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Jorge Perez, MD, PhD; Daniela Tardito, PhD; Silvia Mori, PhD; Giorgio Racagni, PhD; Enrico Smeraldi, MD; Raffaella Zanardi, MD

Arch Gen Psychiatry. 1999;56:248-253.

Background  Abnormalities in the cyclic adenosine monophosphate (cAMP)–dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects.

Methods  Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging.

Results  The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons.

Conclusions  Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.

From the Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, School of Medicine (Drs Perez, Smeraldi, and Zanardi), and the Center of Neuropharmacology, Institute of Pharmacological Sciences (Drs Tardito, Mori, and Racagni), University of Milan, Milan; and the Istituto di Ricovero e Cura a Carattere Scientifico Centro San Giovanni di Dio-Fatebenefratelli, Brescia (Drs Tardito and Racagni), Italy.

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