Understanding Depression

• Antidepressants are a class of medications used to treat depression.
• Kennedy Edem Kukuia, PhD, is an Associate Professor of Neuropsychopharmacology.

Depression

• Depression is an affective disorder characterized by persistently low mood and loss of interest or pleasure (anhedonia) in almost all a person's usual activities or pastimes.
• Depression symptoms include emotional and biological components.
• Emotional symptoms: misery, apathy, pessimism, low self-esteem, feelings of guilt, inadequacy, ugliness, indecisiveness, and loss of motivation.
• Biological symptoms: retardation of thought and action, loss of libido, sleep disturbance, and loss of appetite.
• Depression: multifactorial brain disorder - symptom's can reflect abnormal functioning in many parts of the brain.
• Sleep disturbances occur in the brainstem and hypothalamus.
• Appetite and energy issues occur in various hypothalamic areas.
• Anhedonia or mania occur in limbic structures.
• Anxiety occurs in the amygdala.
• Alterations in thought content occur in the cortex.

The Mood Spectrum

• Bipolar I disorder includes mania, hypomania, euthymia (normal mood), dysthymia and major depression
• Bipolar II disorder includes hypomania, euthymia (normal mood), dysthymia and major depression.
• Cyclothymia includes hypomania, euthymia (normal mood), and dysthymia.

DSM-V-TR Criteria for Major Depressive Episode

• Five or more symptoms must be present during the same 2-week period, representing a change from previous functioning.
• At least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
• Depressed mood present most of the day nearly every day
• Markedly diminished interest or pleasure in all, or almost all, activities most of the day nearly every day
• Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day
• Insomnia or hypersomnia nearly every day
• Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings)
• Fatigue or loss of energy nearly every day
• Feelings of worthlessness/ excessive or inappropriate guilt nearly every day
• Diminished ability to think or concentrate, or indecisiveness, nearly every day
• Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
• B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).
• D. The symptoms are not better accounted for by bereavement.
• Symptoms must persist for longer than 2 months.
• Symptoms are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

Depressive Disorders

• Major depressive disorder.
• No manic or hypomanic episodes
• Can be recurrent or single episode
• Persistent depressive disorder (dysthymia).
• No high phases
• Lasts much longer than typical MDD.
• Usually not severe enough to be called an episode of MDD
• Disruptive mood dysregulation disorder.
• Usually occurs in children
• Mood is persistently negative between frequent, severe explosions of temper
• Premenstrual dysphoric disorder.
• Occurs a few days before menses
• A woman experiences symptoms of depression and anxiety
• Depressive disorder due to another medical condition.
• Depressive symptoms due to medical or neurological conditions
• Substance/medication-induced depressive disorder.
• Alcohol or other substances (intoxication or withdrawal)

Neurobiology of Depression

• Stress increases Glutamate which can decrease good and increase detrimental transcription responses.
• This causes neural apoptosis, prevents neurogenesis and causes depressive symptoms.

Monoamine Theory

• Serotonin becomes Metabolites with the help of MAO-A
• Serotonin is either sent to the postsynaptic axon, or back into the system with the help of SERT, to become serotonin again

Neurotrophic Hypothesis

• Glucocorticoids can put the brain in a depressed state.
• BDNF, Monoamines, Glutamate and other elements, are decreased in a depressed state as compared to a treated state.

Antidepressant Classes

• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-noradrenaline reuptake inhibitors (SNRIs)
• Atypical antidepressants/ heterocyclics
• St. John's Worts- herbal medication
• Melatonin receptor agonists- Agomelatine
• NMDA receptor antagonists*- ketamine, esketamine

Tricyclic Antidepressants

• So-called because of three-ring structure
• Closely resemble the phenothiazines
• Imipramine and amitriptyline are prototypes examples
• Other examples: Trimipramine, doxepine, clomipramine, nortriptyline, desipramine, and protriptyline

