Montgomery-Asberg Depression Rating Scale (MADRS)
– Self-rated:
• Patient Health Questionnaire (PHQ-9) for Depression
– Score >= 10 = moderate depression
– Score >= 20 = severe depression
• Quick Inventory for Depressive Symptoms (IDS) -SR
• Beck Depression Inventory (BDI)
Treatment management for depression
Combination of Non-Pharmacological and Pharmacological Management
(A) Non-pharmacological
• Sleep Hygiene – to improve sleep habits
• Psychotherapy
– not suitable as monotherapy in moderate – severe depression
– usually in combination with antidepressants.
• Neurostimulation
– Electroconvulsive Treatment (ECT) – for severe/ refractory cases
– Repetitive Transcranial Magnetic Stimulation (rTMS)
(B) Pharmacological
• Antidepressants ± Adjunctive meds
– selection based on target symptoms, comorbid conditions, drug interactions, prior response, preference • Antidepressant Effectiveness
– Efficacy in RCTs: Response Rate 60%–70% (regardless of antidepressant)
– Effectiveness in real life is lower, ~ 50%–60%.
– Remission Rate with first antidepressant is about 30% (STAR*D Trial)
• Choice of Antidepressant – First Line (antidepressant monotherapy):
- Usually SSRI, SNRI, Mirtazapine or Bupropion
Choice of Antidepressant
– First Line (antidepressant monotherapy):
- Usually SSRI, SNRI, Mirtazapine or Bupropion
Phases of treatment for depression
• Acute Phase Treatment
– Adequate Trial = adequate dose + duration (4-8wks, APA Guidelines 2010). Max 12 wks
– Delayed onset due to down-regulation of pre-synaptic autoreceptors
– Time Course of Treatment Response
» Physical Sxs may improve in 1-2 weeks (e.g. sleep, appetite)
» Mood Sxs take longer time to improve, e.g. 4-6 weeks
• Continuation Phase
– 1st episode of MDD: continue at least 4-9 months after acute-phase treatment (i.e. Total = 6-12 months)
• Longer-term Maintenance Therapy:
– Consider if High Risks, >= 2 episodes MDD & geriatric MDD
first line antidepressant
SSRI / SNRI
Complementary and alternative medicine (treatment)
Nutritional – Vit. B12 – L-methylfolate – Vit. D – S-adenosylmethionine (SAMe) – Omega-3 fatty acids – 5-hydroxytryptophan (5-HTP)
Herbal
– St. John’s Wort (inducer)
• drug interactions with antidepressant
• Do not use concomitantly with antidepressants
Exercise
Relaxation techniques
Sleep Hygiene
Others, as appropriate
Approaches for Treatment Resistant Depression
(A) Switching (cannot tolerate/not effective after 1-2mth therapy)
• Switch to alternative Antidepressant
• E.g. SSRI –> SNRI, or SSRI –> Mirtazapine
– CROSS TITRATION (watch for serotonin syndrome if combining serotonergic agents)
• E.g. DECREASE Fluoxetine plus INCREASE Mirtazapine
– DISCONTINUATION
• If using regularly for > = 8 weeks, recommended to gradually reduce dose over 4 weeks or more; watch for withdrawal syndrome if abruptly stopped.
– Esp. if switching from Serotoninergic to Non-serotoninergic agent (e.g. from SSRI/SNRI –> to Bupropion)
• Wash-out period necessary for MAOIs
– If switching from MAOI to another antidepressants
- Wash-out 2wks
- or 3wks if starting Clomipramine or Imipramine
– If switching from another antidepressant to MAOI
- Wash-out at least 2 wks; - or 3wks if stopping Clomipramine or Imipramine; - or 5 wks if stopping Fluoxetine
(B) Augmentation (partial response <50% response; symptoms reduction)
Combine different classes of Antidepressants
– Objective = INCREASE monoamines: 5HT, NE and/or
DA
– Add: Bupropion-SR, Mirtazapine, or Nortriptyline Buspirone, T3 (Liothyronine), Lithium
Adjunctive SGAs: Quetiapine XR, Aripiprazole
Note in pregnancy
Pregnancy
- Avoid Paroxetine, Bupropion;
- Birth defects have also been reported with other SSRIs, e.g. Sertraline and Citalopram
- Nortriptyline in late pregnancy may be considered
Choice
- counsel
- supportive therapy
- ECT
Breast Feeding
- May consider Sertraline or Nortriptyline.
Renal impairment
May consider Sertraline > Imipramine
Hepatic impairment
- None are safe.
