Antidepressants and Depression treatment

Major Depressive Disorder (MDD)

• MDD is also known as unipolar depression, or just depression.
• Diagnosis requires at least five symptoms almost every day for at least 2 weeks.
• A requirement is a depressed mood or anhedonia (loss of interest in pleasurable activities).
• Additional symptoms include sleep disturbances, changes in weight or appetite, decreased energy, feelings of guilt or worthlessness, psychomotor retardation or agitation, decreased concentration, and suicidal ideation.
• The symptoms must interfere with the patient's everyday ability to function.
• Persistant depressive disorder or dysthymia includes a chronic depressed mood occuring more days than not for at least 2 years but that does not meet the criteria for MDD.

Assessment of the Patients

• Psychiatric history is important to asses
• Clinician rating scales
• Patient rating scales
• Physical examinations and lab tests
• Biologic testing
• Assess medication and substances
• Assess suicidal ideation

Clinician Rating Scales

• Hamilton Rating Scale for Depression (HAM-D/HDRS)
  • Enrolment scale > 18 (moderate-severe), a response = 50% reduction
  • Remission is ≤ 7
• Clinical Global Impression Scale (CGI)
• Montegomry-Asberg Depression Rating Scale (MADRS)

Patient Rating Scales

• These are patient-completed rating instruments.
• Answers to the questions are used to identify and assess the level of depression.
• Patient Health Questionnaire-9 (PHQ-9) is based on the DSM-5 diagnostic criteria for major depression.
• Beck Depression Inventory (BDI)
• Quick Inventory of Depressive Symptoms (QIDS)
• Geriatric Depression Scale (GDS)

Physical Examination and Lab Tests

• Necessary to rule out physical causes like thyroid disorders and vitamin deficiencies.

Biologic Testing

• Depression is commonly associated with abnormalities in the dexamethasone suppression test and tests of the thyroid axis although these tests are not routinely used in clinical practice.

Medications and substances

• Interferons, benzodiazepines, barbiturates, alcohol, central nervous system (CNS) depressants, and withdrawal from stimulants (cocaine, amphetamines) can have depression as an adverse effect.
• Pharmacists should perform a medication and substance use review to identify possible causes.

Suicidal Ideation

• All patients should be screened for suicidal ideation.

Therapeutic Options

• Examples of non-pharmacologic treatment options include interpersonal psychotherapy and CBT.
• Psychotherapy takes longer to achieve effective results than pharmacotherapy.
• Psychotherapy can have broader and longer-lasting effects than pharmacotherapy monotherapy.
• Psychotherapy is recommended as monotherapy for initial treatment in patients with mild to moderate MDD, especially CBT and interpersonal therapy as they have the best evidence.
• Psychotherapy combined with pharmacotherapy is recommended for moderate to severe depression, this combination is more effective than either intervention alone.

Electroconvulsive therapy (ECT)

• This is an option for refractory depression, depression in pregnancy, psychotic depression, and other conditions for which medications may not be optimal or effective.
• A usual induction cycle consists of two or three treatments per week for 6-12 treatments.
• Maintenance dosing is individualized, and frequency can vary from weekly to monthly.
• Temporary memory loss is common. Medications that affect seizure threshold must be tapered or held before treatment.
• ECT is suggested as initial treatment if symptoms are severe or life-threatening.

Pharmacotherapeutic Options

• All antidepressants are considered equally efficacious.
• Antidepressant therapy may lead to a more rapid response than psychotherapy, but when discontinued, there is a risk of relapse and adverse effects.
• Select first-line medications including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, and vortioxetine.
• When prescribing medication, consider possible drug-drug and drug-disease interactions, concurrent illnesses, prior responses, family members' prior responses, patient preference, and cost.

Goals and timeframes for treatment

• An adequate medication trial includes the correct drug for the patient and a therapeutic dose for an appropriate duration.
• A therapeutic trial lasts 4-8 weeks.
• A response is usually defined as a 50% reduction in symptoms.
• Remission is a return to normal mood, for example achieving a HAM-D of 7 or less, or PHQ-9 less than 5).
• Remission can also mean being at least 3 weeks with no symptoms of depressed mood and anhedonia and no more than three remaining symptoms of depression.
• Remission is the goal of therapy, optimizing the dose or duration is important.

Treatment Phases

• The goal of the acute phase is remission.
• The onset of antidepressant effect: physical symptoms like energy levels, and sleep disturbances improve before affective symptoms. Therefore patients must carefully watch patients with suicidal ideation.
• Early response meaning a 20%-30% reduction in symptoms is achieved in the first 2-4 weeks is a strong predictor of remission at 12 weeks.
• If there is a partial response in the first 4 weeks, allow a longer trial at the full therapeutic dose before moving on to other therapy.
• In general, it takes 4-6 weeks to see the full effect of antidepressants with the correct drug, dose, and adherence. It may take as long as 8 weeks to see a response. Remission may take up to 12 weeks.