Mechanism of Action

• Block reuptake of NA and 5HT by competing for the binding site of the transport protein
• Does not affect synthesis, storage, and release of these amines directly
• Some TCAs increase transmitter release by blocking presynaptic α₂-adrenoceptors
• Block of 5HT reuptake improves emotional symptoms
• Block of NA reuptake improves biological symptoms
• Beta-adrenoceptor down-regulation occurs at central noradrenergic synapses
• Focuses on a cascade of adaptive changes at the noradrenergic synapse that appears to be triggered by inhibition of noradrenaline neuronal reuptake
• Time Dependent changes in beta-adrenoceptor function parallel the time delay associated with clinical efficacy of these drugs (2-3 weeks)
• Density increase in the postsynaptic 5-HT1A receptors leads to supersensitivity to serotonin (5-HT1A) receptor agonists at serotonin synapses
• 5-HT1A supersensitivity parallels the delayed onset of the therapeutic actions of these agents (2-3 weeks)

Actions and Unwanted Effects

• Unwanted effects can be due to antimuscarinic, antihistaminergic (H1) and anti-adrenergic (a1) properties
• In the non-depressed, TCAs cause sedation, confusion & motor incoordination.
• Effects also occur in depressed patients in the first few days of treatment, but tend to wear off in 1-2 weeks as the antidepressant effect develops.
• Dry mouth, blurred vision, constipation and urinary retention occurs
• Strong with amitriptyline and much weaker with desipramine.
• This is attributed to the antimuscarinic effect
• Postural hypotension occurs with TCAs and is possibly results from an effect on adrenergic transmission in the medullary vasomotor center.
• This is known at the a1 inhibition
• Sedation, drowsiness, difficulty in concentrating & weight gain.
• Attributed to Antihistaminergic effect
• Usual therapeutic doses of TCAs increase the risk of sudden cardiac death
• In overdose, may cause ventricular dysrhythmias associated with prolongation of the QT interval.
• Therapeutic doses of the TCA drugs lower the seizure threshold and at toxic doses can cause life-threatening seizures.
• The initial effect of TCA overdosage is to cause excitement and delirium, which may be accompanied by convulsions.
• This is followed by coma and respiratory depression lasting for some days.
• Anticholinesterase drugs have been used to counter atropine-like effects but are no longer recommended.

Pharmacokinetics of TCAs

• Most are well absorbed orally and undergo extensive first pass metabolism
• Half-lives range from 8 to 89 hours.
• Several days to weeks are required both to achieve steady-state serum levels and for complete elimination of these agents from the body
• Once daily dosing due to long half-life, generally at bedtime
• Volume of distribution is large
• High lipophilicity & high protein binding
• Metabolism occurs by two major routes:
• Transformation of the tricyclic nucleus by hydroxylation
• Alteration of the aliphatic side chain: demethylation of tertiary amines leads to active metabolites such as desipramine and nortriptyline
• Conjugation of hydroxylated products to glucuronides

Interactions with Other Drugs

• Inhibition of metabolism by competing drugs (e.g. antipsychotics, oral contraceptives, and some SSRIs).
• Phenytoin, aspirin, phenothiazines compete with protein binding
• Potentiate the effects of alcohol and anaesthetic agents.
• Deaths occur when severe respiratory depression has followed a bout of drinking.
• Simultaneous administration with MAOIs can cause CNS toxicity (hyperpyrexia, convulsions, and coma).
• In TCA-resistant patients, it is advisable to discontinue the TCA drug for 2 to 3 weeks before initiation of a MAOI agent.
• Interfere with the action of various antihypertensive drugs, with potentially dangerous consequences
• Their use in hypertensive patients requires close monitoring.