- May consider Desvenlafaxine
Post-MI depression
Prefer Sertraline post-MI and in heart failure
Elderly
Avoid TCAs and those with anticholinergic, CNS, hypotensive or cardiac adverse effects
Hyponatremia
SNS (drowsiness, confusion or convulsions)
- SIADH, usually in elderly
- associated with ALL antidepressants; mostly reported for SSRIs
- -> switch to mirtazapine
Antidepressants and Suicidality (Children, Young Adults)
- Patient counselling for self-monitoring, regular review
- Medication guide must be provided before dispensing
Serotonin syndrome SNS and causes
- altered mental status (confusion, agitation, seizures),
- dysautonomia (diarrhea, diaphoresis, hypertension, fever/shivering, mydriasis, tachycardia), and
- neuromuscular changes (myoclonus, tremor, ataxia, hyperreflexia, rigidity)
- Causes: concomitant Rx of serotonergic meds, e.g.:
- Triptans, Sibutramine
- Opioid Analgesics (Tramadol, Fentanyl, Meperidine), Dextromethorphan
- Linezolid, Ritonavir
SSRI increases risk of _________
- SSRIs: INCREASE Risks of bleeding
- Risks in elderly on NSAIDs, Warfarin, Steroids; Consider add PPI.
- Consider stopping Serotonergic antidepressant 2 weeks before surgery if high bleeding risks
- Bupropion and Mirtazapine and agomelatine likely safe
CNS depressants effects with Alcohol and other CNS depressants
“Do not take medication at the same time as alcohol, separate them 4-6 hrs apart
ADD ON Anticholinergic agents causes excessive anticholinergic effects
ADD ON Anticholinergic agents causes excessive anticholinergic effects
DDI
DDI present in
(Cyp1A2)
Theophylline, warfarin, agomelatine, amiodarone + Fluvoxamine, cipro (inhibitor)
(CYP2D6)
metoprolol, codeine, oxycodone, hydrocodone, tramadol
+ fluoxetine/paroxetine/ bupropion (inhibitor)
CYP2c19
Warfarin + fluoxamine (inhibitor)
CYP 3A4
Simvastatin, lovastatin + fluoxamine, cipro
CYP2C9 substrate
Tolbutamide, warfarin, phenytoin
fewer cyp interaction
mirtazapine escitalopram venlafaxine desvenlafaine vortioxetine
Treatment: Discontinuation
Discontinuation Syndrome of Antidepressants
– Worse with abrupt discontinuation of regular therapy
• Especially with paroxetine, venlafaxine
– Symptoms: • Dizziness, nausea, paresthesia, anxiety/insomnia, flu-like symptoms, “electric shock” sensation in extremities.
– Onset: 36-72hrs
– Duration: 3 – 7 days; typically resolves over 1-2 weeks without treatment
• Antidepressant gradual discontinuation after regular treatment for ≥8 weeks: taper over at least 4 weeks
– Fluoxetine and Bupropion: generally unnecessary
– TCAs: decrease by 10 – 25% every 1 – 2 weeks
– Fluvoxamine reduce by 50mg every 1-2 week, with final dose of 25mg.
– Sertraline reduce by 50mg every 1 – 2 weeks, with final dose of 25mg.
– Paroxetine CR: reduce by 12.5mg every 1 – 2 weeks
– Escitalopram: reduce by 5mg every 1 – 2 weeks
– Venlafaxine: reduce by 25% every 1 – 2 weeks
– gradually as clinically indicated
• Benzodiazepines: Gradual Discontinuation of Long-term, High-dose Use
– E.g. ↓dose by 25% weekly until reaching 50% of dose, then reduce one eighth every 4-7 days, or as gradually as per clinically indicated
Patient Counselling
- Antidepressants may take at least a couple of weeks to help with symptoms of low mood, poor sleep and appetite, may need at least a couple of months to help with anxiety.
- Do not take at same time as alcohol (space 4-6 hours apart)
- Tell your Drs & nurses what other medicines you are using
- If you feel your condition is worsening, suicidal or bothered by side effects, contact Dr.
- Possible Side Effects (but not everybody will experience these)
– DROWSY - “take at bedtime”
– INSOMNIA - “take in the morning”
– DIZZY/ LIGHT-HEADEDNESS- “rise up slowly”
– STOMACH UPSET - “take after food”
– CHANGES in SEXUAL FUNCTION - “may cause CHANGES in sexual functioning in some people. Tell your doctor if you notice any changes since this can be reversed and treated if it occurs.” (NB: This side effect is less likely with Mirtazapine, Bupropion, Agomelatine)
