MDD Diagnostic Criteria and Assessment

MDD Diagnostic Criteria

• Major Depressive Disorder (MDD) is also known as unipolar depression
• MDD diagnosis requires at least five symptoms nearly every day for a minimum of 2 weeks
• One key symptom is a depressed mood or anhedonia which is a loss of interest in pleasurable activities
• Additional MDD symptoms include:
  • Sleep disturbances
  • Changes in weight or appetite
  • Decreased energy
  • Feelings of guilt or worthlessness
  • Psychomotor retardation or agitation
  • Decreased concentration
  • Suicidal ideation
• Persistent Depressive Disorder (Dysthymia) involves chronic depressed mood for the majority of days over at least 2 years.
• Dysthymia does not meet the full criteria for MDD.

Assessment of MDD Patients

• A thorough psychiatric history is gathered and compared to diagnostic criteria to establish a diagnosis.
• Clinician rating scales are psychometric tools for identifying depression and assessing its severity
• Common clinician rating scales include:
  • Hamilton Rating Scale for Depression (HAM-D/HDRS) which is often used in clinical trials for FDA approval of antidepressants
    • A typical clinical trial enrollment score exceeds 18, indicating moderate-severe depression
    • A positive response is generally defined by at least a 50% reduction in the HAM-D score
    • Remission is defined as a return to a normal state, or a HAM-D score of 7 or less
  • CGI (Clinical Global Impressions) scale is a clinician-rated metric that evaluates the overall severity and improvement.
  • MADRS (Montgomery-Åsberg Depression Rating Scale)evaluates depression symptoms and is used in clinical trials.
• Patient-completed rating instruments, using questionnaires, help identify and assess the degree of depression.
• Patient Health Questionnaire-9 (PHQ-9) aligns with DSM-5 criteria for major depression.
  • The PHQ-9 is simple to administer and assess
  • It is often used in primary care settings
  • An abbreviated version can be used for screening (PHQ-2)
  • The PHQ-9 is also used to monitor treatment response
• Other patient-completed tools include:
  • Beck Depression Inventory (BDI)
  • Quick Inventory of Depressive Symptoms (QIDS), which is self-rated
  • Geriatric Depression Scale (GDS)
• Physical exams and lab tests help rule out underlying conditions that mimic depression, like thyroid disorders or vitamin deficiencies.
• Common biologic laboratory tests include dexamethasone suppression and thyroid axis tests, however, these are not routinely used.
• The medication and substance history including interferons, benzodiazepines, barbiturates, alcohol, and CNS depressants, needs to be reviewed as they can have adverse effects.
• Pharmacists should perform the medication and substance review to identify possible causes
• All patients should be screened for suicidal ideation

Therapeutic Options for MDD

• Non-pharmacologic options are interpersonal psychotherapy and CBT.
• Psychotherapy takes longer than pharmacotherapy.
• Psychotherapy may produce broader and longer-lasting effects than pharmacotherapy alone.
• Mild to moderate MDD treatment often starts with psychotherapy alone, especially CBT and interpersonal therapy.
• A mix of psychotherapy and pharmacotherapy is used for patients with moderate to severe depression.
• Combining both methods is more effective than either alone.
• Pharmacotherapy works faster than psychotherapy.
• Discontinuing pharmacotherapy can lead to relapse and adverse effects.
• Electroconvulsive therapy (ECT) is an option for:
  • Refractory depression
  • Pregnancy depression
  • Psychotic depression
  • Conditions where medication may not be optimal or effective
• ECT involves two or three treatments weekly for 6-12 weeks.
• Maintenance dosing is tailored to the individual, with frequency varying from weekly to monthly.
• Temporary memory loss is a common side effect
• Medications affecting seizure threshold must be tapered or held before ECT
• ECT may also be considered as initial treatment when symptoms are severe or life threatening

