Antidepressants

Antidepressants are the second- most-prescribed-medication in the United States
15 million Americans are affected by depression each year
7% of all visits to the primary care doctors involve the doctor prescribing antidepressant medication
$10 billion dollars a year are spent on antidepressants

Антидепрессанты - второе по популярности лекарство в США
15 миллионов американцев страдают от депрессии каждый год
7% всех обращений к врачам первичной медико-санитарной помощи связаны с назначением врачом антидепрессантов.
10 миллиардов долларов в год тратится на антидепрессанты

Antidepressant are use for the treatment of several different forms of depression and other psychological disorders.
Psychological disorders that may accompany, precede, or cause depression:
Bipolar Disorder, (OCD) obsessive compulsive disorder and (PTSD) Post Traumatic Stress Disorder

Антидепрессанты используются для лечения различных форм депрессии и других психологических расстройств
Психологические расстройства, которые могут сопровождать, предшествовать или вызывать депрессию: Bipolar Disorder, (OCD) obsessive compulsive disorder and (PTSD) Post Traumatic Stress Disorder

Depression is not uniform. Everyone does not experience the same the signs and symptoms. The severity, duration, and triggers of one’s symptoms depend on the individual person and his or her illness.

Депрессия не однородна.
У всех разные признаки и симптомы. Выраженность, продолжительность и триггеры симптомов зависят от человека и его болезни.

Antidepressants
Tricyclic and related antidepressants (TCA)
E.g. amitriptyline, imipramine, doxepin, mianserin, trazodone
Monoamine-oxidase inhibitors (MAOI)
E.g. moclobemide, phenelzine, isocarboxazid, tranylcypromine
Selective serotonin reuptake inhibitors (SSRI)
E.g. fluoxetine, paroxetine, sertraline, citalopram
Other antidepressants
E.g. mirtazapine, venlafaxine, duloxetine, flupentixol

Tricyclic and related antidepressants (TCA)
Amitriptyline (Saroten®)
Clomipramine (Anafranil®)
Dothiepin (a.k.a. dosulepin, Prothiaden®)
Doxepin (Sinequan®)
Imipramine (Tofranil®)
Mianserin (Tolvon®)
Nortriptyline (Nortrilen®)
Trazodone (Trittico®)
Trimipramine (Surmontil®)

Tricyclic and related antidepressants (TCA)
Mechanism of action
Blocks neuronal uptake both norepinephrine and serotonin
Initial response develops in 1-3 weeks
Maximal response develops in 1-2 months
Older tricyclics
Marked anticholinergic Adverse effects
Risk of cardiotoxicity
Tricyclic-related drugs (e.g. trazodone)
Fewer anticholinergic adverse effects
Sedation, dizziness, priapism (persistent penile erection accompanied by pain and tenderness)

Antidepressant treatment causes inhibition of serotonin and norepinephrine reuptake or breakdown.
Short-term antidepressant treatment increase extracellular levels of serotonin and norepinephrine.
Long-term treatment leads to decrease in the function and expression of serotonin and
norepinephrine receptors, to increase in the cAMP signal transduction and to increase in
expression of CREB (cAMP response element binding).
Increased activity of the cAMP signal transduction cascade indicates that the functional
output of 5-HT and NE are up-regulated, even though levels of certain 5-HT and NE
receptors are down-regulated.
Expression of BDNF and its receptor trkB is also increased by long-term antidepressant
treatment, so increased neuronal survival, function, and remodelling of synaptic
architecture are provided.

Antidepressant treatment causes inhibition of serotonin and norepinephrine reuptake or breakdown.
Кратковременное лечение антидепрессантами увеличивает внеклеточный уровень serotonin и norepinephrine
Длительное лечение приводит к снижению функции и экспрессии serotonin и
рецепторов norepinephrine, для увеличения передачи сигнала cAMP и увеличения
выражение CREB (cAMP response element binding).
Повышенная активность каскада передачи сигнала cAMP указывает на то, что
функциональный выход 5-HT и NE регулируется с повышением, даже если уровни
определенных 5-HT и NE рецепторы подавлены.
Экспрессия BDNF и его рецептора trkB также увеличивается при длительном
приеме антидепрессанта, таким образом увеличивая выживаемость нейронов,
их функцию и ремоделирование архитектуры синапсов.

