4,5-Substituted Picolinamide and picolinonitrile compounds of formula (I), where R4 is CONH2 or CN and R1 is an optionally substituted aryl or heteroaryl, are negative allosteric modulators of the metabotropic glutamate receptor 2 (mGlu2). The compounds and pharmaceutical compositions including the compounds may be useful for treating depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, or autism spectrum disorders in a subject.