Pharmacotherapeutic Options: Considerations and Keys to Use

• All antidepressants have equal efficacy.
• First-line medications are SSRIs, SNRIs, bupropion, mirtazapine, and vortioxetine.
• Selection of medication should include consideration of:
  • Drug-drug interactions
  • Concurrent illnesses
  • Prior responses
  • Family history
  • Patient preference
  • Cost
• An adequate trial of medication requires the correct drug, dose, and duration for the patient.
• A therapeutic trial typically lasts 4-8 weeks.
• Response is a 50% reduction in symptoms.
• Remission is a return to normal mood with a:
  • HAM-D score of 7 or less
  • PHQ-9 score less than 5
  • At least 3 weeks without depressed mood/anhedonia, and not more than three remaining symptoms.
• Remission is the goal of MDD therapy.
• Optimizing dose and duration is important for achieving remission.

Treatment Phases for MDD

• The acute phase's goal is remission.
• Physical symptoms such as energy levels and sleep disturbances, improve before affective symptoms.
• For patients with suicidal thoughts, there is an increased risk of acting on plans as energy improves, requiring monitoring.
• An early response (20%-30% reduction in symptoms) in the initial 2-4 weeks is a strong predictor of remission at 12 weeks.
• A patient with a partial response after 4 weeks should have an extended trial at a therapeutic dose before moving on.
• Antidepressants generally require 4-6 weeks to take full effect, given adherence, correct drug and dose, but it may take up to 8 weeks.
• Remission can take up to 12 weeks.
• Monitoring includes interviews and rating scales.
• Patients and their support systems should be educated about therapy and closely monitored for adverse effects.
• Adverse effects may affect adherence, even if they are not life-threatening
• Non-responders can switch to another antidepressant in the same or a different class.
• SSRI non-responders may respond to another SSRI as per the STAR*D trial.
• After remission, treatment should continue for at least 6-9 months
• Risk factors for recurrent depression include:
  • Frequent, recurrent episodes
  • Severe episodes (psychosis, severe impairment, suicidality)
  • Chronic episodes
  • Comorbid psychiatric or medical conditions
  • Residual or difficult-to-treat symptoms
• Antidepressants show efficacy in 60%-70% of patients in clinical trials.
• Real-world effectiveness is around 50%-60%.
• A single antidepressant trial results in about a 30% remission rate, as observed in the STAR*D trial.
• Many antidepressants are metabolized or inhibited by CYP enzymes.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs increase serotonin concentrations by selectively inhibiting serotonin reuptake and desensitizing presynaptic serotonin autoreceptors.
• Vortioxetine and vilazodone have additional activity besides serotonin reuptake inhibition.
• The different SSRIs have equal efficacy, adverse effect profiles and patient tolerance vary.
• Blocking serotonin reuptake increases serotonin overall affecting all serotonin receptor subtypes, leading to adverse effects
• Overstimulation of 5HT2A, 5HT2C, 5HT3, and 5HT4 receptors can cause insomnia, restlessness and GI concerns.
• Activation, agitation, anxiety, or panic may occur early in therapy.
• Common side effects are GI issues, insomnia, restlessness, headache, and sexual dysfunction.
• Fluoxetine and sertraline tend to be activating
• Paroxetine and fluvoxamine tend to be sedating
• Citalopram and escitalopram have minimal sedating or activating effect
• Sexual dysfunction is more common than the prescribing information indicates, affecting over 50% of patients.
• Interventions for SSRI-induced sexual dysfunction:
  • Wait-and-see approach
  • Adding Bupropion
  • Lowering the SSRI dose
  • Using PDE-5 inhibitors may help men
  • Alternative interventions like buspirone and mirtazapine have less firm data for women
• Because of their potent serotonergic activity, SSRIs combined with other serotonergic drugs can lead to serotonin syndrome
• Serotonin syndrome can result when combined with MAOIs, dextromethorphan, meperidine, sympathomimetics, linezolid, lithium, TCAs, and SNRIs
  • Triptans’ potential for serotonin syndrome is poorly supported, with studies and the FDA reconsidering warnings.
• Triptans bind to different serotonin receptors than SNRIs or SSRIs, posing a low risk when taken with them.
