First- and second-generation antipsychotics

Joseph P McEvoy, MD1; Daniel Zigman, MD2; Howard C Margolese, MD, CM, MSc, FRCPC3 Can J Psychiatry. 2010;55(3):144-149. Are SGAs Better Than FGAs? No The FGAs are a group of drugs with the common pharmacological action of D2 blockade. D2 blockade offers impressive (relative to placebo) but limited therapeutic benefit in the treatment of acute psychotic exacerbations and in the prevention of psychotic relapse. Most patients have incomplete relief of psychopathology.1 However, the FGAs are a pharmacologically disparate group, ranging from relatively clean D2 blocking agents (for example, perphenazine) to agents with multiple additional pharmacological actions (for example, thioridazine) that underwrite an array of unnecessary side effects. One might surmise that an FGA that produced severe anticholinergic toxicities, distressing autonomic side effects (for example, sexual dysfunction and orthostatic hypotension), and disproportionate prolactin elevations would have been rarely prescribed. In fact, thioridazine was the most widely prescribed FGA in the United States for a time; it was sedating and had fewer propensities for EPSEs. It was widely used for children who, when taking it, could review the same schoolwork over and over again and experience each page's content as new and exciting each time they read it. It was also widely used in the elderly (for example, someone my age) in whom cholinergic neurons are disappearing at alarming rates. And so it goes. The only useful thing that FGAs do is block D2 receptors. When about 60% to 70% D2 blockade is achieved, mesolimbic dopamine-releasing neurons begin a transition into depolarization block, a process that underlies therapeutic recovery. The induction of this process is a yes or no phenomenon, not a graded phenomenon, an on-off switch rather than a rheostat. More pressure on the switch (that is, higher doses) does not hasten the process or intensify it.1 However, clinicians treated an FGA dose as a rheostat, a throttle, a gas pedal (despite study after study proving the incorrectness of this approach) in futile efforts to obtain more therapeutic benefit than the FGAs had to offer, and accepted unnecessary coarse EPSE. They added anticholinergic drugs to hide these EPSE, accepting unnecessary dry mouth, blurred vision, constipation, and memory impairment, and leaving patients at high risk for TD. To use FGAs well, clinicians must tailor doses to the achievement of 60% to 70% D2 blockade. This can be done grandly with positron emission tomography scanning or hormone challenge procedures. Or, this can be done humbly by examining patients for muscle tone and fluidity of movement prior to starting an FGA, and then repeating this examination as dose is slowly increased. The examination takes less than 2 minutes. When a slight increase in bradykinesia-rigidity is induced, 60% to 70% D2 blockade has been achieved. As much therapeutic response as an individual patient will garner from an FGA will unfold over the next few weeks. Higher doses bring coarse EPSE and do not hasten or enhance therapeutic response.2 If therapeutic response is inadequate, a different approach (for example, clozapine), not higher doses, is needed. Consider if clinicians treated every patient with epilepsy with diphenylhydantoin 300 mg daily, many patients would do well, some would have inadequate brain levels and unnecessary seizures, and some would have toxic ataxias. If these same clinicians instead repeatedly examined patients and adjusted diphenylhydantoin doses upward or downward to the appearance of mild nystagmus or ataxia, more patients would do well and few if any would be under- or overdosed. If clinicians treated every patient with psychosis with an FGA at doses that produced mild bradykinesia-rigidity (instead of at some standard dose), more would do well and few if any would be under- or overdosed. Unfortunately, the use of such a fundamental pharmacological principle never became routine practice among clinicians prescribing FGAs. …