Understanding Depression

Depression

• A mood disorder affecting cognitive, behavioral, and emotional aspects
• A long-term disease, but can be treated and cured
• Can affect anyone at any time in their life
• Requires treatment by a specialist
• It is a disease, not a weakness

Depression Symptoms

• Emotional Symptoms: Apathy, pessimism, sadness, low self-esteem
• Biological Symptoms: Sleep disorders, loss of motivation, loss of appetite, suicidal thoughts, delayed thinking and action, loss of libido

Other Forms of Depression

• Postpartum depression
• Premenstrual disorder
• Affective emotional disorder

Treatment of Depression

• Prevention
• Psychotherapy (mild depression)
• Psychotherapy + pharmacological treatment (moderate depression)
• Hospitalization (severe depression)
• ECT (Electroconvulsive Therapy)

Pharmacological Treatment of Depression

• Depression associated with decreased neurotransmitter release in the synapse, particularly Dopamine and 5-HT
• Treatment phases:
  • Remission phase: takes 2-4 weeks for antidepressants to start working
  • Continuation phase: 6-12 months

Tricyclic Antidepressants (TCA)

• Mechanism of action: Block the uptake of amines, inhibit noradrenaline and 5-HT uptake (less effect on dopamine uptake)
• Improves emotional symptoms: enhancement of 5-HT
• Relieves biological symptoms: facilitation of noradrenergic transmission (α receptors)
• Affect other receptors: antimuscarinic effects responsible for various side effects

TCA Pharmacokinetics

• Highly liposoluble drugs
• Good distribution (BBB)
• Taken orally, in progressively increasing doses
• Fixed to plasma proteins
• Hepatic metabolism
• Active metabolites
• Long elimination half-life (10-80 h), even longer in elderly patients
• Developing side effects

TCA Pharmacological Actions

• Antidepressant action seen during the first 4 weeks of treatment
• Improves sleep, appetite, psychomotor activity
• By the fourth week, depressed mood and feelings of despondency and hopelessness improve
• Clinical efficacy limited and varies among individuals
• Different classes of antidepressants have similar efficacy but different side effects
• Choice of drug based on individual aspects including concomitant disease
• SSRIs preferred as better tolerated and less dangerous in overdose
• Antidepressant drugs take several weeks to be effective, avoid changing dose or class prematurely
• MAOIs only prescribed by specialists
• Effective regimen should be continued for at least 2 years
• In urgent situations, specialist may consider electroconvulsive therapy (ECT)
• Anxiolytic (e.g. benzodiazepine), or antipsychotic drugs may be useful in some patients

Bipolar Disorder

• Mental health condition with extreme mood swings, including episodes of mania and depression
• These phases can significantly impact behavior, energy levels, and daily functioning

Treatment of Bipolar Disorder

• Lithium Salts: Lithium carbonate
  • Orally administered
  • Excreted by kidney
  • Narrow therapeutic margin (monitoring of plasma concentration essential)
  • Mechanism of action unknown
  • Effective in both manic and depressive phases, acting as a stabilizer
  • Increases the release of NA and 5-HT in the brain
  • May be beneficial in neurodegenerative diseases such as Alzheimer's disease

Lithium Salts ADRs

• Gastric discomfort, nausea, vomiting, diarrhea
• Anorexia
• Weight gain
• Polyuria, thirst (due to inhibition of antidiuretic hormone action)
• Trembling hands
• In chronic administrations: Thyroid disorders, kidney disorders
• In the first months of pregnancy, can induce fetal malformations

Lithium Salts Therapeutic applications

• Drug of first choice in controlling manic phases and preventing bipolar disorder

Depression

• Depression is a mood disorder with cognitive, behavioral, and emotional alterations.
• It is a long-term disease, but one that can be treated and cured.
• Depression can affect anyone at any time in their life.
• It requires specialist treatment and is a disease, not a weakness.

Depression Symptoms

• Emotional: Apathy, pessimism, sadness, low self-esteem.
• Biological: Sleep disorders, loss of motivation, loss of appetite, suicidal thoughts, delayed thinking and action, loss of libido.
• Other forms of depression include postpartum depression, premenstrual disorder, and affective emotional disorder.

Treatment of Depression

• Prevention is crucial.
• Psychotherapy is effective for mild depression.
• Psychotherapy + Pharmacological Treatment is recommended for moderate depression.
• Hospitalization is necessary for severe depression.
• ECT (Electroconvulsive Therapy) can be used for treatment-resistant cases.

Pharmacological Treatment of Depression

• Depression is linked to decreased neurotransmitter release in the synapse, especially dopamine and serotonin.
• Treatment phases:
  • Remission phase: Antidepressants take 2-4 weeks to start working.
  • Continuation phase: Requires 6-12 months of treatment.

Tricyclic Antidepressants (TCA)

• Actions: Anxiolytic, sedative, analgesic (particularly for chronic pain associated with depression), used in neuropathic pain treatment.
• ADRs:
  • Cardiovascular: Orthostatic hypotension, palpitations, tachycardia.
  • Antimuscarinic Effect: Dry mouth, constipation, urinary retention, nasal congestion, blurred vision.
  • Neurological: Tremors in hands and head.
  • Other: Weight gain, excessive sweating, photosensitivity, gastrointestinal discomfort.
  • Intoxication: Overdose is common due to suicidal tendencies, leading to arrhythmias, convulsions, and coma.

