Pharmacological Management of Depression

• The presentation provides information on the pharmacological management of depression.
• The presenter is Weronika Rodak, and her email is [email protected].

Affective Disorders

• Affective disorders are a group of diagnoses characterized by mood disturbances as the main symptoms.
• Mood disorders include: Mania with Psychosis, Mania, Hypo-Mania, Elation, Normal Mood, Dysthymia, Mild Depression, Moderate Depression, Severe Depression, Severe Depression with Psychosis, Cyclothymia, Recurrent Depressive Disorder, and Bipolar Affective Disorder.

Depression - Clinical Symptoms

• Lowering of mood, reduction of energy, and decrease in activity are clinical symptoms of depression.
• Reduced capacity for enjoyment (anhedonia), interest, energy, and concentration are clinical symptoms of depression.
• Reduced self-esteem and self-confidence, along with ideas of guilt and worthlessness are clinical symptoms of depression.
• Other clinical symptoms include psychomotor retardation, disturbed sleep, diminished appetite, and loss of libido.

Antidepressants

• Antidepressants are most prescribed psychiatric drugs worldwide, often for long-term treatment.
• Improvement with antidepressants leads to 20-30% reduction of symptoms.
• Response with antidepressants leads to 50% reduction of symptoms.
• Remission with antidepressants is the lack of symptoms.
• Healing with antidepressants is remission lasting longer than 6-12 months.
• The recommended treatment duration is 4-9 months following a therapeutic response in the first episode.
  • For the second episode, treatment should last 2-3 years.
  • For the third episode, treatment should last 5 years.
• Registration drugs are tested in clinical trials before registration and show a therapeutic response in 2/3 of patients in 8 weeks.
• STAR*D (Sequence Treatment Alternatives to Relieve Depression) in 2006 showed a therapeutic response in only 1/3 of patients with the first drug and remission in only 2/3 of patients after a year-long treatment with 4 drugs, each for 12 weeks.

Monoamine Theory

• All effective antidepressants enhance the synaptic action of serotonin, norepinephrine, or dopamine.
• A secondary response involves influencing gene expression to evoke an adaptive response in receptor expression.

Antidepressant Classification

• Antidepressants can be classified into several categories: SSRIs, SNRIs, SARIs, SMSs, NRIs, NDRIs, TCAs, TeCAs, MAO-Is, and Others.

SSRIs

• SSRIs are selective serotonin reuptake inhibitors that work by blocking SERT.
• SSRIs include Sertraline, Paroxetine, Citalopram, Escitalopram, Fluoxetine, and Fluvoxamine.
• SSRIs are often the first choice of drugs in most cases of depression because they are effective, have few side effects, and are quite safe in case of overdose.
• SSRIs are indicated for depression (sertraline, fluvoxamine – psychotic depression; sigma1 Ag?), obsessive-compulsive disorder, anxiety (panic attacks), bulimia (fluoxetine - 5HT2C Antg), PTSD and social phobia.
• SSRI side effects include GIT problems, headaches, vertigo, sexual dysfunctions, hiponatremia, and risk of bleeding.

SNRIs

• SNRIs are serotonin-noradrenaline reuptake inhibitors.
• SNRIs include Venlafaxine, Duloxetine, and Milnacipran.
• Venlafaxine (XR) is a 5-HT reuptake inhibitor across the dosage range, a NA reuptake inhibitor above 150mg/d, and a D reuptake inhibitor above 225mg/d.
• Duloxetine is also a weak Dopamine inhibitor.
• Milnacipran is a stronger noradrenaline inhibitor than a 5-HT inhibitor.
• SNRIs are indicated for depression, anxiety, social phobia, peripheral neuropathy (in diabetes), Fibromyalgia, Chronic pain, Urine incontinence, and Menopausal flushing.
• SNRIs side effects include: Nausea & other GIT symptoms and hypertension.
• !!! discontinuation symptoms

SARIs

• SARIs are serotonin antagonist/reuptake inhibitors including: Trazodone and Nefazodone.
• These are phenylpiperazine derivatives.