• Serotonin syndrome encompasses the following symptom clusters:
  • Neuromuscular hyperactivity: Myoclonus, rigidity, tremors, incoordination
  • Altered mental status: Agitation, confusion, hypomania
  • Autonomic instability: Hyperthermia, diaphoresis
• Serotonin Syndrome onset can be subtle and may be confused with Neuroleptic Malignant Syndrome (NMS).
• Hunter criteria are preferred for identifying serotonin syndrome.
• Diagnosis relies heavily on neurological findings, with clonus being prominent, though tremor plus hyperreflexia is adequate for diagnosis.
• Treatment for serotonin Syndrome:
  • Discontinuing the offending agent
  • Providing supportive measures like cooling blankets and respiratory assistance
  • Administering cyproheptadine, or benzodiazepine for myoclonus; anticonvulsants for seizures; and nifedipine for hypertension
• SSRIs are linked to EPS, which include akathisia, dystonia, and bradykinesia, but it is uncommon. EPS results from 5HT effects on DA neurotransmission in the basal ganglia.
• SSRIs can induce hyponatremia from SIADH, especially in older patients.
• Monitor susceptible individuals for suggestive symptoms.
• Gradual dose reductions (over 2-4 weeks) prevent the SSRI withdrawal syndrome, particularly with shorter half-life drugs.
  • Symptoms are flu-like (nausea, chills) or neurologic (paresthesias, insomnia, anxiety, electric shock sensations).
• To treat severe or persistent SSRI withdrawal syndrome, reinitiate the original dose, then reduce gradually.
• Withdrawal syndrome timing correlates with SSRI half-life (so paroxetine withdrawal symptoms are the earliest)
• Fluoxetine has a much longer half-life, so withdrawal symptoms may be delayed.
• The FDA limited the daily dose of citalopram to 40 mg over QTc prolongation risk at higher doses of 40 mg daily.
• The maximum recommended citalopram dose is 20 mg/day for patients with hepatic impairment, patients older than 60, 2C19 poor metabolizers, and concomitant 2C19 inhibitors
• Use of SSRIs is warranted as first-line therapy due to their safety, tolerability and low cost.
• Fluoxetine 90 mg can be taken weekly but is usually for continuation, rather than initial treatment.
• Paroxetine controlled release (CR) may have lower nausea rates in the first week.
• Escitalopram, the S-isomer of citalopram, is the active component
  • It is at least as effective as Citalopram 20mg, when at a dose of 10mg, and it has fewer adverse effects
  • The advantage is less pronounced at higher doses.
• SSRIs increase bleeding risk by inhibiting serotonin reuptake, decreasing serotonin-mediated platelet activation.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran block the reuptake of norepinephrine and serotonin.
  • Milnacipran, although an SNRI, is only FDA-approved for fibromyalgia
  • SNRIs have decreased anticholinergic and antihistaminic effects, unlike TCAs, except for duloxetine
  • Duloxetine has a slightly higher incidence of anticholinergic symptoms.
  • Compared to desvenlafaxine and duloxetine, venlafaxine has a dose-related effect on norepinephrine
  • Venlafaxine is a serotonin reuptake inhibitor at doses of less than 150 mg/day
• It is debated whether the venlafaxine dual action is more effective than SSRIs.
• Some patients with treatment resistance or anhedonia benefit from combinations of drugs. that target norepinephrine and serotonin.
• Venlafaxine's adverse effect profile is similar to the SSRIs, notably GI concerns.
• SNRIs can elevate blood pressure, but the rise is mild and not clinically significant unless the patient has uncontrolled hypertension
• The dose-related elevations are more pronounced for venlafaxine and desvenlafaxine.
• Levomilnacipran and desvenlafaxine are also associated with OH Side Effects.
• Levomilnacipran is a more potent enantiomer of milnacipran that is only approved for depression.
  • The dose must be adjusted in renal insufficiency and is not recommended in end-stage renal disease.
  • Can cause hyponatremia and increase bleeding risk.
  • The capsule is not to be crushed or opened.
  • Liver toxicity can result if 3A4 inhibitors are used concomitantly; monitor for potential toxicities
  • Blood pressure elevations and OH can occur, leading to heart rate increases and palpitations, and discontinuation.
  • Levomilnacipran is a more potent norepinephrine inhibitor than venlafaxine or duloxetine.
  • Serotonin is slightly preferred to norepinephrine

More Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• All SNRIs can lead to serotonin syndrome
  • In overdose, duloxetine and venlafaxine have been associated with higher rates of death than SSRIs
  • The risk of death from SNRI overdose is still lower than with TCAs.
• Duloxetine is also been approved for:
  • Diabetic peripheral neuropathy
  • Fibromyalgia,
  • Chronic musculoskeletal pain caused by chronic lower back pain
  • Osteoarthritis pain.
• Exercise caution when using duloxetine with 2D6 inhibitors.
• Monitor blood pressure because increases have been observed with duloxetine use
• Duloxetine can cause liver toxicity, so avoid in patients with hepatic insufficiency, end-stage renal disease with dialysis, and severe renal impairment.
• SNRIs can cause a withdrawal syndrome similar to SSRIs, requiring slow tapering upon discontinuation.
• Desvenlafaxine is an active metabolite of venlafaxine with reduced CYP metabolism, which is an advantage for patients with hepatic insufficiency or those taking major 2D6 inducers or inhibitors.
• Desvenlafaxine has limited benefits over venlafaxine
• Renal dosing adjustments are needed for both desvenlafaxine and levomilnacipran.

Mixed Serotonergic Medications

• Vilazodone is an SSRI and partial agonist at the 5HT1A receptor, but the the clinical consequence for this effect is unknown.
  • Its half-life is about 25 hours, but it has no active metabolites
  • Usual and maximum doses are 40 mg daily.
  • Vilazodone should be taken with food.
  • Common side effects are nausea and diarrhea.
  • May cause a lower incidence of sexual dysfunction.
  • Should not be used in patients with a history of seizure disorder.
  • Decrease the dose if given with strong 3A4 inhibitors.
• Although post-marketing reports include acute pancreatitis and sleep paralysis, the true frequency is unknown and unchanged in labeling.
• Vortioxetine has additional agonist activity at the 5HT1A, partial agonist 5HT1B, and antagonistic activity at the 5HT3, 5HT1D, and 5HT7 receptors.
  • The clinical significance of effects on serotonin receptors is unknown, but it improves cognitive function and appears independent of antidepressant effects.
  • Vortioxetine has a long half-life of 66 hours without any active metabolites.
  • Dosing starts at 10 mg daily, the maximum is 20 mg daily
  • It is metabolized by 2D6, limit the maximum dose to 10 mg daily for both:
    • Poor metabolizers
    • Those taking a strong 2D6 inhibitor
• Has a lower incidence of sexual dysfunction
• Common side effects of vortioxetine include nausea, dizziness, vomiting, xerostomia, diarrhea, and constipation.
• Trazodone is a serotonin reuptake inhibitor that blocks 5HT2A receptors.
  • Trazodone, unlike TCAs, has no anticholinergic or cardiotoxic effects, but it still causes OH and sedation.
  • Trazodone is a sedative, so it is often used for insomnia in small doses
  • Be aware of priapism potential even though it is rare. Patients should be educated and treated in a medical emergency
• Nefazodone is a 5HT2A antagonist like trazodone that blocks 5HT and NE reuptake, also known as "serotonin antagonist reuptake inhibitors."
  • Unlike trazodone, nefazodone has minimal influence on sexual function and less OH
• It selectively blocks 5HT2A, making it more effective for anxiety associated with depression
  • Administer short half life doses twice daily
  • Side effects include sedation, GI concerns, dry mouth, constipation, confusion, & light-headedness Potent 3A4 inhibitor
  • Do not use concomitantly with drugs metabolized in this system
  • Liver toxicity with Black Box Warning, nefazodone is now both a second- or third-line agent, with liver function monitored during use.
• Mirtazapine is an antagonist of presynaptic α2-autoreceptors and heteroreceptors, augmenting norepinephrine and serotonin neurotransmission. It blocks 5HT2A (decreased sexual dysfunction), 5HT3 (decreased nausea) & 5HT2C (weight gain).
  • It can still cause sedation, increased appetite, weight gain, constipation, and asthenia despite better tolerance than TCAs.
  • Abnormal liver function tests can occur, and there is a very small risk of neutropenia or agranulocytosis.
  • More sedating in lower doses insomnia in higher doses.
• Bupropion is primarily a inhibitors of dopamine and norepinephrine reuptake with minimal serotonin effects.
  • Its action is exactly defined.
  • The parent drug prevents dopamine reuptake, while its metabolite NE reuptake
• High risk of is seizures.
  • Minimize by avoiding susceptible patients (seizure disorder history, eating disorders), limiting the dosage (450 mg/day IR/ER, 400 SR), and avoiding frequent titrations (every 4 days for SR/ER, 3 for IR).
  • The SR and ER products reduce adverse effects better than IR.
• Common side effects are
  • insomnia, anxiety, irritability, headache
  • Decreases appetite
  • May increase energy & cause psychosis in susceptible individuals by improving sexual function and may be useful for those that do not tolerate other agents.
• Bupropion is used off-label for ADHD and improve concentration.
• TCAs are effective but limited due to their adverse effects.
• TCAs have declined, but are still prescribed off-label for migraine & anxiety & pain
• Tricyclics block serotonin & NE.
• Tertiary amines increase serotonin uptake and turn into active secondary amines.
• Block alpha adrenergic, antihistaminic, and anticholinergic reactions, leading to OH, sedation, and the respective anticholinergic symptoms like sexual dysfunction.
• Be can cardiotoxic
• Prolonged QTc and Torsades De Pointes
• Monitor the ECGs in patients with TCAs
• TCAs are cautioned for cardiac seizures, and for those with the risk factor Adherence can ensure is appropriate

