Dopaminergic therapy in aphasia

Figures & data

Figure 1. (a) The two main dopaminergic nuclei are close to each other in the midbrain with the substantia nigra projecting to the striatum and the ventral tegmental area projecting to both the nucleus accumbens (part of the ventral striatum) and the frontal cortex. (b) The nigrostriatal pathway affects cortical function indirectly through a series of cortico-basal ganglia circuits. The substantia nigra (pars compacta) projects to the striatum (caudate and putamen in blue). The main output of the striatum is to the globus pallidus (green) and thence to the thalamus (pink) and cortex (green arrows). The cortex feeds back to the striatum (green arrows) to close the loop on the cortico-basal ganglia circuits. There are also dopaminergic receptors on many cortical neurons (not shown). http://en.wikipedia.org/wiki/File:Basal_ganglia_circuits.svg. Mikael Häggström, based on images by Andrew Gillies.

TABLE 1 Summary of the 15 studies covered by this review

Title, 1st author, year	Trial type	Drug and dose	No. Pts	Aphasia type and chronicity	Main outcomes, comments
Pharmacotherapy for aphasia. Albert (1988).	Single case, no placebo, ABA design.	Bromocriptine, 15 then 30 mg	1	Transcortical motor aphasia. 3.5 years post-stroke.	Paired with therapy. Reduced hesitancy, decreased paraphrasias and increased naming ability. Return to baseline after cessation of therapy.
The effects of bromocriptine on speech and language function in a man with transcortical motor aphasia. MacLennan, 1990.	Single case, placebo-controlled, single blinded, AB design.	Bromocriptine 2.5 mg increased to 15 mg	1	Transcortical motor aphasia. 4 years post-stroke.	An increase in no. words and correct information units, but no statistical analysis made. Changes could be due to practice or carry-over effects.
Bromocriptine treatment of non-fluent aphasia. Gupta (1992).	Two cases, no placebo, AB design.	Bromocriptine, escalated dose: 10 mg, 30 mg	2	1 = Broca’s aphasia; 1 = transcortical motor aphasia. 18 months and 10 years post-stroke.	Drug alone, not paired with therapy. Fluency of speech improved in both. In the second case worse on 30 mg and improved when dose deescalated to 10 mg.
An open label trial of bromocriptine in non-fluent aphasia. Sabe (1992).	No placebo, ABA ramp-up, ramp-down design.	Bromocriptine, up to 60 mg/day	7	4 = transcortical motor aphasia; 2 = Broca’s aphasia; 1 = global aphasia. >1 year post-stroke.	Paired with therapy. An improvement seen in those who were moderately affected (4:3) with increased word finding and verbal fluency increasing on drug compared with baseline and then decreasing as the drug was withdrawn.
A randomised, double blind, placebo controlled study of bromocriptine in non-fluent aphasia. Sabe (1995).	Randomised*, double-blind, placebo-controlled, crossover design.	Bromocriptine, up to 60 mg/day	7	2 = Broca’s aphasia; 3 = transcortical motor aphasia; 2 = anomic aphasia. >1 year post-stroke.	No benefit measured over placebo in hesitancy, verbal naming, verbal fluency, content words or content units. High rate of side effects in therapy block (57%) compared with control block (0%).
Bromocriptine treatment of non-fluent aphasia. Gupta (1995).	Double-blind, placebo-controlled, crossover design.	Bromocriptine, up to 15 mg/day	20	7 = transcortical motor aphasia; 4 = Broca’s aphasia; 9 = “mixed anterior aphasia”. >1 year post-stroke.	Drug alone, not paired with therapy (therapy was not allowed during the trial). No improvement in speech fluency, language content, overall aphasia severity or non-verbal cognitive problems.
Bromocriptine is ineffective in the treatment of chronic non-fluent aphasia. Ozeren (1995).	No placebo, AB design.	Bromocriptine, 10–25 mg/day	4	2 = Broca’s aphasia; 1 = transcortical motor aphasia; 1 = global. 24 to 35 months post-stroke.	No significant improvements on “aphasia tests” (a speech sample rated on an ordinal scale of three points). Outcome measure almost certainly not sensitive to change.
Transcortical motor aphasia. Berthier (1999).	Single case, no placebo, AB design.	Bromocriptine, titrated to 20 mg/day	1	Transcortical motor aphasia. Bilateral striatocapsular strokes (12 and 5 months prior to study) with Parkinsonian features.	Patient improved markedly on spoken picture description and aphasia quotient of the WAB. Mixture of improvements in Parkinsonian (motoric) and word finding aspects of speech.
An open label trial of bromocriptine in non-fluent aphasia: a qualitative analysis of word storage and retrieval. Gold (2000).	No placebo, ABBA design.	Bromocriptine, 15 mg/day	4	2 = Broca’s aphasia; 2 = transcortical motor aphasia. 7 to 78 months post-stroke.	Drug alone, not paired with SALT. A significant improvement in word retrieval for all four on bromocriptine therapy with three experiencing decreases after withdrawal.
Bromocriptine and speech therapy in nonfluent chronic aphasia after stroke. Bragoni (2000).	Double-blind placebo-controlled, but not randomised (placebo 1st block; bromocriptine 2nd block).	Bromocriptine, 30 mg/day	11 (5#)	9 = Broca’s aphasia; 2 = global aphasia. 6 to 96 months post-stroke.	Improved dictation, reading-comprehension, repetition and verbal latency but only 5/11 completed the study. Supposedly double-blind but high level of side effects. Placebo-controlled but not block-randomised.
Effects of bromocriptine in a patient with crossed non-fluent aphasia: a case report. Raymer (2001).	Single case, no placebo, ABABA design.	Bromocriptine, escalating dose up to 20 mg/day	1	Transcortical motor aphasia. NB: right frontal stroke involving IFG. 2 months post-stroke.	Improved verbal fluency sustained during withdrawal phases—this could have been due to spontaneous recovery.
A clinical trial of bromocriptine for treatment of primary progressive aphasia. Reed (2004).	Randomised, double-blinded, placebo-controlled, crossover.	Bromocriptine, 22.5 mg per day	6	Primary progressive aphasia (mean age 66.8 years).	Increased mean length of utterance but no effect on fluency or naming. Suggests a slowing of decline of the motoric aspects of speech.
A randomised double blind trial of bromocriptine efficacy in non-fluent aphasia after stroke. Ashtary (2006).	Randomised, double-blind, placebo-controlled.	Bromocriptine, up to 10 mg/day	38	Non-fluent aphasic patients, Persian speakers, in the “acute” phase.	Patients in both groups (placebo and bromocriptine) improved on all measures. No significant differences between the groups.
New approach to the rehabilitation of post-stroke focal cognitive syndrome: effect of levodopa combined with speech and language therapy on functional recovery from aphasia. Seniow (2009).	Randomised, double-blind, placebo-controlled.	L-dopa, 100 mg/day. Used in a phasic manner and paired with SALT	39	Any aphasia subtype. Acute phase (˜5 weeks post-stroke). In-patients.	Increased naming and repetition on L-dopa compared with placebo. First study to attempt a sub-group analysis on lesion site (patients with “anterior” lesions responded better to L-dopa).
Crossover trial of subacute computerised aphasia therapy for anomia with the addition of either levodopa or placebo. Leeman, Laganaro, Chetelat-Mabillard, and Schnider (2011).	Randomised, double-blind, placebo-controlled, crossover.	L-dopa, 100 mg/day. Used in a phasic manner and paired with computerised therapy and SALT.	12	2 = Broca’s; 2 = Wernicke’s; 6 = anomic; 1= conduction. Acute (˜7.5 weeks) Post-stroke (9) or traumatic brain injury (3). In-patients.	Significant improvements on the treated items from the computerised therapy battery but no interaction with drug/placebo block.