Trazodone

• Trazodone's side effect is drowsiness.
  • It is taken in the evening.
  • Low doses improve sleep with no antidepressant effects.
• Trazodone indications include depression, anxiety disorder and insomnia.

SMSs

• SMSs are serotonin modulator and stimulator antidepressants.
• Vortioxetine is an example of a SMS antidepressant
  • It is recommended it cognitive symptoms in MDD.
  • It is safe in patients with various comorbidities.

NRIs

• NRIs are noradrenaline reuptake inhibitors.
• Reboxetine (EU) is NRIs, meant for depression, and might be the least effective antidepressant.
• Atomoxetine is NRIs, indicated for ADHD.

NDRIs

• NDRIs are noradrenaline dopamine reuptake inhibitors.
• Bupropion is a type of NDRI
  • It is prescribed in patients unsusceptible to SERT blockage.
  • It is prescribed in patients suffering due to sexual dysfunctions from SSRIs.
• NDRIs indications include: MDD, SAD, and smoking cessation.

TCAs

• TCAs (tricyclic antidepressants) are classical antidepressants.
• TCAs include Clomipramine, Maprotyline, Amitryptyline, and Doxepin.
• TCAs work by blocking of SERT and NET + H1 Antg + M Antg + alfa1 Antg + Na+ channels blockage, but these blockages are the reasons for SIDE EFFECTS!!!
• TCAs are indicated for depression, obsessive-compulsive disorder, fobias, axiety disorder (with panic attacks), chronic pain, neuropathic pain, nocturnal enuresis, overproduction of saliva

TeCAs

• TeCAs (tetracyclic antidepressants) - also known as:
• NaSSAs (noradrenergic and specific serotonergic antidepressants)
• TeCAs Mechanism of action involves alfa2 blockage (presynaptic) and SNDIs (serotonine noradrenaline disinhibitors).
• TeCAs examples includes: Mianserin (EU) and Mirtazapine
  • • 5HT2A/2C Antg → sleep improvement, no sexual dysfunctions
  • • H1 Antg → weight gain, drowsiness
• TeCAs indications: MDD, anxiety disorders (OFF LABEL), insomnia (OFF LABEL) and OCD (OFF LABEL)

MAO-Is

• MAO-Is (monoamine oxidase inhibitors) are classical antidepressants.
• MAO-Is historically derive from isoniazide.
• Irreversible & non-selective MAO-Is include: Phenelzine, Tranylcypromine, and Isocarboxazid which are "suicide inhibitors".
• Reversible & MAO-A selective (RIMA) includes: Moclobemid
• MAO-Is are indicated for MDD and various anxiety disorders.
• While taking MAO-Is it is important to avoid foods containing tyramine to prevent a risk of hypertensive crisis!!! especially with non-selective, irreversible MAO-I

Foods to Avoid with MAO Inhibitors

• It is important to avoid:
  • All matured or aged cheeses.
  • Fermented/dry sausage (salami, mortadella, summer sausage, etc.).
  • Alcoholic beverages.
  • Fava or broad bean pods (not beans).
  • Marmite concentrated yeast extract, Sauerkraut, Soy sauce, and other soy bean condiments.
• Foods which you can eat include:
  • Fresh meat, poultry, and fish, including fresh processed meats (such as lunch meats, hot dogs, breakfast sausage, and sliced ham).
  • Processed cheese, mozzarella, ricotta cheese, cottage cheese, and yogurt.
  • Up to one cup a day of caffeine-containing beverages (coffee, tea, cola, hot chocolate).
  • Other beverages containing little to no caffeine or tyramine   - Brewer's yeast, baker's yeast, Soy milk.   - Pizza from commercial chain restaurants prepared with cheese low in tyramine.
• All other vegetables.

