escitalopram

a) 12 healthy subjects were treated with the related drug citalopram 40 mg daily, amitriptyline 50 mg daily or matching placebo for 1 week in randomized crossover fashion. On the morning of day 8, subjects ingested a dose of ethanol calculated to achieve a blood alcohol content of 80 mg/100 mL (0.8% - the legal intoxication limit in many countries at the time of the study). On a variety of tests measuring cognitive and psychomotor performance, effects of alcohol combined with citalopram were not potentiated compared to subjects receiving alcohol and placebo. 

b) 12 healthy subjects were treated with related medication fluoxetine 40 mg daily, amitriptyline 75 mg daily or matching placebo for 1 week in randomized crossover fashion (There was a 28 day washout between administration due to long fluoxetine half-life). On the morning of day 8, subjects ingested a dose of ethanol calculated to achieve a blood alcohol content of 80 mg/100 mL (0.8% - the legal intoxication limit in many countries at the time of the study). On a variety of tests measuring cognitive and psychomotor performance, effects appeared to be mostly due to alcohol, and effects in patients receiving alcohol with fluoxetine were not potentiated compared to subjects receiving alcohol and placebo. 

c) The manufacturers of escitalopram state there is no pharmacodynamic interaction noted in clinical studies in which related drug, citalopram was given with alcohol. 

d) There are many case reports (at least 93; however, many are anecdotal) in which patients treated with SSRIs developed new or worsened alcohol use disorders. These generally resolved once the medication was discontinued. This occurred in patients who drank minimal alcohol before starting an SSRI as well as patients who already had alcohol use disorders. 

e) 265 patients with a diagnosis of alcohol abuse/dependence (per DSM-IV criteria) were titrated up with related drug citalopram 40 mg daily over 2 weeks, which they received for 10 weeks, or were given placebo. They all underwent standard psychotherapy. At 12 weeks the citalopram group had more heavy drinking days and smaller changes in the frequency and amount of alcohol consumption. 

f) There are at least 100 case reports describing "pathological intoxication" when SSRIs were taken with alcohol. Patients taking relatively small amounts of alcohol (that were tolerated will before SSRI initiation) have lead to unexpectedly gross disinhibition and even violence or suicide. In at least 4 patient, re-exposure to the same or a related antidepressant reproduced this finding. 32 of these patients reported an increased or altered pattern of alcohol use after SSRI initiation.

g) One case study reports a 26 year old man who developed serotonin syndrome after taking his medications (escitalopram, clomipramine, flunitrazepam) with a can of beer (350 mL).

h) A case study reports a patient with Parkinson disease who was stable on rasagiline (1 mg daily) and escitalopram (10 mg daily) developed serotonin syndrome after ingestion of alcohol (36% ABV).

a,b) Lack of direct potentiation of alcohol effects has been consistently noted with drugs that primarily affect serotonin reuptake (e.g. citalopram and other SSRIs). This class of medications lacks affinity for the histamine H1 receptor, blockade of which is associated with sedation. Many older antidepressant agents (e.g. amitriptyline and other tricyclics) produce strong H1 blockade.

g,h) Additive serotonergic effects could contribute to an increased risk of serotonin syndrome. Ethanol is a serotonergic agent that has been shown to decrease extracellular serotonin clearance in mice. 

a-c) It was concluded that in practice, citalopram and fluoxetine interactions with ethanol should be unremarkable in terms of psychomotor impairment. This appears likely to be the case with most other SSRIs (escitalopram) and SNRIs as well, though formal studies with each individual agent have not been conducted. 

d) Patients started on escitalopram should be monitored for increased alcohol cravings or consumptions. 

e) As an enantiomer of citalopram, escitalopram should not be used in the treatment of alcohol dependence. It should be used very cautiously for other indications in alcohol dependent patients who are in early recovery. 

f) It is possible that patients initiating SSRI therapy may experience higher levels of intoxication with amounts of alcohol that they previously tolerated. They should be aware that this may affect their ability to drive or do other activities that require alertness or attention safely.

g,h) The significance of these case reports are unclear as both patients were taking multiple serotonergic medications. Patients taking escitalopram and using alcohol should be educated about the risk of serotonin syndrome and monitored for signs and symptoms. 

a) A study in 130 people found no significant correlation between escitalopram serum levels and smoking.

b) In a retrospective analysis of 124 patients (including 36 smokers), smokers had significantly lower escitalopram serum concentrations compared to non-smokers despite taking higher daily doses of escitalopram. 

b) It is speculated that the mechanism of the interaction may be due to induction of enzymatic pathways (CYP3A4, CYP2C19) by polycyclic aromatic hydrocarbons in cigarette smoke. Escitalopram is a CYP3A4 and CYP2C19 substrate. 

b) Smokers may require higher escitalopram dosages. Additionally, when patients are taking escitalopram and then quit smoking, escitalopram dosage may need to be reduced to prevent emergent adverse effects.