Down&Up-regulation’s
Normal synapse, no depression
Depression caused by neurotransmitter deficiency

As a result of the depletion of neurotransmitters, the receptors increase ('upregulate')
Reuptake blocking antidepressant (TCA, SSRI or SNRI) causes increase in neurotransmitters to normal state
Down&Up-regulation’s

SSRI blocks the reuptake pump, causing more neurotransmitter to be in the synapse.
Increase in neurotransmitter causes receptors to down-regulate, eventually.
Down&Up-regulation’s

Tricyclic and related antidepressants (TCA)
Properties
Inexpensive, generic
Some with off-label use, e.g.
Neuropathy with amitriptyline
Refractory skin diseases with doxepin
Very dangerous in overdose
Life threatening
Lethal dose only 8 times average daily dose
Acutely depressed patients should not be given more than 1-week TCA supply at one time

Tricyclic and related antidepressants (TCA)
Adverse effects
Orthostatic hypotension
Reduced by moving slowly when assuming upright posture
Sit or lie down if symptoms (dizziness, lightheadedness) occur
Divided doses and slow titration
Anticholinergic effects
Dry mouth, blurred vision, photophobia, constipation, urinary retention, tachycardia
Tolerance may develop as treatment persists
Divided doses and slow titration
Sedation
Dose at bedtime

Tricyclic and related antidepressants (TCA)
Adverse effects
Cardiac toxicity
Arrhythmias and heart block
ECG recommended before initiation
Do not use in heart block
Seizures
Lowered seizure threshold
Hypomania (mild mania)
Elevated mood
Patient should be evaluated to determine dose reduction or bipolar disorder
Diaphoresis
Paradoxical effect

Tricyclic and related antidepressants (TCA)
Drug interactions
CNS depressants
Narcotics, benzodiazepines
Additive CNS depression
Anticholinergics
Additive anticholinergic effects
P450 enzyme inducers/inhibitors

Monoamine-oxidase inhibitors (MAOI)
Moclobemide (Aurorix®) (RIMAs - Reversible Inhibitors of Monoamine Oxidase)
Phenelzine
Isocarboxazid
Tranylcypromine

Monoamine-oxidase inhibitors (MAOI)
Mechanism of action
Inhibit both MAO-A and MAO-B
Phenelzine, tranylcypromine
Selective & reversible inhibitor of MAO-A
Moclobemide

Monoamine-oxidase inhibitors (MAOI)
Properties
Useful in atypical depression (somnolence and weight gain), refractory disorders and certain types of anxiety disorders
Less prescribed than tricyclics, SSRIs and other antidepressants
Danger of dietary and drug interactions

Monoamine-oxidase inhibitors (MAOI)
Properties
Drug interactions
Other antidepressants should not be started for 2 weeks after MAOI has been stopped (3 weeks for clomipramine or imipramine)
MAOI should not be started for 7-14 days after a tricyclic or related antidepressant (3 weeks for clomipramine or imipramine)
MAOI should not be started for at least 2 weeks after a previous MAOI

Monoamine-oxidase inhibitors (MAOI)
Adverse effects
Hypertensive crisis
Severe occipital headache, photophobia, palpitation, sharply increased in BP due to additive effect between MAOI and adrenergic stimulants
Tyramine-rich food e.g. cheese, wine ( ), smoked/aged/picked meat or fish, alcohol
Amphetamins
Pseudoephedrine

Monoamine-oxidase inhibitors (MAOI)
Adverse effects
Hypertensive crisis
Severe occipital headache, photophobia, palpitation, sharply increased in BP due to additive effect between MAOI and adrenergic stimulants
Tyramine-rich food e.g. cheese, wine (Chianti ), smoked/aged/picked meat or fish, alcohol
Amphetamins
Pseudoephedrine

Monoamine-oxidase inhibitors (MAOI)
Adverse effects
Orthostatic hypotension
Insomnia
Weight gain
Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRI)
Fluoxetine (Prozac®)
Fluvoxamine (Faverin®)
Paroxetine (Seroxat®)
Sertraline (Zoloft®)
Citalopram (Cipram®)
Escitalopram (Lexapro®)