Clinical Indications of TCAs

• Mood disorders: major depressive disorder, dysthymia, treatment-resistant variants.
• Anxiety disorders: GAD, SAD, OCD, panic disorder, PTSD
• Eating disorders: anorexia nervosa and bulimia nervosa
• Certain personality disorders
• Neurological disorders: ADHD
• Parkinson's disease
• Chronic pain, neuropathic pain, fibromyalgia, headache, migraine
• Smoking cessation
• Tourette syndrome
• Irritable bowel syndrome
• Interstitial cystitis
• Nocturnal enuresis
• Narcolepsy, insomnia
• Pathological crying and/or laughing
• Chronic hiccups
• Ciguatera poisoning
• As an adjunct in schizophrenia.

Monoamine Oxidase Inhibitors

• Iproniazid, originally developed for the treatment of TB, exhibited mood-elevating properties during clinical trials in TB patients with depression.
• There are Hydrazides and Non-hydrazides which are subgroups of Monoamine Oxidase Inhibitors
• Hydrazides include: Phenelzine and Isocarboxazid
• Non-hydrazides include Tranylcypromine
• They are readily absorbed from the GIT, gastro intestinal tract
• Phenelzine is acetylated in the liver and manifests differences in elimination depending on the acetylation phenotype of the individual
• Inhibition of MAO persists even after these drugs are no longer detectable in plasma.
• Conventional p'cokinetic parameters (t1/2, etc) are not very helpful in governing dosage.
• Be prudent to assume that the drug effect will persist for 7 days (tranylcypromine) to 2 or 3 weeks (phenelzine) after discontinuance of the drug.
• They can cause life-threatening effects such as Hepatotoxicity & dietary tyramine-induced hypertensive crisis and are also as effective as SSRIs and heterocyclics so should be reserved for treatment-resistant depressions
• Transdermal formulation of selegiline reduces the common side-effects.

Mechanism of Action

• MAO-A: noradrenaline, serotonin and dopamine
• MAO-B: dopamine
• Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B.
• Inhibition of MAO-A is responsible for antidepressant action
• There are selective MAO-A inhibitors E.g. clorgyline or moclobemide
• Inhibition is achieved clinically within a few days of treatment, while the antidepressant effects are not observed for 2 to 3 weeks
• This suggests additional actions must be involved
• MAOIs induce adaptive changes in the CNS synaptic physiology over 2 to 3 weeks.
• down-regulation of synaptic transmission mediated through noradrenergic a- and beta-adrenoceptors
• up-regulation or enhancement of synaptic transmission at serotonin synapses (5HT1A receptors).

Adverse Effects

• Hepatotoxicity
• Tyramine-induced hypertensive crisis: increased BP
• Tremors
• Orthostatic hypotension
• Ejaculatory delay
• Dry mouth
• Fatigue
• Weight gain

Drug Interactions

• Serious hypertension can occur with concomitant administration of over-the-counter cough and cold medications containing sympathomimetic amines.
• Switching from an MAOI to another antidepressant, such as a SSRI, requires a drug-free period of 2 weeks to allow for the regeneration of tissue MAO and elimination of the MAOI.
• Switching from an antidepressant, such as an SSRI, to a MAOI, requires sufficient time for the SSRI to be cleared from the body (at least 5 half-lives) before starting the MAOI.
• Coadministration of a MAOI and an SSRI or venlafaxine can overstimulate the serotonin receptors in the brainstem and spinal cord, and can be lethal due to serotonin syndrome.

Serotonin Syndrome

• Potentially lethal
• Serotonin syndrome consists of a constellation of psychiatric, neurological, and cardiovascular symptoms.
  • Symptoms: Confusion, elevated or dysphoric mood, tremor, myoclonus, incoordination, hyperthermia & cardiovascular collapse
  • Treatment: discontinue serotoninergic agents, treat symptoms, give 5-HT antagonists eg; cyproheptadine, or methysergide, give dantrolene

Selective Serotonin Reuptake Inhibitors

• Fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine
• Improved safety and tolerability
• Have little or no affinity for cholinergic, histamine and β-adrenergic receptors
• Do not interfere with cardiac conduction
• Tolerated by those with heart disease and the elderly

