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First-line antidepressants escitalopram sertraline bupropion mirtazapine by Dr Jason Cafer MD

For first-episode depression, it is customary to start with an SSRI. For adults, no SSRI is clearly more effective than others, although escitalopram (Lexapro) has a slight advantage over the others for tolerability, and possibly for efficacy. For children, fluoxetine (Prozac) has the best evidence. For adults, escitalopram and sertraline (Zoloft) are preferred because they have fewer drug-drug interactions compared to fluoxetine or paroxetine (Paxil). Although quite safe, citalopram (Celexa) is a bit riskier than the other SSRIs due to mild QT prolongation, for which FDA lowered the recommended maximum from 60 mg to 40 mg.  There is no reason to choose citalopram over escitalopram.


If the patient is not eating or sleeping, consider starting with mirtazapine (Remeron). If insomnia is prominent but weight gain is not desired, consider choosing an SSRI plus trazodone (Desyrel) 50 mg at bedtime, PRN or scheduled ($4). The FDA max for trazodone is 400 mg, but prescribed doses rarely exceed 200 mg.


For depressed patients with fibromyalgia or other types of chronic pain, an SNRI like venlafaxine (Effexor) or duloxetine (Cymbalta) would be a reasonable first-line choice. Effexor XR is dosed 75–225 mg QD. Cymbalta is 30–60 mg QD (FDA max 120 mg). 

Antidepressants and Related Medications

Triclyclic antidepressant table Cafer's Psychopharmacology
SSRI antidepressant table Cafer's Psychopharmacology
Atypical antidepressant table Cafer's Psychopharmacology
MAOI NMDA receptor antigonist antidepressant table Cafer's Psychopharmacology
Cafer's antidepressants rain cloud icons for antidepressants

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is defined as failure of two 6-week antidepressant trials. For TRD, trying a third antidepressant is no more effective than placebo.


Augmenting the antidepressant is twice as effective as placebo (Zhou et al, 2015). Lithium (0.5–0.8 mmol/L) and aripiprazole (Abilify) 5–15 mg are the top choices for augmentation. Other proven options include quetiapine (Seroquel) 100–300 mg HS, risperidone (Risperdal) 0.5–3 mg HS and liothyronine (Cytomel, T3 thyroid hormone) 50 mcg.


There is moderate evidence for adding olanzapine (Zyprexa) 5–15 mg or buspirone (Buspar) 5–15 mg BID–TID. About 50% of TRD cases are actually bipolar disorder (Francesca et al, 2014), for which lithium or lamotrigine (Lamictal) are superior to antidepressants in preventing the next depressive episode.


Intravenous ketamine or intranasal esketamine are quickly effective for TRD. Electroconvulsive therapy (ECT) has the highest rate of response and remission of any form of antidepressant treatment. 


All antidepressants have a black box warning of increased suicidal thoughts and behavior in children, adolescents and young adults. Increased risk of completed suicide has not been established. For adults beyond age 24, incidence of suicidal thoughts does not exceed placebo. For those age 65 and older, antidepressants decrease suicidal thoughts. In reduction of suicide risk, lithium is superior to antidepressants. 


For children and adolescents, antidepressants (SSRIs, SNRIs) show more prominent benefit for anxiety than for depression (Locher et al, 2017).


All antidepressants have the potential to induce a “switch” to mania, usually in the context of undiagnosed bipolar disorder. Patients with known bipolar disorder suffering a depressive episode may be treated with an antidepressant combined with a mood stabilizer or an antipsychotic. Upon successful treatment of a bipolar depressive episode, consider tapering off the antidepressant after a few months to avoid destabilization of mood over the long term.


Following a Mediterranean diet can improve acute depression and prevent future depressive episodes (Jacka et al 2017; Parletta et al, 2017). 30–60 minutes of light therapy every morning can produce benefits comparable to medication for seasonal and non-seasonal depression (Penders et al, 2016). All depressed patients should be screened for hypothyroidism—ordering serum TSH level is sufficient.

Metabolism of Antidepressants


Almost all antidepressants are metabolized, at least in part, by CYP2D6. For patients with a 2D6 ultrarapid metabolizer (UM) genotype (3%), non-response to a wide range of antidepressants (at standard doses) is possible. 

CYP2D6 ultrarapid metaboliser mnemonic Dr Cafer's Psychopharmacology

For the 10% of individuals who are 2D6 poor metabolizers (PM), antidepressant levels may be higher than expected, possibly leading to side effects. For a known 2D6 PM, it is recommended to dose the following at half-strength: tricyclics (TCAs), vortioxetine  (Trintellix), and atomoxetine (Strattera).

CYP2D6 poor metabolizer mnemonic by Dr Jason Cafer's Psychopharmacology

Antidepressant-Associated Sexual Dysfunction


Serotonergic medications commonly decrease sexual desire, disrupt the sexual pleasure response, and increase latency to orgasm. Here are some drugs ranked (approximately) from worst to best in regard to their effect on sexual functioning.