Others

• This class constitutes a collection of other antidepressants.
• An example drug is Agomelatine.
  • Agomelatine is a melatonin receptor agonist (MT1 and MT2)
  • Agomelatine is a 5-HT2C receptor antagonist
  • It offers sleep improvement
  • It has no sexual dysfunctions and no withdrawal effect

Management of Depressive Episode

• Depressive episodes can be treated by GPs when there is a:
  • mild/moderate episode
  • lack of psychotic symptoms
  • lack of suicidal ideations/tendencies
  • good response to pharmacological treatment in the past
  • patient's preference
• Patients must be told several key facts prior to begining treatment:
  • antidepressants do not cause dependency
  • antidepressants shall be taken every day (as prescribed)
  • antidepressant effects might be observed in 2-4 weeks time (or later) so be patient
  • side effects are usually observed at the begining of the treatment and last for a few days, do not stop taking the drug before consulting with the doctor
  • treatment will last for a few months (6-9 months in a first episode)
• The treatment plan must be a continuous process with the following stages:
  • Starting the treatment, a observation is required every 4-6 weeks.
    • With a lack of a respons, the dose is maximilizied for 2-4 weeks at a time. (If still lack of a response, another drug can be used with another 4-6 observation period).*
    • With a good response, continuation of treatment, for 6-9 months is required.
    • In the event of drug intolerance, another drug is used with another 4-6 observation period. (If there is a lack of response or drug intolerance another new drug will require 4-6 weeks of observation)
  • If treatment is treatment resistance, review the following:
    • A = adequacy of treatment (type of drug, dose, duration of therapy)
    • B = behavioral factors (stresful life events, family problems, financial problems)
    • C = compliance ( 40% of patients discontinue treatment during first month)
    • D = diagnosis (bipolar disorder, somatic diseases...)
  • If treatment is still needed consider:
    • changing the drug
    • adding one AD to another (different mechanism of action)
    • potentiation by adding: lithium, thyroid hormones, or atypical antipsychotic drugs (olanzapine, aripiprazole)
  • Alternative drug options to consider: antiepileptic drugs, tryptophane, pindolol, psychostimulants (modafinil), glutaminergic agents (ketamine), and zinc
• Conditions that can evoke depressive symptoms include:
  • Chronic pain (60-87%)
  • Cushing syndrome (50-70%)
  • Hypothyroidism (>50%)
  • Cancer (>50%)
  • Cardiac ischemic disease (40%) with values of: (following MI (25%), following by-pass surgery (70%))
  • Diabetes (36%)
  • Dialysis (severe renal insufficiency) (20%)
  • Hyperthyroidism (20-30%)
• Be aware that DRUGS can evoke depressive symptoms, exampled include:
  • Sympatholitycs: Beta-blockers (propranolol, carvedilol), clonidine (alfa2-blocker) and rezerpine, and alfa-methyldopa
  • Butyrophenone neuroleptics (haloperidol)
  • Cholinergic agents
  • Calcium channel blockers
  • Dopaminergic agents (amantadine, bromocryptine)
  • Hormones (ACTH, adrenal steroids, progesterone+estrogens)

Common Depressive Symptom Management

• For a typical episode, an SSRI is the drug of choice.
• For apathy and decreased psychomotor activity: Bupropion (NDRI), venlafaxine (SNRI), moclobemide (MAO-I), or an SSRI may be used.
• For anxiety: an SSRI, SNRI, agomelatine, or moclobemide may be used.
• For agitation: Mirtazapine, mianserine, or a TCA may be used.
• For insomnia: Mirtazapine, mianserine, trazodone, or agomelatine are options.
• For pain: SNRI or TCA antidepressant may be used.
• For cognitive impairment: SSRI, vortioxetine, or bupropione may be used.
• For seasonal depression: bupropione or phototherapy may be used.

Continuation Treatment

• The length of treatment varies according to patient medical history:
  • 6 months is the period for a typical episode, fast&good response
  • 9 months is the period for a long-lasting episode, psychotic or residual symptoms
  • Two years or more is a period for those who had: one depressive episode in the past, high recurrence, psychotic symptoms, suicidal tenders, long-lasting episodes, or recurrence after AD discontinuation in the past