Monoamine Oxidase Inhibitors (MAOIs)

• MAOIs irreversibly block enzymes that break down neurotransmitters, like norepinephrine.
• They come as two forms:
• MAO-A,
• MAO-B
• drugs are able to halt one.
• Nonselective MAOIs approved for use:
  • Isocarboxazid
  • Phenelzine
  • Tranylcypromine
• Patients needs to cut all tyramine, because for hypertensive issues.
• Drug conflicts
• Watchlist drugs
• Patch available to help depression and anxiety and other mental issues

Antidepressants and Suicidality

• All antidepressants contain an FDA box of increased risks of mental behaviors for children. Risks:
  • Thoughts
• Adjustment
• Monitor signs, agitation, anxiety, and symptoms that make sure that they get help The risk does not need to cause suicide to lead to death in adolescents The meta-analysis results has shown some cases in patients that were 65 or older from antidepressants The number that needs to happen to one with SSRI depression prevents suicidal thoughts

Partial Antidepressant Treatment

• Confirm compliance and received treatment of medicine
• If a patient is adherent switch antidepressants of receive adjacent therapy
• Adding antidepressants helps (bupropion or mirtazapine with SSRIs) But make sure to check for the risk agents SGAs can be used that helps treat most medical illnesses and conditions for FDA approved

Olanzapine

• Ketamine are used for depression and off-label in patients
• Check if the patient is not responsive to antidepressants such as: Lithium, and liothyronine Lithium

Treatment - Resistant Depression

• The definition is inadequate

  • It has two treatments approved: Olanzapine and Fluoxetine and those 6-18 mg for depression Esketamine (Intranasal) help treat a number of other conditions. NMDA (N-methyl and aspartate) The actions symptoms is with in hours

• Dosings is the phase action over a period of time

• Dosing has black warnings signs that leads to suicidal behaviors

• Side effects increase a lot of stress on patients Patients can only must must join a REEMS program And patients must be treated within two hours of taking that medicine