Monitoring

• Patients should be monitored for response through interviews or by repeating rating scales.
• Patients, along with their support systems should be educated about therapy and closely monitored for adverse effects. Although most adverse effects are not life-threatening, they do affect adherence.

Next steps

• If there is a non-response, the patient can be changed to another antidepressant within either the same class or a different class.
• A patient who does not respond to one SSRI may respond to another in the same class.

Maintenance Therapy

• Once a patient has achieved remission, treatment should continue for at least another 6-9 months.
• Treat those with risk factors for recurrent depression for 2 years or longer.
• Risk factors include frequent, recurrent episodes; severe episodes (including psychosis, severe impairment, or suicidality), chronic episodes, presence of comorbid psychiatric or medical conditions, presence of residual symptoms or difficult-to-treat episodes.

Medication facts

• The efficacy of antidepressants according to rigorous clinical trials occurs in 60%-70% of patients, regardless of drug.
• Effectiveness is more reflective of clinical practice, at around 50%-60%.
• The remission rate with one antidepressant trial is about 30%, as seen in the STAR*D trial.
• Many antidepressants are metabolized or inhibited by CYP enzymes.
• All antidepressants have an FDA black box warning for an increased risk of suicidal thinking and behaviors in children, adolescents, and young adults (up to 24 years of age). Risk is highest at treatment initiation or dose adjustment.
• Watch for agitation, anxiety, or other unusual symptoms.

Partial Response to Antidepressant Treatment

• First, ensure the patient is adherent and has received therapeutic trials of medication.
• Patients can either be changed to a new antidepressant or receive adjunctive therapy.
• An antidepressant with a different mechanism of action can be added, for example, bupropion or mirtazapine to an SSRI or SNRI, however data are not strong for this practice.
• When combining agents caution must be used to avoid potential serotonin syndrome for at-risk agents.

Adjuncts

• SGAs may be used as adjuncts to antidepressant therapy. Almost all SGAs have been used, only aripiprazole, brexpiprazole, and quetiapine have received FDA approval for this indication.
• Evidence supports the use of risperidone. Olanzapine is also approved in combination with fluoxetine, but specifically for treatment-resistant depression.
• Ketamine infusions are used off-label for depression and suicidality, particularly in patients who are not responsive or who are only partly responsive to antidepressants.
• Other adjuncts include lithium, liothyronine, stimulants (including methylphenidate and modafinil), and buspirone.

Treatment-Resistant Depression

• Usually defined as an inadequate response to at least two antidepressants.
• FDA-approved treatments:
  • Olanzapine plus fluoxetine: Initial dosing is 6 mg/25 mg once daily, in usual doses of 6-18 mg/25-50 mg daily.
  • Esketamine (intranasal; Spravato)
    • Approved for use in conjunction with an oral antidepressant and for major depression with suicidality.
    • The mechanism of action is as an NMDA (N-methyl-d-aspartate) antagonist.
    • Onset for treating depression symptoms is within hours.
    • Dosing occurs in two phases: twice weekly during the induction phase, which lasts for 2 weeks, followed by the maintenance phase, in which dosing is weekly for 4 weeks and then every 1-2 weeks thereafter.
    • Carries black box warnings for sedation, dissociation, abuse and misuse, and suicidal thoughts and behaviors.
    • Common adverse reactions: Increased blood pressure, dissociative reactions including derealization and depersonalization, sedation, dizziness, anxiety, nausea, vomiting, and dysgeusia.
    • Long-term use or misuse of ketamine has also been associated with ulcerative or interstitial cystitis, although it has not been observed with esketamine in clinical trials but should be monitored.
    • Only available through a REMS program that patients must be enrolled in. Only approved pharmacies can dispense the agent, it must be administered in a certified health care setting where patients are observed for at least 2 hours after administration.
    • Mental status and blood pressure must be monitored, and patients cannot drive until the following day.

Selective Serotonin Reuptake Inhibitors

• Common sides effects for SSRIs GI symptoms, restlessnessness, insomnia, sexual dysfunction and headache
• Fluoxetine and sertraline are the most activating SSRIs
• Paroxetine and fluvoxamine are the most sedating
• Citalopram and escitalopram have no appreciable sedating or activating effects

Serotonin Syndrome

• Causes for serotonin syndrome include concomitant use of SSRIs with:
  • Monoamine oxidase inhibitors (MAOIs)
  • Dextromethorphan
  • Meperidine
  • Tramadol
  • Sympathomimetics
  • Linezolid
  • lithium
  • TCAS
  • SNRIs
• Symptoms for serotonin syndrome
  • Neuromuscular hyperactivity (e.g., myoclonus, rigidity, tremors, incoordination).
  • Altered mental status (agitation, confusion, hypomania).
  • Autonomic instability (hyperthermia, diaphoresis).