Antidepressant-associated sexual dysfunction Dr Jason Cafer's Psychopharmacology

About half of individuals taking antipsychotics also experience sexual dysfunction, particularly with antipsychotics that elevate prolactin like haloperidol (Haldol), risperidone (Risperdal), and paliperidone (Invega). Among antipsychotics, aripiprazole (Abilify)  is the least likely to cause sexual dysfunction, followed by ziprasidone (Geodon), and quetiapine (Seroquel). Mood stabilizers are generally unlikely to cause sexual dysfunction. Lamotrigine (Lamictal) does not have sexual side effects. 

Dapper Dan mnemonic for dapoxetine Dr Jason Cafer's psychopharmacology

Anticholinergic burden of antidepressants

Anticholinergic burden is strongly linked to adverse outcomes among older adults, potentially causing the individual to be:


“Dry as a bone”

  • Constipation (risk of ileus, bowel rupture)

  • Urinary retention (risk of urinary tract obstruction)

  • Decreased sweating; flushing—“Red as a beet”

  • Dry mouth (risk of sublingual adenitis)

  • Dry nasal mucosa


“Blind as a bat”

  • Cycloplegia (loss of accommodation); Lens cannot focus on near objects

  • Photophobia due to mydriasis (dilated pupils)

  • Increased intraocular pressure, glaucoma


“Mad as a hatter”

  • Confusion, memory problems

  • Increased risk of developing dementia

  • Delirium with visual hallucinations


“Fast as flash”

  • Tachycardia

Anticholinergic (antimuscarinic) side effects Dr Jason Cafer's Psychopharmacology
Anticholinergic Burden Scale "mad as a hatter" Dr Jason Cafer's Psychopharmacology
Anticholinergic Burden Scantipsychotics Anticholinergic Risk Scale Dr Jason Cafer's Psychopharmacology
Antihistamine Burden Scantipsychotics Anticholinergic Risk ScaleDr Jason Cafer's Psychopharmacology
Muscle relaxants Anticholinergic Burden Scale by Dr Jason Cafer's Psychopharmacology

Serotonin Syndrome

Serotonin syndrome, better understood as serotonin toxicity, is a rare condition that can occur when serotonergic drugs are combined, especially with monoamine oxidase inhibitors (MAOIs). The mechanism involves serotonin overload in the brain stem. 50% of cases onset within 2 hours of adding the offending serotonergic. Only 25% of cases persist longer than 24 hours. 70% of cases resolve within 24 hours.


15% of SSRI overdoses lead to serotonin toxicity. Overdoses of a combination of a SSRI plus a MAOI have a 50% likelihood of causing serotonin syndrome. 


Although it may rarely progress to multi-organ failure and death, serotonin syndrome is not as dangerous as the Neuroleptic Malignant Syndrome (NMS) caused by antipsychotic medications. Refer to pages 128–129 for a head to head comparison of 5-HT toxicity and NMS.


The diagnosis of 5-HT Syndrome is defined by the Hunter Serotonin Toxicity Criteria with 84% sensitivity and 97% specificity. The criteria focus on clonus, ocular clonus, and hyperreflexia. 

Serotonin syndrome frog mnemonic Dr Jason Cafer's Psychopharmacology

On physical exam, the sufferer of 5-HT toxicity may appear uncomfortable and twitchy. Deep tendon reflexes may be very brisk. Try to elicit clonus by flexing the patient’s foot and watching for rhythmic contractions of the ankle. Assess for ataxia through observation of gait, Romberg testing, and point-to-point testing.


Be careful if combining antidepressants with other medications that have serotonergic properties: 


    ❖   dextromethorphan (DXM) – cough suppressant 

    ❖   tramadol (Ultram) – pain medication (SNRI + weak opioid)

    ❖   methadone – opioid

    ❖   fentanyl – opioid

    ❖   meperidine (Demerol) – opioid

    ❖   metaxalone (Skelaxin) – muscle relaxant, MAOI activity

    ❖   cyclobenzaprine (Flexeril) – a tricyclic  muscle relaxant

    ❖   St. John’s wort – herbal antidepressant

    ❖   LSD (“acid”) – hallucinogen

    ❖   MDMA (ecstasy) – a common cause of serotonin toxicity

    ❖   linezolid (Zyvox) – an antimicrobial with MAOI activity 

    ❖   methylene blue (Urelle) – urinary tract antiseptic

Despite an FDA warning, the risk of serotonin syndrome with a triptan migraine medication (Imitrex, Maxalt, etc) is miniscule, if not nonexistent. Orlova et al (2018) estimated the risk at about 1 in 10,000 person-years of exposure to a triptan plus an SSRI/SNRI. Serotonin syndrome is hypothesized to involve 5-HT2A and 5-HT1A receptors, while triptans are agonists at 5-HT1B and 5-HT1D receptors. 


Combining SSRIs, combining SNRIs, or combining an SSRI with an SNRI makes no sense therapeutically, but is unlikely to cause serotonin toxicity at standard doses. Switching between SSRIs and SNRIs can generally be done without much of a washout period. A couple of days should suffice, other than when changing from fluoxetine (Prozac). Due to fluoxetine’s long half-life, 1 to 2 weeks washout is prudent before starting a different SSRI or SNRI.