Selective serotonin reuptake inhibitors (SSRI)
Mechanism of action
Inhibits reuptake of serotonin (5-HT - hydroxytryptophan) presynaptic uptake
Increases availability of serotonin at synapses

Selective serotonin reuptake inhibitors (SSRI)
Properties
Overdose less likely to be fatal
Less anticholinergic side effects
But more GI side effects
Seems to be better tolerated

Selective serotonin reuptake inhibitors (SSRI)
Properties
Fluoxetine
Most stimulating SSRI
Indicated for Premenstrual Dysphoric Disorder (PMDD) (as Sarafem®)(?)
Long half-life, ensure 5 week washout before MAOI (2 week for other SSRI)
Some SSRIs also indicated for
Obsessive-compulsive disorder (OCD)
Panic disorder
Eating disorders
Social phobia
Post traumatic stress disorder (PTSD)

Selective serotonin reuptake inhibitors (SSRI)
Adverse effects
Headache
GI
Nausea, diarrhoea, loss of appetite
Titrate dose to minimize side effect
May be taken with food
Anticholinergic Adverse effects
Fever than TCA
Tend to see more with Paroxetine

Selective Serotonin Reuptake |Inhibitors (SSRI)
Adverse effects
Somnolence or insomnia
Dose in morning for insomnia
Increase in anxiety, agitation, akathisia early in treatment (esp. fluoxetine)
Agitation or nervousness
Sexual dysfunction

Selective Serotonin Reuptake |Inhibitors (SSRI)
Adverse effects
Serotonergic syndrome
Aetiology - SSRI or MAOI + something else
(usually with sl. Different serotonin action)
Редкое, но потенциально смертельное взаимодействие между 2 или более препаратами, повышающими уровень серотонина. Confusion, Anxiety, shivering, diaphoresis, tremor, hyperflexia, clonus, autonomic instability (BP, pulse) tachycardia, flushing
Fatal if malignant hyperthermia - ICU
Management
Mild: resolve in 24-48 hours after discontinuing offending agent
Severe: 5-HT antagonist, cyproheptidine, propranolol, methysergide, dantrolene (hyperthermia)

Serotonin Norepinephrine Reuptake Inhibitor (SNRI)
Duloxetine (Cymbalta®)
Venlafaxine (Efexor®, Efexor XR®)
Mechanism of action
Inhibits norepinephrine and serotonin reuptake
Potentiates neurotransmitter activity in the CNS

Serotonin Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine (Efexor®, Efexor XR®)
Properties and Adverse effects
Also for anxiety disorders
Lacks sedative and anticholinergic effects predominant with TCAs
Nausea, dizziness, sexual dysfunction, hypertension (when > 300mg/day)

Serotonin Norepinephrine Reuptake Inhibitor (SNRI)
Duloxetine (Cymbalta®)
Properties and Adverse effects
More potent than venlafaxine?!
Also indicated for diabetic neuropathy
Insomnia, nausea, headache

Mixed serotonin norepinephrine effects
Mirtazapine (Mirtazon®, Remeron®, Remeron SolTab®) Tetracyclic antidepressant (noradrenergic and specific serotonergic antidepressants - NaSSAs).
Mechanism of action
NaSSAs bind to and inhibit both noradrenaline a2-autoreceptors and noradrenaline a2-heteroeceptors. This action prevents the negative feedback effect of synaptic noradrenaline on 5-HT and noradrenaline neurotransmission, and neurotransmission sustained.
have a dual mechanism of action that increases the concentration of 5-HT and noradrenaline in the synaptic cleft to within the normal range.
NaSSAs also block 5-HT2 and 5-HT3 receptors on the post-synaptic membrane, which causes enhanced 5-HT1 mediated neurotransmission.
Increases central noradrenergic and serotonergic neurotransmission

Mixed serotonin norepinephrine effects
Mirtazapine (Mirtazon®, Remeron®, Remeron SolTab®)
Properties and Adverse effects
Fewer anticholinergic effects
Marked sedation during initial treatment
Stimulating as dose increases
Increased appetite and weight gain
Constipation, dry mouth

