Modafinil and Armodafinil – Mechanism of Action | Psychopharmacology | Clinical Application

MECHANISMS OF ACTION

The wake-promoting pharmacological profile of modafinil is notably different from other psychostimulants such as amphetamine and methylphenidate, with studies suggesting a complex profile of neurochemical and behavioural effects. [Ballon and Feifel 2006]

Effects on Dopamine :

• Modafinil is primarily a weak dopamine reuptake inhibitor through its competitive binding to the cell-membrane dopamine transporter (DAT). Its binding affinity to DAT is lower than Bupropion. This interaction with DAT and the subsequent increase in a dopaminergic tone is central to its wake-promoting effects.  It has no direct or indirect effects on dopamine receptors. 

• However, research also shows evidence that modafinil similarly binds to the norepinephrine transporter (NET) and that it has additional effects on several other CNS systems such as GABA, glutamate, histamine, and orexin pathways. [Minzenberg and Carter 2008] 
• Of note, modafinil and armodafinil demonstrate similar binding and functional activities at DAT and NAT; however, there are stereospecific differences in elimination kinetics. 
• Overall, Modafinil increases HA, NE, 5-HT, and DA levels in the brain.

Mechanism of Enhancing Wakefulness: 

• Histamine, serotonin, and norepinephrine tone is directly related to the arousal state and that neurons releasing these chemicals are almost silent in REM sleep. The peptide orexin (ORX) released from neurons of the lateral hypothalamus plays an important role in the maintenance of vigilance.

• Potentiation of glutaminergic synapses on hypocretin/orexin neurons and monoaminergic systems together with inhibitory effects on GABA is thought to mediate the wakefulness-promoting effects of modafinil. It may also account for the observed clinical effect of armodafinil. [Schwartz et al., 2010]
• However, Modafinil is also capable of promoting wakefulness in the absence of orexin receptors or orexinergic neurons. [Gerrard & Malcolm, 2007]
• In narcolepsy, modafinil reverses decreased alpha and beta activity. [Read more about EEG waves in sleep in our article on the neurobiology of insomnia.]

PHARMACOKINETICS

Modafinil is readily absorbed and has dose-dependent pharmacokinetics between 200 mg and 600 mg, reaching peak plasma concentrations 2–4 hours after dosing. The starting dose is 200 mg PO (dosed in am), with steady-state occurring after 2–4 days. [Robertson and Hellriegel 2003]

• The S-isomer has a relatively short terminal elimination half-life of 4–5 hours compared with that of armodafinil, which is approximately 15 hours [Wong et al. 1999] 

Modafinil has been observed to have variable wakefulness-promoting effects throughout the day with a once-daily dose of 200 mg. As such, some patients may require a 400 mg or a 600 mg split dose of modafinil to alleviate ES later in the day.

Interestingly, armodafinil at 200 mg can maintain wakefulness later in the day due to its long elimination half-life. [Dinges et al. 2006] 

• Armodafinil plasma concentration at 7–11 hours after dosing was 43% higher in comparison with modafinil. 
• Furthermore, pharmacokinetic studies have shown that over a 24-hour period, armodafinil had 28% less fluctuation and 42% less swing in plasma concentrations. [Darwish et al 2009a] and [Darwish et al 2009b] 

DOSING

Narcolepsy:

Modafinil :

• 200 to 400 mg/day, given as a single dose in the morning or two divided doses in the morning and at noon.
• Doses of 400 mg/day have been well-tolerated, but there is no statistically significant evidence that this dose confers additional benefit beyond the 200 mg dose.
• For patients who require more than 200 mg/day, the dose should be increased, to a maximum of 400 mg/day, in increments of 100 mg as needed and tolerated.

Armodafinil (Nuvigil): 

• 150 mg or 250 mg given once daily in the morning

Obstructive sleep apnea-hypopnea syndrome (OSAHS) :

Modafinil: 

• In OSAHS, modafinil is indicated as an adjunct to continuous positive airway pressure (CPAP).
• Clinicians should make a  maximal effort to treat OSAHS with CPAP for an adequate period of time before initiating modafinil.
• If modafinil is used adjunctively with CPAP, encouraging CPAP and periodic assessment of CPAP compliance is necessary.
• 200 to 400 mg/day, given as a single dose in the morning or two divided doses in the morning and at noon. Doses of 400 mg/day have been well-tolerated, but there is no statistically significant evidence that this dose confers additional benefit beyond the 200 mg dose.

Armodafinil:

• The recommended dose of Armodafinil for patients with OSAHS is 150 mg or 250 mg, given once daily in the morning.
• In patients with OSAHS, doses up to 250 mg/day, given as a single dose, have been well-tolerated, but there is no consistent evidence that these doses confer additional benefit beyond the 150 mg/day dose
• There was a slight trend for reduced CPAP use over time with Armodafinil use.

Moderate to Severe Chronic Shift Work Sleep Disorder

Modafinil: 

• 200 mg daily as a single dose approximately 1 hour before the start of the work shift.

Armodafinil: 

• 150 mg daily approximately 1 hour before the start of their work shift.

SAFETY PROFILE

Modafinil and armodafinil are well tolerated, with most adverse events classified as mild or moderate in severity. The most common adverse events (≥5%) reported in randomized controlled trials are: [PROVIGIL package insert]  

• Headache
• Nausea
• Nervousness
• Rhinitis
• Diarrhoea
• Back pain
• Anxiety
• Insomnia
• Dizziness
• Dyspepsia. 