Mechanism of Action

• Inhibition of 5-HT reuptake by nerve terminals
• Increased 5-HT levels activate 5-HT1A autoreceptors resulting in decreased neuronal firing
• Desensitization of autoreceptors results in enhanced serotonin release
• There is desensitization of 5-HT1B autoreceptors as well

SSRI Considerations

• Patients can experience agitation and anxiety with therapy initiation
• Start with low dose and titrate up
• Insomnia is also common
• May have to add sedating agent at bed time
• Nausea and loose stools are frequent
• Take medication with food
• Up to 1/3 complain of sexual dysfunction, including decreased libido, delayed ejaculation, and anorgasmia.
• With the exception of paroxetine, they do not affect weight.

Fluoxetine Considerations

• Given in the morning because of its potential for being activating and causing insomnia.
• Food does not affect its systemic bioavailability, and may actually lessen the nausea reported by some patients.
• Highly bound to serum proteins and may interact with other highly protein bound drugs.
• Demethylated in the liver to form an active metabolite, norfluoxetine.
• Inactive metabolites are excreted by the kidney.
• Doses must be reduced in patients with liver disease.
• The slow elimination of fluoxetine and norfluoxetine lead to special clinical concerns when adjusting doses and discontinuing this medication.
• Steady state is not reached until 4 to 6 weeks, and similarly, complete elimination takes 4 to 6 weeks after discontinuation of the medication.
• A 4- to 6-week waiting period should be permitted before starting a medication with potential for an interaction with fluoxetine, such as a MAOI.
• A potent inhibitor of cytochrome P450 2D6 and can significantly elevate levels of drugs metabolized by this route.
• Co-administration of drugs with a narrow therapeutic index, such as TCAs and type 1C antiarrhythmics, including flecainide and propafenone, are a particular concern.

Sertraline Considerations

• Has an elimination t1/2 of 25 hr and can be administered once a day, usually in the morning to avoid insomnia.
• Sertraline undergoes extensive hepatic metabolism, and doses must be reduced in patients with liver disease.
• Sertraline may produce more GI side effects, such as nausea and diarrhoea, than does fluoxetine BUT generally less activating than fluoxetine.
• Highly bound to serum proteins (98%) and may alter plasma protein binding of other medications.
• A 14-day washout period is recommended before starting a MAOI.
• Weak inhibitor of cytochrome P450 2D6.
• Intensive therapeutic drug monitoring is indicated when combining sertraline with drugs metabolized by this route that have:
• Narrow therapeutic index such as the TCAs and the type 1C antiarrhythmics, propafenone, encainide, and flecainide.

Paroxetine Considerations

• Has an elimination half-life of 21 hours and is also highly bound to plasma proteins, so it requires special attention when administered with drugs such as warfarin.
• Potent inhibitor of the cytochrome P450 2D6 isoenzyme and can raise the plasma levels of drugs metabolized via this route.
• Drugs with a narrow therapeutic index, such as TCAs and the type 1C antiarrhythmics flecainide, propafenone, and encainide, are of particular concern.
• Paroxetine itself is metabolized by this enzyme and inhibits its own metabolism, leading to nonlinear kinetics.
• Weight gain is higher with paroxetine than with the other SSRIs, and it tends to be more sedating, presumably because of its potential anticholinergic effects.
• Patients have had difficulty with abrupt discontinuation, reporting a flulike syndrome
• This symptom can be avoided by tapering the medication

Citalopram Considerations

• Has an elimination half-life of 35 hours and is 80% bound to plasma proteins.
• It has the least effect on the cytochrome P450 system and has the most favourable profile regarding drug-drug interactions.