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)
Bupropion (Wellbutrin SR®)
Mechanism of action
Inhibits weakly the neuronal uptake of dopamine, norepinephrine and serotonin
Does not inhibit monoamine oxidase
Also acts as a nicotinic acetylcholine receptor antagonist

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)
Bupropion (Wellbutrin SR®)
Properties and side effects
GI side effects, confusion, dizziness, headache, insomnia, tremor
Seizure risk at high doses
Minimal risk of sexual dysfunction
Also licensed for smoking cessation (Zyban®)

Other antidepressants
Flupenthixol (Fluanxol®)
Typical antipsychotic
Antidepressant effect at low doses
Antipsychotic dose: 3-9mg twice daily
Antidepressant dose: 1-3mg daily
Combined with another antidepressant as Deanxit®
Flupenthixol 0.5mg + melitracen 10mg
For depression and anxiety
- Trazodone, Nefazodone - Serotonin antagonists and reuptake inhibitors (SARIs)

Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40
47% response rate
on citalopram
(by *QIDS-SR, 50% ↓
in sxs)
Sequenced Treatment Alternatives for the Relief of Depression
(STAR*D), n = 2,876 (qualifying pts)
33% remission rate
on citalopram
(by QIDS-SR, score <5)
Rx choice:
according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx
6-8wk trials each (preferable)
augmentation v. switch?
*QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27)
http://www.ids-qids.org/

Antidepressants in depression
Choice of agents
All are equally efficacious for depression
Selection based on
Side effect profile
Potential drug interaction
Response failure to an antidepressant does not predict response to another drug class or another drug within class

Antidepressants in depression
Geriatrics
Reduce initial dose by half
Gradual dose titration
Risk of dizziness and syncope
Hyponatremia
Pediatrics
Decrease initial dose by half
Recent evidence links SSRIs with suicide in adolescents?

Antidepressants in depression
Treatment response
Weeks 1-2
Physical responses
Improvement in appetite and sleep
Weeks 3-4
Energy and cognitive responses
Improvement in energy
Improvement in guilt, concentration
Weeks 5-6
Emotional responses
Improvement in mood

Antidepressants in depression
Continuation therapy
To prevent relapse
4-9 months after complete remission of symptoms
At therapeutic doses
Lifelong maintenance therapy
Recommended by some investigators for patients at greater risk or reoccurrence
< 40 years with ≥ 2 prior episodes
Any age with ≥ 3 prior episodes

Antidepressant Discontinuation
Neuro
Dizziness / confusion
agitation or anxiety,
tremor
sensory disturbances
paraesthesia
electric shock sensations),
sleep disturbances (including intense dreams),
Somatic
Nausea
sweating,
headache,
diarrhoea
Usually resolve within 2 weeks but lasts 2-3 months for some
Taper if previous hx.
Worst TCA, venlafaxine, paroxetine (incl. flu like illness)

SSRI side effects
Sexual A. Anorgasmia or delayed orgasm
B. Reduced libido C. Ejaculatory dysfunction esp.
retarded/delayed ejaculation
D. Erectile dysfunction

Pregnancy and TCAs

Risks of SSRIs and Pregnancy

Risks of SSRIs and Pregnancy

Non-antidepressants in depression
Anxiolytics
Antipsychotics
Use may mask the true diagnosis
Used with caution
But are still useful adjuncts in agitated patients
Lithium and thyroid
To potentiate effect of antidepressants in refractory cases
Lithium: plasma level 0.4-0.8mEq/L
Thyroid supplement: 25mcg/day

Take away
Есть несколько групп антидепрессантов:
а. отличающихся по химической структуре, б. по воздействию на нейротрансмитерную
передачу
Начало антидепрессивного эффекта ч/з две недели
На 3-4 неделю возвращается физическая активность (критическое время в отношении возможного суицида? При наличии идей виновности и суицидальных планов)

Take away
Все антидепрессанты эффективны одинаков
При назначении антидепрессантов очень важно учитывать и, за частую, использовать «в мирных целях» побочные эффекты
У пожилых и детей начинают лечение с половинной терапевтической дозы
Основная задача – добиться ремиссии? А не реакции на лечение/
Длительность лечения, после выхода в ремиссию - 4-9 месяцев (лучше 9)