TCA Drug Interactions

• Pharmacodynamic: Enhances the actions of catecholamines and MAOIs.
• Pharmacokinetic:
  • Increases the activity of oral anticoagulants leading to increased bleeding risk.
  • Oral contraceptives inhibit TCA metabolism.
  • Potentiates the effects of alcohol and anesthetic agents, potentially causing death.
  • Interferes with antihypertensive drugs.

TCA Therapeutic Applications

• Depressive syndromes.
• Anxiety syndromes (panic attacks).
• Hyperactivity syndrome: Imipramine.
• Treatment of enuresis: Children over 5 years old (imipramine).
• Pain: Neurogenic (phantom limb syndrome), oncological, headaches.

Selective Serotonin Reuptake Inhibitors (SSRI)

• Mechanism: Inhibits serotonin reuptake in the synapse, increasing serotonin concentration.
• Drugs: Fluoxetine, Paroxetine, Citalopram, Sertraline.
• Commonly prescribed antidepressant: Fewer cardiac side effects than TCAs.
• Less effective than TCAs for severe depression, equally effective for moderate depression.
• Pharmacokinetics: Oral administration, half-life of 15-24 hours.
• ADRs: Orthostatic hypotension, tremors, excitement, insomnia, convulsions (overdose), increased appetite.

Monoamine Oxidase Inhibitors (MAOI)

• Mechanism: Inhibits the enzyme MAO, preventing the breakdown of neurotransmitters like norepinephrine, dopamine, and serotonin.
• Drug Interactions:
  • Tyramine: Consumption of tyramine-rich foods (aged cheese, red wine, beer, cured meats) can lead to hypertensive crisis.
  • SSRIs or TCAs: Risk of serotonin syndrome.
  • Other drugs: Enhances depressant effects of sympathomimetics, antihistamines, and opioids, increasing the risk of overdose.
• Therapeutic applications: Reserve antidepressant, used when tricyclics and derivatives fail or in cases of atypical depression.

Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)

• Mechanism: Non-selective inhibition of serotonin and norepinephrine reuptake.
• Drugs: Venlafaxine, Desvenlafaxine, Duloxetine.
• Widely used antidepressants, effective for some anxiety disorders.
• Potential uses: Treating perimenopausal symptoms (hot flushes and insomnia), neuropathic pain and fibromyalgia, urinary incontinence.
• Pharmacokinetics: Active orally, slow-release formulation available for venlafaxine to reduce nausea.
• ADRs: Headache, insomnia, sexual dysfunction, dry mouth, dizziness, sweating, decreased appetite, CNS depression (overdose), serotonin toxicity, convulsions, cardiac conduction abnormalities.
• Duloxetine: Reports of hepatotoxicity, contraindicated in patients with hepatic impairment.

Other Noradrenaline Uptake Inhibitors

• Bupropion:
  • Inhibits both norepinephrine and dopamine reuptake.
  • No abuse potential.
  • Used for nicotine dependence treatment.
  • Can induce seizures at high doses.
• Reboxetine and Atomoxetine:
  • Highly selective for norepinephrine reuptake.
  • Less effective for depression than TCAs.
  • Atomoxetine is used for attention deficit/hyperactivity disorder.

Others: Natural Compounds

• Hypericum perforatum (St. John's Wort):
  • Main active ingredient: Hyperforin.
  • Inhibits reuptake of serotonin, dopamine, norepinephrine, GABA, and glutamate.
  • Antidepressant and anxiolytic effects.
  • Significant drug interactions.

Monoamine Receptor Antagonists

• Mirtazapine:
  • Blocks alpha-2, 5-HT2C (antidepressant effects), and H1 receptors.
• Trazodone:
  • Combines 5-HT2A and 5-HT2C receptor antagonism with serotonin reuptake inhibition.

Melatonin Agonist

• Agomelatine:
  • Agonist of MT1 and MT2 receptors.
  • Short biological half-life.
  • Used to treat severe depression, usually taken once daily before bed.
  • May work by correcting circadian rhythm disturbances.
  • Associated with hepatotoxicity.

Electroconvulsive Therapy (ECT)

• Used for patients not responding to antidepressant drugs, especially severe suicidal depression.
• Effective treatment.
• Causes confusion and memory loss lasting for days or weeks.

Repetitive Transcranial Magnetic Stimulation (TMS)

• Less effective than ECT.

Clinical Use of Antidepressants

• Mild depression is often best treated with non-drug measures.
• Antidepressant drugs are advisable for moderate to severe depression.
• Doses should be adjusted to individual patient characteristics.

Lithium Carbonate

• Used for treatment of mania-depressive (bipolar) disorders.
• Improves 70% of cases, taking 1-2 weeks to take effect.

Bipolar Disorder: Antiepileptic Drugs

• Carbamazepine, Valproate, Lamotrogine:
  • Fewer side effects than lithium, effective for bipolar disorder.
  • Valproate and carbamazepine are used for acute mania and long-term treatment.
  • Lamotrigine prevents recurrence of mania and depression.
  • Induce liver enzymes, modifying the actions of other drugs.
  • Carbamazepine: Enzyme inducer.
  • Valproic acid (valproate): Highly teratogenic, can cause spina bifida.

Bipolar Disorder: Atypical Antipsychotic Drugs

• Olanzapine, Risperidone, Quetiapine, Aripiprazole:
  • Second-generation drugs developed for schizophrenia.
  • Antagonists of D2-dopamine and 5-HT2A receptors.
  • Effective against mania.
  • Used in combination with lithium or valproate for bipolar depression.
  • Olanzapine is given with fluoxetine (antidepressant).
• Haloperidol: Indicated for prophylaxis of mania-depressive disease.