Clinical Indications of SSRIs

• Major depressive disorder
• Anxiety disorders
• Social anxiety disorder
• Panic disorders
• Obsessive-compulsive disorder (OCD)
• Posttraumatic stress disorder (PTSD)
• Eating disorders
• Chronic pain
• Depersonalization disorder

Heterocyclics

• 2nd Generation: Trazodone, amoxapine, maprotyline, bupropion
• 3rd Generation: Nefazodone, mirtazapine, venlafaxine

Venlafaxine

• Inhibits the reuptake of both 5-HT and NA at their presynaptic sites.
• Does not have significant effects at muscarinic, histamine or a-adrenergic receptors; so it's devoid of many of the side effects of TCAS.
• Venlafaxine and its active metabolite, O-desmethyl-venlafaxine, have t1/2 of 5 and 11 hr respectively, so dosing twice a day is necessary.
• Extended release preparation now allows for once-daily dosing and better tolerance.
• Has a side effect profile similar to that of the SSRIs
• Higher doses of venlafaxine result in modest increases in blood pressure in approximately 5% of patients.
• Has minimal effects on the cytochrome P450 enzyme system.

Duloxetine

• This is an SNRI with a more balanced reuptake inhibitory effect when compared with venlafaxine
• Duloxetine is well absorbed; half-life (12 hrs); however it is dosed once daily.
• It is tightly bound to protein (97%) and undergoes extensive oxidative metabolism via CYP2D6 and CYP1A2.
• Hepatic impairment significantly alters duloxetine levels unlike desvenlafaxine.

Bupropion

• It is a weak inhibitor of both dopamine and NA neuronal reuptake.
• However, its actual antidepressant activity is not well understood.
• Generally well tolerated and does not block muscarinic, histaminergic, or adrenergic receptors.
• Unlike the SSRIs and venlafaxine, bupropion does not cause sexual side effects.
• Can cause CNS stimulation, including restlessness and insomnia.
• High doses of bupropion are associated with a risk of seizures in 0.4% of patients.
• This risk is lower with slow-release bupropion.
• This formulation still requires dosing twice a day,
• Bupropion is contraindicated in patients with a history of seizures.
• It inhibits the cytochrome P450 2D6 isoenzyme, and may elevate blood levels of drugs metabolized by this route.

Mirtazapine

• Enhances both serotonergic and noradrenergic neurotransmission.
• By blocking presynaptic a2-adrenoceptors, mirtazapine causes release of norepinephrine.
• Indirectly, through noradrenergic modulation of serotonin systems, mirtazapine also causes increased release of serotonin.
• It is an antagonist at the 5-HT2A1 5HT2C1 5-HT3, and histamine receptors but has minimal affinity for muscarinic or a₁-receptors.
• Mirtazapine does not inhibit neuronal reuptake of serotonin or norepinephrine.
• Weight gain and sedation are common side effects.
• Sedation necessitates dosing at bedtime.
• Does not have significant effects on cytochrome P450 isoenzymes.

Trazodone

• It blocks the neuronal reuptake of serotonin and is an antagonist at the 5HT2-receptor.
• Its major metabolite, m-chlorophenylpiperazine (mCPP), is a postsynaptic serotonin receptor agonist.
• When compared to the TCAs, trazodone is relatively free of antimuscarinic side effects, but it does block the α-adrenoceptor.
• Common side effects include marked sedation, dizziness, orthostatic hypotension, and nausea
• Priapism is an uncommon but serious side effect requiring surgical intervention in one-third of the cases reported.
• Because of trazodone's sedating quality, it is often used in low doses to counter the insomnia associated with the newer antidepressants, such as the SSRIs.

Nefazodone

• Structurally related to trazodone, it is less sedating.
• Does not block a1-adrenoreceptors, and its use is not associated with priapism but there are reports of clitoral priapism.
• Inhibits the neuronal reuptake of serotonin and blocks 5HT2A receptors.
• Has short half-life that requires dosing twice a day.
• It is not associated with weight gain or sexual dysfunction in men.
• It :inhibits the cytochrome P450 3A4 isoenzyme that is responsible for 50% of known oxidative metabolism.
• It can therefore elevate levels of drugs dependent on this pathway for metabolism.
• It is associated with hepatic injury- should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases.

Assignment

• Read on Lithium in the management of mania
• Read on the role of Electroconvulsive shock therapy in the treatment of depression