No information currently available.

a) As a CNS depressant, escitalopram has the potential to enhance the adverse or toxic effects of other CNS depressants, such as cannabis. 

b) In a study of 6 patients with related drug citalopram, a mean increase of 88% in citalopram plasma concentration was observed at week 8 with concurrent cannabidiol (CBD) administration.

a) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive. 

b) Cannabidiol (CBD) inhibits CYP2C19 and CYP3A4. Escitalopram is a substrate for CYP2C19 and CYP3A4.

a) It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness. 

b) Patients taking escitalopram and using cannabis may experience increased adverse effects from escitalopram.

ALL OPIOIDS: As a CNS depressant, escitalopram has the potential to enhance the adverse or toxic effects of other CNS depressants such as opioids. 

DEXTROMETHORPHAN: a) One case study reports a 20-year-old man who developed serotonin syndrome after ingesting dextromethorphan overdoses, while receiving escitalopram. 

b) One case study reports that a 6-year-old patient developed serotonin syndrome after ingesting dextromethorphan overdoses while receiving a related drug, sertraline. 

FENTANYL/OXYCODONE: a) A case report describes a 59 year old woman who was taking escitalopram and oxycodone and received fentanyl 250 mcg and morphine during surgery. The patient developed symptoms of serotonin syndrome the following morning. 

b) A case report describes a 66 year old male who was taking oxycodone 120 mg daily and fentanyl 200 mcg intranasally up to QID. Escitalopram 5 mg/day was initiated and he developed serotonin syndrome. The majority of his symptoms resolved in 2 days but he continued to suffer from blurred vision. 

HYDROCODONE: A 90 year old woman was taking hydrocodone and her citalopram 10 mg daily was changed to escitalopram 10 mg daily. She developed hallucinations, and hydrocodone was discontinued due to improved pain. The hallucinations resolved. She had previously taken paroxetine with the same dose of hydrocodone with no hallucinations or signs of serotonin-syndrome. 

HYDROMORPHONE: An 81 year old woman who took related drug fluoxetine 20 mg daily and other medications for several years developed abnormal movements, confusion, incoherent speech, sweating, redness, tremor, hyperreflexia and muscle spasm 2 days after starting hydromorphone 12 mg daily. Fluoxetine was stopped and the symptoms resolved. 

LOPERAMIDE: QTc prolongation has been observed with escitalopram. Concomitant use with high-dose loperamide (>100 mg/day) may result in an arrhythmia with the potential to develop Torsades de Pointes. 

MEPERIDINE: Taking meperidine and escitalopram together increases the risk of serotonin syndrome. 

MORPHINE: A patient, who had been taking related drug paroxetine prior to surgery, was given morphine and ondansetron during the surgery. She experienced post-operative delirium (agitation, confusion, uncontrolled limb movements, abnormal ocular function, hypertension, pyrexia, brisk reflexes, ankle clonus, elevated creatinine phosphokinase (CPK)) during the following 2 days. 

METHADONE: QTc interval prolongation has been observed with escitalopram, thus concomitant use with methadone may result in an arrhythmia with the potential to develop Torsades de Pointes. 

OXYCODONE: Symptoms of serotonin syndrome occurred in a patient taking escitalopram and extended release oxycodone after the oxycodone dose was increased. 

TRAMADOL: a) A placebo-controlled crossover study was preformed where 15 healthy volunteers were given escitalopram 20 mg daily and tramadol 150 mg. The median AUC of (+)-O-desmethyltramadol (tramadol metabolite) was decreased by 29% in those taking escitalopram. The analgesic effect was assessed by the cold pressor test; it was unaffected. 

b) An increase in seizure risk was noted by the manufacturer of tramadol when used with SSRIs. 

c) There are multiple case reports of patients experiencing serotonin syndrome due to a combination of tramadol and related drug citalopram. 

d) A 58 year old male patient was taking escitalopram 20 mg daily as well as quetiapine 300 mg daily, oxazepam 60 mg daily, alprazolam 2 mg daily, and zolpidem 12.5 mg daily. He was also treated with baclofen for 5 months for alcohol dependence. He was also on various other medications for non-psychiatric conditions (diabetes, cardiovascular disease, benign prostatic hyperplasia and urinary incontinence). Tramadol 50 mg BID was prescribed, although the patient may have taken more than prescribed. One month later the patient was arrested and diagnosed with a manic episode. He also had a positive urinary screen for tetrahydrocannabinol. Tramadol was discontinued on admission and escitalopram was discontinued 1 week later, but the patient wasn't able to be discharged for 3 months due to his symptoms, despite treatment with quetiapine, oxazepam, and lithium. 

OTHER OPIOIDS: The serotonergic effects of SSRIs may be enhanced by concomitant use with serotonergic opioids.

ALL OPIOIDS: b) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive. 

