Long-Term Studies on the Effects of Methylphenidate
August 18, 2015 at 03:51 AM | categories: adhd
Contents
1 Long-term studies
methylphenidate (MPH)-elicited dopamine (DA) increases in ventral striatum are associated with long-term symptom improvement in adults with attention-deficit/hyperactivity disorder (ADHD) [5]. Adult ADHD subjects who were treated with a titrated regimen of MPH for one year showed significant improvement on the Conners’ Adult ADHD Rating Scale, and the improvement in clinical symptoms (before treatment vs. after long-term treatment) was correlated to the DA increase elicited by i.v. MPH (quantified as a reduction in D2/D3 receptor availability in striatal regions, and in frontal and temporal cortical regions) [5]. Individual subjects with the largest increases in DA also had the greatest reduction in symptoms with long-term MPH treatment. Decreases in D2/D3 receptor availability with i.v. MPH in prefrontal and temporal cortices were associated with decreased ratings of inattention when subjects were clinically treated, which suggests that enhancement of DA signaling in these cortical regions may contribute to the therapeutic actions of oral MPH [5]. Volkow et al. [5] also saw an attenuation of MPH-induced DA increases in striatum and a trend toward lower baseline levels of D2/D3 receptor availability in striatum after long-term treatment with oral MPH. MPH could ameliorate inattention by both enhancing saliency (through effects on the ventral striatum) and enhancing the executive components of attention that are mediated through prefrontal regions (including cingulate gyrus) [3–5].
Long-term treatment with MPH decreased MPH-induced DA increases in striatum but not in cortex. Because MPH blood levels are associated with the level of dopamine transporter (DAT) blockade [2] and the concentration of MPH in plasma after i.v. MPH did not differ for treatment-naïve and long-term treatment conditions [5], the lower DA increases in striatum over the year of treatment suggest changes that decrease DA release. These reductions are likely to reflect neuroplasticity effects of chronic MPH treatment. Because the attenuation was in striatum and not in cortical regions, this suggests that they reflect changes in DA autoreceptor sensitivity and/or DAT upregulation because cortical DA projections are much less sensitive to regulation by DA autoreceptors or DAT [1]. Indeed, Wang et al. [6] recently showed that 12 month treatment with oral MPH resulted in upregulation of DAT in striatum.
Acronyms
- ADHD
- attention-deficit/hyperactivity disorder
- DAT
- dopamine transporter
- DA
- dopamine
- MPH
- methylphenidate
References
[1] S. Lammel, A. Hetzel, O. Häckel, I. Jones, B. Liss, and J. Roeper. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron, 57(5):760–73, Mar 2008. doi: 10.1016/j.neuron. 2008.01.022.
[2] N. D. Volkow, G. J. Wang, J. S. Fowler, S. J. Gatley, J. Logan, Y. S. Ding, R. Hitzemann, and N. Pappas. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry, 155(10):1325–1331, Oct 1998.
[3] N. D. Volkow, G. Wang, J. S. Fowler, J. Logan, M. Gerasimov, L. Maynard, Y. Ding, S. J. Gatley, A. Gifford, and D. Franceschi. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci, 21(2):RC121, Jan 2001.
[4] N. D. Volkow, J. S. Fowler, G.-J. Wang, and J. M. Swanson. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry, 9(6):557–569, Jun 2004. doi: 10.1038/sj.mp. 4001507. URL http://dx.doi.org/10.1038/sj.mp.4001507.
[5] N. D. Volkow, G.-J. Wang, D. Tomasi, S. H. Kollins, T. L. Wigal, J. H. Newcorn, F. W. Telang, J. S. Fowler, J. Logan, C. T. Wong, and J. M. Swanson. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci, 32(3):841–9, Jan 2012. doi: 10.1523/JNEUROSCI.4461-_11.2012.
[6] G. Wang, N. Volkow, T. Wigal, S. Kollins, J. Newcorn, F. Telang, J. Logan, C. Wong, J. Fowler, and J. Swanson. Chronic treatment with methylphenidate increases dopamine transporter density in patients with attention deficit hyperactive disorder. In Society of Nuclear Medicine Annual Meeting Abstracts, volume 50, page 1283. Soc Nuclear Med, 2009.