Patient Cases

• Patient #1:
  • A 26-year-old woman presented with symptoms developing over about 4 weeks.
    • She had lowering of mood, decrease in activity, and anhedonia.
    • She described a feeling of reduced self-esteem and confirmed that ideas of worthlessness were present.
    • She did not fulfil the criteria for delusions and denied having suicidal thoughts.
  • Further symptoms included diminished appetite, and disturbed sleep with problems falling asleep and waking up around 3 am.
    • The patient never had psychiatric treatment or long-term medical treatment.
    • This patient is experiencing a depressive episode.
    • Drugs of choice include citalopram, escitalopram, sertraline,
    • Additionally, sleep disturbances can be treated with drugs registered only for sleep disturbances such as zolpidem, zopiclone, and zaleplone although dependency is a risk.
    • Alternatively, antidepressants with hypnotic activity such as Trazodone, Mianserine, Mirtazapine or Agomelatine can be used.
  • A treatment plan for this patient was sertraline and low-dose trazodone, which improved his sleep and mood.
  • Trazodone was later discontinued, due to concerns for loss of libido.
  • An alternate option was using Bupropion monotherapy.
  • Ultimately treatment was switched to Bupropion and improvement of mood and libido were reported.
  • The treatment period should continue for for 6 months.
• Patient #2.
  • A 47-year-old man presented with depressive symptoms developing over the previous few weeks.
    • The main complaint was reduced energy levels and motivation, accompanied by a feeling of psychomotor retardation, lowering of mood, reduced capacity of enjoyment and generalized anxiety symptoms.
    • The patient had two depressive episodes in the past and was successfully treated with escitalopram, and has essential hypertension.
    • A course of escitalopram at 10mg reduced symptoms by 20%.
  • The escitalopram dose was increased to the maximum of 20mg, and after further weeks the patient did not report noticeable improvement, especially with energy and activity levels.
  • A higher choice of drug was venlafaxine or duloxetine, however, the patient experiences essential hypertension.
  • Ultimately the treatment was venlafaxine and the patient's mental state remarkably improved after 4 weeks.
  • This patient will require treatment for at least 5 years.
• Patient #3.
  • A 35-year-old woman, with multiple comorbidities.
    • Chronic kidney discase (post renal transplant, on dialysis), epilepsy, Epstein syndrome (trombocytopenia, hearing loss, renal insufficiency), purpura, coeliac disesase, and glaucoma, currently undergoing therapy with antibiotics (gentamicin, meropenem) due to sepsis.
    • Before the dialysis, the patient complained of a severe headache and was given metamizole i.v. and tramadol, however, the CT scans showed no pathology.
    • The patient is treated for depression and is on sertraline (50mg/d), fluoxetine (40mg/d), and trazodone (150mg/d).
  • Multiple mistakes occur within this patient's treatment, including:
    • Never combine two (or more) drugs with serotonin action due to the risk of serotonin syndrome.
  • Sertaline and fluoxetine are are two drugs which should never be used in tandem.
  • Trazodone acts of serratonin in doses of 150mg and up.
  • Tramadol further induces serotonin action.
• Patient #4.
  • A 76-year-old patient with a history of:
    • Type 2 diabetes, hypothyroidism, and recurrent depressive disorder (in remission).
    • He is being treated with citalopram (40mg/d), metformin (1500mg/d) and levothyroxine (50ug/d).
• The patient lab results were: pH 7.417 [7,350 - 7,450], pCO2 40.5 mmHg [35,0 - 48,0], CtHb 9.8 g/dL [12,0 - 16,0] L, Hct 30.4% [34,0 - 44,0] L, FCOHb 0.8 % [0,5 - 1,5], FMetHb 0.6 % [0,0 - 1,5], CK+ 3.8 mmol/l [3,5 - 5,0], CNa+ 122.0 mmol/l [136,0 - 146,0], CCa2+ 1.18 mmol/l [1,15 - 1,29], CCI- 104.0 mmol/l [98,0 - 106,0], CGlu 6.8 mmol/l [3,9 - 5,8], CLac 1.0 mmol/l [0,5 - 1,6], CCrea 108.0 umol/l [44,0 - 124,0], CtBil 6.0 umol/l [1,0 - 17,0].
  • This patient electrocardiogram results were regular sinus rythm, 75bpm, and QTc = 470ms.
  • The drug should be changed because citalopram has the highest risk of QTc prolongation.