Treatment of 5-HT toxicity involves stopping the offending agent and aggressive cooling of high fever. In some cases, medications with anti-serotonergic activity may be helpful, such as the antihistamine cyproheptadine (Periactin) or the antipsychotic chlorpromazine (Thorazine).

History lesson:  A high-profile case of serotonin syndrome occurred in 1984. Libby Zion, an 18-year-old college freshman taking the MAOI phenelzine presented to the ER and was treated with meperidine (Demerol) to control “strange jerking movements” (think twitchy frog). She was hospitalized, developed a fever of 107°F, and died of a heart attack within hours.

Her father, an attorney, believed her death was the result of overworked resident physicians. In 1989 New York state adopted the “Libby Zion Law” which limited medical residents to 80 hours per week. In 2003 all accredited medical training institutions adopted a similar regulation, limiting residents to 80 hours per week and 24 consecutive hours.

QT Prolongation

QT Prolongation Cutie Heart by Dr Jason Cafer's Psychopharmacology

On electrocardiogram (ECG), the QT interval, measured from the beginning of the QRS complex to the end of the T-wave, reflects the rate of electrical conduction through the ventricles as they contract and relax. The useful number for our purposes is the QTc interval, which is QT corrected for heart rate, which takes into account that QT interval is naturally longer at slower heart rate. 

QT Prolongation QRS Complex Dr Jason Cafer's Psychopharmacology

On electrocardiogram (ECG), the QT interval, measured from the beginning of the QRS complex to the end of the T-wave, reflects the rate of electrical conduction through the ventricles as they contract and relax. The useful number for our purposes is the QTc interval, which is QT corrected for heart rate, which takes into account that QT interval is naturally longer at slower heart rate. 

QT prolongation is a delay in cardiac conduction that can trigger Torsades de pointes (French “twisting of points”). This may precede sudden death. 

Many psychotropic medications prolong QT interval, including most antidepressants and antipsychotics. In overdose scenarios involving antidepressants or antipsychotics, QT interval is usually long, necessitating a trip to the ICU. As you will see in the next chapter, tricyclic antidepressants (TCAs) are particularly deadly in overdose due to disruption of cardiac conduction manifested by, among other measures, prolonged QT. 


Roughly speaking,  QTc > 460 milliseconds is long and QTc > 500 msec can be dangerous. An increase in QTc > 60 msec caused by a medication would be of concern.

The risk of torsades is the highest within the first few days of initiating treatment with a QT prolonger. For most drugs that prolong QT, the risk of torsades is so low that routine ECG screening is unnecessary. Although combining QT prolonging medications does prolong QT interval, the magnitude of the effect is likely to be tiny, with a very low probability of clinical consequences (Carlat Report, March 2018). However, it is prudent to check an ECG for patients taking high doses of multiple QT prolonging medications, or individuals with these risk factors:


 Risk factors for QT prolongation

  ► Hypokalemia (low K+)

  ► Hypomagnesemia (low Mg+)

  ► Bradycardia

  ► Left ventricular hypertrophy


Patients with congenital long QT syndrome should not be given QT prolonging medications. Do not add a QT prolonging medication when QTc is near 500 msec. 


Medications that prolong QT interval:

Psychotropic medications that prolong QT interval Dr Jason Cafer's Psychopharmacology

*Intravenous haloperidol poses high risk of QT prolongation.


Due to the extent of QT prolongation caused by thioridazine (Mellaril), most psychiatrists avoid prescribing it. For healthy patients taking ziprasidone (Geodon), the author checks an ECG before exceeding the FDA maximum dose of ziprasidone (80 mg BID) or when combining 3 or more medications known to prolong QT interval. Check an ECG if a patient taking QT prolonging medications experiences palpitations or syncope/presyncope.

Medications that cause QT prolongation Dr Jason Cafer's Psychopharmacology

Toxicity of Antidepressants in Overdose

Tricyclics: A relatively high percentage of single-drug TCA overdoses are fatal, but of those who reach the hospital, only 2–3% die (Tsai et al, 2017). Over 40% of antidepressant fatalities are due to amitriptyline, because it is the most prescribed TCA. Causes of death by TCA overdose include cardiac conduction disturbance, hypotension, seizure and coma. Clomipramine appears to be much safer than other tricyclics, with no reported deaths from 1,745 exposures. Risk of death from any medication is dose-dependent. Taking a thirty tabs of low-dose doxepin 10 mg will not be fatal.

SSRIs: Overdosing on a 30-day supply of an SSRI may cause minimal symptoms, with drowsiness as the primary manifestation. Pupils may become dilated. 15% have symptoms of serotonin toxicity as described on the next page. Taking > 75 times the common daily dose may cause seizures, EKG changes and decreased consciousness. A single drug overdose on Lexapro, Zoloft or Prozac is usually benign. An overdose on Celexa is 4x more dangerous than Lexapro due to cardiac conduction disturbance (QT prolongation), but the absolute risk is low.

Toxicity of antidepressants in overdose Dr Jason Cafer's Psychopharmacology
Psychotropic toxicity Dr Jason Cafer's Psychopharmacology cafermed

from Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots

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