*Although reported as randomised (block randomised), all 7 patients were randomised to drug first then placebo. See text for further comment.

#High drop-out rate (54%). Only 5 completed the study.

Albert, M. L., Bachman, D. L., Morgan, A., & Helm-Estabrooks, N. (1988). Pharmacotherapy for aphasia. Neurology, 38, 877–879.

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Gupta, S. R., & Mlcoch, A. G. (1992). Bromocriptine treatment of nonfluent aphasia. Archives of Physical Medicine and Rehabilitation, 73, 373–376.

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Sabe, L., Leiguarda, R., & Starkstein, S. E. (1992). An open-label trial of bromocriptine in nonfluent aphasia. Neurology, 42, 1637–1638.

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Sabe, L., Salvarezza, F., Garcia Cuerva, A., Leiguarda, R., & Starkstein, S. (1995). A randomized, double-blind, placebo-controlled study of bromocriptine in nonfluent aphasia. Neurology, 45, 2272–2274.

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Gupta, S. R., Mlcoch, A. G., Scolaro, C., & Moritz, T. (1995). Bromocriptine treatment of nonfluent aphasia. Neurology, 45, 2170–2173.

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Ozeren, A., Sarica, Y., Mavi, H., & Demirkiran, M. (1995). Bromocriptine is ineffective in the treatment of chronic nonfluent aphasia. Acta Neurologica Belgica, 95, 235–238.

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Berthier, M. L. (1999). Transcortical motor aphasia. In M. L. Berthier (Ed.), Transcortical aphasias (37–74). Hove: Psychology Press.

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Gold, M., VanDam, D., & Silliman, E. R. (2000). An open-label trial of bromocriptine in nonfluent aphasia: A qualitative analysis of word storage and retrieval. Brain Language, 74, 141–156.

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Bragoni, M., Altieri, M., Di Piero, V., Padovani, A., Mostardini, C., & Lenzi, G. L. (2000). Bromocriptine and speech therapy in non-fluent chronic aphasia after stroke. Neurological Sciences, 21, 19–22.

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Raymer, A. M., Bandy, D., Adair, J. C., Schwartz, R. L., Williamson, D. J., Gonzalez Rothi, L. J., & Heilman, K. M. (2001). Effects of bromocriptine in a patient with crossed nonfluent aphasia: A case report. Archives of Physical Medicine and Rehabilitation, 82, 139–144.

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Reed, D. A., Johnson, N. A., Thompson, C., Weintraub, S., & Mesulam, M. M. (2004). A clinical trial of bromocriptine for treatment of primary progressive aphasia. Annals of Neurology, 56, 750.

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Ashtary, F., Janghorbani, M., Chitsaz, A., Reisi, M., & Bahrami, A. (2006). A randomized, double-blind trial of bromocriptine efficacy in nonfluent aphasia after stroke. Neurology, 66, 914–916.

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Seniow, J., Litwin, M., Litwin, T., Lesniak, M., & Czlonkowska, A. (2009). New approach to the rehabilitation of post-stroke focal cognitive syndrome: Effect of levodopa combined with speech and language therapy on functional recovery from aphasia. Journal of the Neurological Sciences, 283, 214–218.

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