For some drugs, all the little tweaks don’t make a big difference in how the medication acts. That’s how it should be.

The real challenge comes from extended-release medicines designed to be taken just once a day instead of twice or three times daily.

We discovered quite by accident that the FDA has not paid nearly enough attention to the timed-release process.

Readers of our newspaper column began reporting problems with a long-acting generic antidepressant called Budeprion XL 300 shortly after it appeared on the market.

These people had been taking the brand name, Wellbutrin XL 300, without difficulty. But after switching to the generic, many reported side effects such as anxiety, headache, irritability, dizziness, nausea, tremor, insomnia, mood swings, and loss of antidepressant effectiveness.

Some people became suicidal.

The reason was that the brand-name drug released its active ingredients quite differently from the generic. We pleaded with the FDA to conduct further testing and eventually the agency did.

The FDA finally admitted that this particular generic formulation was “not therapeutically equivalent” to the brand-name product, and needed to be taken off the market.

Antidepressants are not the only medicines that have caused patients consternation when switching to generic formulation.

People with epilepsy have reported trouble with generic anticonvulsants, as this person told us: “I took Keppra for epilepsy. In January 2009 I was given generic Keppra (levetiracetam). I felt sick to my stomach and had multiple seizures. My neurologist told me to stay on the brand med and even wrote ‘brand necessary’ on the scrip, but the insurance company refused and gave me generic.

“I had seizures for five weeks before they allowed me to go back on the brand. My blood level on the generic was much lower than on the brand and I found the generic was not as effective.”

The FDA is now paying far greater attention to long-acting generic drugs. But that does not make up for the hundreds of sustained-release generic drugs that have been approved over the last few decades.