When comparing modafinil 200, 300, and 400 mg/day, headache and anxiety were dose-related.

For armodafinil 150 and 250 mg/day, adverse events that are potentially dose-dependent include headache, rash, depression, dry mouth, insomnia, and nausea. [NUVIGIL package insert]

Serious rash requiring hospitalisation and discontinuation of treatment has been reported in adults in association with the use of Modafinil and Armodafinil.

Clinicians should exercise caution in giving modafinil to patients with a history of psychiatric disorders, including psychosis, depression, mania, major anxiety, agitation, insomnia or substance abuse.

It has been reported that there is abuse and dependency potential with modafinil. Although this has not been investigated for armodafinil, it is likely to be similar to modafinil. Although it is important to state that this potential is lower in comparison with amphetamine-like stimulants. [Myrick et al. 2004] 

Cardiac evaluation and blood pressure should be monitored.

Patients with a history of substance use should be closely monitored as modafinil and armodafinil produce psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants.  (methylphenidate or dexamphetamine).

Drug interactions

Modafinil has displayed some interactions in vitro with the CYP isoenzyme system, although it is less apparent in vivo. Of note, modafinil exerts a reversible inhibition of CYP2C19 as well as a concentration-dependent induction of CYP1A2, CYP2B6, and CYP3A4. [Robertson et al. 2000]

It has also been shown that there is also a small degree of CYP2C9 activity inhibition. 

• As such, there is potential for modafinil to interact with substrates of CYP2C19, which includes diazepam, phenytoin, and omeprazole. 
• Although caution is advised, a clinically significant effect is likely to be low with substrates of CYP2C19. [Robertson and Hellriegel 2003] 

Interestingly, armodafinil (250 mg/day) does not induce CYP1A2. However, it does moderately induce CYP3A4 and moderately inhibits CYP2C19. [Darwish et al. 2008]

The pharmacokinetics of CYP3A4 (e.g., midazolam, ciclosporin, triazolam, and steroidal contraceptives) and CYP2C19 (e.g., diazepam, omeprazole, and phenytoin) may be affected if co-administered with armodafinil. 

Due to the potential for the concurrent administration of modafinil/armodafinil and methylphenidate, interactions studies have been performed, with one study showing a significant increase in the Cmax for modafinil [Wong et al. 1998]; however, it was suggested that this interaction had no clinical significance (the same lack of significance is suggested for armodafinil). 

Finally, two case reports have reported drug-drug interactions: cyclosporin [Le Cacheux et al. 1997] and clomipramine. [Grözinger et al. 1998]  

• Cyclosporin concentrations were significantly lower after treatment with modafinil, although this patient had recently undergone a kidney transplant.  
• Clomipramine concentrations were significantly higher after treatment with modafinil; however, this patient was genotyped as a CYP2D6 poor metabolizer. 

Please read our detailed article on pharmacogenomics with tables of medications that affect CYP enzymes in psychiatry. 

CLINICAL EVIDENCE

Modafinil and Armodafinil are evidence-based in the treatment of: 

• Narcolepsy
• Obstructive Sleep Apnoea as an adjunct to continuous positive airway pressure (CPAP)
• Moderate to Severe Chronic Shift Work Sleep Disorder
• Treatment-resistant Depression
• Negative symptoms of Schizophrenia

Bipolar Depression: 

• Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation than mood stabilisers or antidepressants in bipolar depression.  [ Pary et al., 2015]
• Armodafinil in patients with bipolar depression added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions in depression. [Calabrese et al., 2010], [Calabrese et al., 2014]

Treatment-Resistant Depression: 

• Modafinil is a useful adjunct for partial responders to SSRIs, resulting in rapid mood improvement and decreased fatigue. [Markovitz et al., 2003]
• Please read our detailed article on melancholic depression in which we cover a case study where armodafinil was used as an augmentation strategy. 

Cognitive Function Improvement: 

• Modafinil and armodafinil are regularly used off-label as cognitive enhancers after translational experiments reported promising results. [Turner et al. 2003]
• This includes patients with schizophrenia [Farrow et al. 2006], patients with ADHD [Swanson et al. 2006], and patients with substance abuse that demonstrate impaired cognitive function. [Brady et al. 2011] 
• Several brain areas associated with cognitive processes are activated after modafinil treatment, including the central nucleus of the amygdala, the paraventricular nucleus of the hypothalamus, and the anterior hypothalamus. [Gerrard and Malcolm 2007] 
• Furthermore, one animal study showed that fronto-cortical areas related to arousal and higher cognitive function were also activated, hinting at modafinil’s wake-promoting and pro-cognitive effects. [Gozzi et al. 2012] 

SUMMARY

Modafinil and its longer-acting R–isomer, armodafinil, are effective psychostimulants that improve wakefulness although they do have different pharmacokinetic profiles. Their action on the wakefulness pathways help in the treatment of sleep disorders such as Narcolepsy, OSAHS and Shift work disorder. 

Additionally, through their inhibitory action on DAT, they increase dopamine (similar to Bupropion albeit at a lower potency) which makes them useful as an adjunct in the management of treatment-resistant depression and bipolar depression.

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