Citalopram / Escitalopram for ADHD

Citalopram and escitalopram are selective serotonin reuptake inhibitors (SSRIs).

Escitalopram is the pure active isomer, while citalopram is the racemic mixture of the active and inactive isomers.¹ The efficacy profile is therefore identical, although the side effects of escitalopram are expected to be slightly milder. Escitalopram was developed and brought to market after the patent protection for citalopram had expired.

ATTENTION:
There are concerns regarding the use of the entire class of serotonin reuptake inhibitors, particularly citalopram and escitalopram, in the treatment of ADHD.
See ⇒ Notes on Selective Serotonin Reuptake Inhibitors (SSRIs) for ADHD In the article ⇒ Medications for ADHD – Overview.

1. Citalopram / Escitalopram in Relation to ADHD¶

• SSRIs had no effect on ADHD²
• Citalopram and escitalopram appear to increase DAT activity^{34 5} , which is detrimental in ADHD.
  One of the main problems associated with ADHD is the low level of extracellular dopamine in the striatum, which is also caused by an excessive number of dopamine transporters that reabsorb the released dopamine presynaptically from the synaptic cleft before it can bind postsynaptically. More active DATs therefore exacerbate the symptoms of ADHD.
  If sleep problems are also present (as is often the case with ADHD), medications that increase serotonin levels may also have adverse effects.⁶
• A higher dose of escitalopram (20 mg) increases the cortisol response to acute stress (TSST).⁷
  When treating comorbid depression in ADHD, it should be noted that an increase in the cortisol response to stress in people with ADHD-HI (who often have a blunted cortisol response, preventing the HPA axis from shutting down) could be beneficial, but may be detrimental from this perspective in people with ADHD-I (who very often have an excessive cortisol response). See ⇒ Notes on Selective Serotonin Reuptake Inhibitors (SSRIs) for ADHD In the article ⇒ Medications for ADHD – Overview.
• Citalopram reduces the striatum’s response to stimulating or negative stimuli.⁸
  The effect on the striatum could also be the cause of the emotional numbness and increased indifference associated with SSRIs.⁹
• Escitalopram leads to increased anxiety scores on the TSST at doses of 10 mg and 20 mg.⁷ The HPA axis is regulated by the amygdala. Increased anxiety is counterproductive in ADHD, and especially in ADHD-I.
• Citalopram reduces the firing rate of serotonergic neurons in the dorsal raphe nuclei.¹⁰
• Citalopram increases serotonin levels, but not dopamine or norepinephrine, in the dorsal hippocampus, frontal cortex, nucleus accumbens, and striatum.¹¹
• Citalopram does not reduce the activity of dopaminergic neurons in the ventral tegmental area¹²
• Citalopram does not reduce the activity of adrenergic neurons in the locus coeruleus¹⁰

Most clinicians do not clearly distinguish between the symptom of dysphoria typical of ADHD* During inactivity—which is a functional stress symptom (the drop in mood during inactivity is intended to keep the person active until the stressor is overcome)—and “true” depression. As a result, they treat people with ADHD inappropriately, as if they had true depression.
*Here, “dysphoria” does not refer to “true” exhaustion-related depression, which can be a consequence of ADHD, but rather to a (chronic) low mood.
⇒ Depression and Dysphoria in ADHD.

In practice, it has been shown that treatment with a significantly reduced dose of escitalopram (compared to its use as an antidepressant) can improve dysphoric mood. In such cases, a dose of 3 to 5 drops per day may already be sufficient.
In our experience, switching from methylphenidate to amphetamine-based medications (Vyvanse)—which, in addition to their strong dopaminergic and noradrenergic effects, also have a mild serotonergic effect—also has a positive impact on the symptom of dysphoria.

2. Metabolism of Escitalopram¶

Source: Schmotz¹³

Escitalopram is primarily influenced by

• Cytochrome P450 (CYP) isoenzyme CYP3A4
• Cytochrome P450 (CYP) isoenzyme 2C19
• Cytochrome P450 (CYP) isoenzyme 2D6

It is metabolized to demethyl-escitalopram. This compound retains 10% of escitalopram’s efficacy and is subsequently metabolized into a didemethyl metabolite.
In patients with liver damage, the metabolism of escitalopram is reduced and plasma levels are elevated.
Escitalopram and its demethylated metabolite have barely any inhibitory effect on the hepatic enzyme system (CYP1A2, -2C9, -2C19, -2E1, and -3A) and only a weak inhibitory effect on CYP2D6.
There are barely any relevant drug interactions with CYP3A4 and CYP2C19 inhibitors.
or CYP2D6 (von Moltke, Greenblatt et al. 2001; Rao 2007).
Both citalopram and escitalopram are primarily excreted by the kidneys, with only a small amount excreted in the feces.

The elimination half-life of escitalopram is approximately 30 hours.