14 January 2009. Modafinil, a psychostimulant prescribed mainly for narcolepsy, was first found to increase cognitive functions in schizophrenic patients when it was used to counteract the sedative properties of atypical antipsychotics (see review by Morein-Zamir et al., 2007). With clinical trials now enrolling schizophrenia patients to confirm the cognition-enhancing properties of modafinil, non-invasive methods are needed to demonstrate its mechanism of action and to better predict patients who are most likely to benefit. Such an innovation appears to have been provided by Michael J. Minzenberg, Cameron Carter, and colleagues from the Department of Psychiatry at the University of California, Davis.
In an article published December 12, 2008, in Science, they elaborate on a noradrenergic mechanism in the brain that may explain the attention-enhancing properties of drugs like modafinil. They used functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent signals (BOLD) to show that modafinil, a modest norepinephrine and dopamine reuptake blocker, decreases the background continuous ("tonic") activity of locus coeruleus (LC) neurons. This enhances the ability of the LC noradrenergic projection to promote phasic increases in anterior cingulate cortex activity during task-associated responses.
In a placebo-controlled, double-blind, crossover study, 21 healthy men and women 18-50 years of age received a single oral dose of placebo or 200 mg of modafinil, separated by a three-day drug-free period before a crossover trial to modafinil or placebo. Using a state-of-the-art 2 Tesla Siemens Trio MRI system, fMRI measurements were conducted 3.6 hours after dosing, when blood modafinil levels peak. Minzenberg and colleagues identified a robust, task-independent deactivation by modafinil of the bilateral pontine nuclei that overlapped with the LC in three dimensions. In contrast, an increase in BOLD contrast was obtained in these nuclei and in the neocortex during task-related cognitive activities. This enhanced LC-neocortex functional connectivity, or "resonance," may explain the procognitive actions of drugs like modafinil.
Perhaps due to the single dose used in this acute study, or the high cognitive performance of the placebo group, modafinil did not improve cognition as measured by group performance accuracy or reaction time. This prevented what would have been an informative analysis between task-related activation of the anterior cingulate or LC and cognitive effects of modafinil. A small subgroup of subjects showed a marginally significant correlation between decreased reaction time and increased LC activity. Perhaps more challenging cognitive tests, made during chronic modafinil administration, would allow a more thorough evaluation of these relationships. It would also be highly informative to determine if baseline LC activation is higher in schizophrenia patients than in normal controls. That would provide compelling support for the therapeutic mechanism they propose, and support analysis of other conditions such as attention deficit-hyperactivity disorder.
Modafinil increases hypocretin/orexinergic neuron signaling, elevates extracellular levels of glutamate, and lowers GABA, but each of these actions is acknowledged by Minzenberg to increase tonic excitation of LC adrenergic neurons. Modafinil seems to block the norepinephrine transporter (NET) more than it does the dopamine transporter (DAT) and is proposed by Minzenberg and Carter, 2008, to promote α2 adrenergic suppression of LC neurons. Though at odds with findings that α2 receptor antagonism with drugs like idazoxan augments cognitive function in rodent models (Marcus et al., 2005) and typical neuroleptic-treated schizophrenia patients (Litman et al., 1996), an α2 agonist feedback mechanism for quieting LC neurons in a task-dependent manner has been shown in humans treated with clonidine (Coull et al., 1999). Whether NET inhibition is truly the defining action of modafinil in these studies is unclear, and the confirmation of this mechanism awaits the use of a selective NET inhibitor such as atomoxetine, the authors write.
Minzenberg and colleagues conclude that modafinil's NET inhibition and LC deactivation collaborate to augment phasic LC responses to salient stimuli, and increase anterior cingulate activation during working memory tasks. This latter effect was first reported by Spence and colleagues (Spence et al., 2005) and is replicated by the Minzenberg report. Interestingly, in the same report, Spence and colleagues also identified several actions of modafinil in human brain that could be exploited by the methods of the Minzenberg study to improve cognitive therapy in schizophrenia. First, they found that the modafinil-treated patients with the greatest anterior cortex activation also received the greatest cognitive benefits from the drug. Thus, fMRI-derived ratios of anterior cingulate or LC activity before and after modafinil might provide an even better biomarker for long-term cognitive improvement. Second, the facilitation or retarding of cognition by concomitant medications could be tested by their augmentation or diminution of either ratio. For example, the potent 5-HT2A antagonism of the atypical antipsychotics is predicted to lessen the cognition-enhancing effects of modafinil (Spence et al., 2005). If so, clinical trials of modafinil in schizophrenia patients with neurocognitive deficits may be more likely to succeed if the patients are stabilized with lower dose typical antipsychotics, rather than the atypical agents that are planned, for example, in the clinical trial being conducted by Marc-André Roy and colleagues of Laval University in Quebec City, Canada.
The value of pairing modafinil with a typical or atypical agent could be evaluated by a comparison of modafinil with a dose of haldol or risperidol that produces equivalent reductions in positive symptoms. An evaluation of the task-related increase in the LC or anterior cingulate BOLD ratio could identify which patients are most likely to experience improved executive and cognitive functions, but without compromising the treatment of positive symptoms. To date, that has been the Achilles heel of partial D2 agonists and stimulants that improve cognitive symptoms of schizophrenia. The importance of identifying biomarkers and a mechanism of action for cognition-enhancing drugs like modafinil may be increased even more, given the advocacy for the widespread use of such drugs to enhance the cognitive abilities of young and old (see, e.g., Greely et al., 2008).—C. Anthony Altar.
Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS. Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI. Science. 2008 Dec 12;322(5908):1700-2. Abstract