Treament

• Treatments include supportive measures such as:
  • cooling blankets
  • respiratory assistance
  • the use of cyproheptadine for myoclonus
  • antiseizure medications
  • nifedipine for hypertension

Side Effects

• Other side effects may include EPS, SIADH (syndrome of inappropriate antidiuretic hormone secretion) in ELDERLY PATIENTS, flu-like Withdrawal symptoms and QTC prolongation in Citalopram.
• SSRIs are not as lethal in overdose cases as TCAS

Serotonin-Norepinephrine Reuptake Inhibitors

• Some patients (e.g., treatment nonresponders or those with significant anhedonia) appear to benefit either from agents that affect norepinephrine and serotonin or from combinations of drugs with that effect.
• All SNRIs can produce serotonin syndrome.
• SNRIs can cause a withdrawal syndrome similar to the SSRIs and tapering slowly when discontinued is indicated.

Mixed Serotonergic Medications

• Vilazodone (Viibryd) is an SSRI with partial agonist activity at the serotonin-1A receptor.
• Vortioxetine (Trintellix) is an SSRI, although its pharmacologic profile differs from other SSRIs.
• Vortioxetine has additional agonist activity at the serotonin-1A receptor, partial agonist activity at the serotonin-1B receptor, and antagonistic activity at the serotonin-3, serotonin-1D, and serotonin-7 receptors

Trazodone (Desyrel)

• Trazodone is a serotonin reuptake inhibitor that also blocks serotonin-2A receptors.
• Trazodone does not cause anticholinergic or cardiotoxic effects as the TCAs, but it still causes OH and sedation.
• Trazodone is often used for insomnia but at lower doses than for depression due to its antihistaminic properties.

Nefazodone (Serzone)

• Nefazodone is a serotonin-2A antagonist like trazodone.
• It also blocks the reuptake of serotonin and norepinephrine.
• Unlike trazodone, nefazodone has minimal effects on sexual function and is less likely to cause OH.
• Nefazodone is more effective for anxiety associated with depression.

Mirtazapine

• Mirtazapine is an antagonist of presynaptic a2 -autoreceptors and heteroreceptors resulting in an increase in norepinephrine and serotonin release in the synapse.
• Mirtazapine also blocks serotonin-2A (resulting in minimal to no sexual dysfunction, anxiety, or sedation), serotonin-3 (no nausea or Gl disturbances), and serotonin-2C (weight gain) receptors.
• Side effects include sedative effects, constipation, asthenia, abnormal liver function tests, increased appetite, weight gain and agranulocytosis.

Bupropion

• Bupropion is primarily an inhibitor of dopamine and norepinephrine reuptake with minimal effects on serotonin.
• A side effect includes an increased risk of seizures.
• Other side effects are insomnia, anxiety, irritability, headache, and decreased appetite.
• Bupropion may also increase energy and cause psychosis in susceptible individuals.
• Bupropion may improve sexual function.

Tricyclic Antidepressants

• TCAs are effective, but adverse effects have limited their use
• Check table on page provided to see Drug interactions as well as info about anticholinergic effects, sedation, orthostatic hypotension and cardiotoxicity.
• TCA serum concentrations can confirm adherence or toxicity, but this is an infrequent clinical practice.
• A withdrawal syndrome can occur if these drugs are discontinued too quickly.
• Symptoms reflect the reversal of anticholinergic effects: lacrimation, nausea, and diarrhea, along with insomnia, restlessness, and possible balance problems.
• Gradual dose reductions help reduce these symptoms.

Monoamine Oxidase Inhibitors

• Nonselective MAOIs include isocarboxazid, phenelzine, and tranylcypromine.
• Patients taking MAOIs must be educated and monitored to avoid foods high in tyramine.
• Drug interactions with MAOIs are considerable and include over-the-counter decongestants, antidepressants, stimulants, and antihypertensives.
• When changing a patient from another antidepressant to an MAOI, it is prudent to wait 2 weeks after the antidepressant is discontinued before initiating the MAOI, except for fluoxetine and vortioxetine. In the special cases of fluoxetine, the waiting period should be 5-6 weeks. In the special case of vortioxetine the timeframe should be 3 weeks. This is to avoid serotonin toxicity.
• When a patient is changed from an MAOI to another antidepressant, a 2-week washout period is usually adequate.

Questions about the side effects of antidepressants, including increased agitation and anxiety. Also, deals with strategies for treatment-resistant depression. Questions about the mechanism of action and administration of Esketamine.