DEXTROMETHORPHAN: Serotonin syndrome is a dose-related response to the use of serotonergic drugs, often in combination. Genetic polymorphism in CYP2D6 function leads to differences in the ability to metabolize dextromethorphan which may explain the differences in clinical experiences reported by those who abuse dextromethorphan for its dissociative effects. 

FENTANYL: a,b) Additive serotonergic effects could contribute to an increased risk of serotonin syndrome. 

LOPERAMIDE: Both escitalopram and high dose loperamide can cause QTc interval prolongation. When used together, these effects may be additive. 

MEPERIDINE: Additive serotonergic effects could contribute to an increased risk of serotonin syndrome. 

METHADONE: Additive QTc prolongation. 

TRAMADOL: a) The analgesic effect of tramadol is thought to be mediated mainly by the (+)-O-desmethyltramadol metabolite. 

b) Tramadol can cause seizures, and SSRIs can lower the seizure threshold. 

c) Additive serotonergic effects could contribute to an increased risk of serotonin syndrome. 

d) The parent compound is an inhibitor of serotonin and norepinephrine reuptake (structural analog of venlafaxine). 

OTHER OPIOIDS: Additive serotonergic effects.

ALL OPIOIDS: It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness. 

DEXTROMETHORPHAN: If therapeutic doses of dextromethorphan and an SSRI are enough to elicit serotonin syndrome, then the combination of these drugs should be avoided. One case study suggests that supra-therapeutic doses of dextromethorphan are a risk factor for the development of serotonin syndrome. 

FENTANYL, MEPERIDINE, TRAMADOL: Fentanyl, meperidine, and tramadol may not be the best choice for analgesic therapy in patients currently maintained on escitalopram due to increased risk of serotonin syndrome. If these combinations cannot be avoided patients should be monitored for signs of serotonin syndrome. 

LOPERAMIDE: Due to increased risk of QTc interval prolongation, it is recommended to avoid concomitant use of high-dose loperamide (>100 mg/day) and escitalopram. 

METHADONE: Due to increased risk of QTc interval prolongation, caution is recommended with concomitant use of methadone and escitalopram. 

TRAMADOL: a) The change in metabolism of tramadol does not appear to affect analgesic efficacy. 

b) Caution with concomitant use of tramadol and SSRIs is recommended in patients who already have increased risks of seizures. 

d) As the exact dose taken is unknown, tramadol abuse is possible. The significance of this case report is unclear, but the mechanism of action of tramadol makes it possible for it to induce mania. 

OTHER OPIOIDS: While there is the potential for increased risk of serotonin syndrome with the concomitant use of SSRIs and opioids, it appears to be relatively rare. Little evidence exists to suggests a contraindication to concomitant use; however, it is recommended to monitor for serotonin syndrome-like symptoms if used in patients with altered mental status, autonomic dysfunction, or those experiencing neuromuscular adverse effects.

LSD: In one study, 28 out of 32 subjects (88%) who had taken an antidepressant with inhibitory effects on serotonin reuptake (fluoxetine, paroxetine, sertraline, trazodone) for over 3 weeks had a subjective decrease or virtual elimination of their responses to LSD. These data are in contrast with a previous study that reported increased responses to LSD during chronic administration of tricyclic antidepressants or lithium. 

3 case reports discuss patients with a history of LSD abuse who experienced onset or worsening of LSD flashbacks when given related SSRIs (fluoxetine, paroxetine or sertraline).

Psilocybin: a) A retrospective anonymous survey of 611 participants who self-identified as having used a moderate or high dose of psilocybin during treatment with antidepressants, found the probability of reporting weaker than expected psilocybin effects during treatment with SSRIs. The probability of weaker effects was 0.47 with a 95% CI [0.40, 0.54] compared with using the same dose without antidepressants or compared with use by individuals not taking antidepressants. 

b) A double-blind, placebo controlled trial evaluated found no effect of escitalopram pre-treatment (10 mg daily for 7 days, then 20 mg daily for 7 days) on the positive mood effects of psilocybin but did significantly decrease psilocybin-associated anxiety and cardiovascular adverse effects. Of note, this study only evaluated 2 weeks of escitalopram pretreatment and may not be generalizable to patients treated with long-term antidepressants.

LSD: The mechanism is not well understood. Increased levels of serotonin may lead to increased stimulation of 5-HT2 and 5-HT1A receptors, changes in extracellular brain serotonin concentrations, and changes in brain catecholamine systems.

Psilocybin: a,b) The mechanism of decreased psilocybin effects is likely to be 5-HT2A receptor downregulation due to long term use of SSRI. Subjective effects of psilocybin are known to be correlated with 5HT2A receptor occupancy. 

LSD: There is limited information on the potential interactions between LSD and escitalopram. The authors of the case studies recommended warning patients with a history of LSD use of the potential for flashbacks or hallucinations.

Psilocybin: a-b) The significance is uncertain. Escitalopram may reduce the psychedelic therapeutic effects of psilocybin, although short-term coadministration has not demonstrated a clinically relevant interaction.