Psychopharmacology in the Decade Ahead

Reading crystal balls has always been difficult. Nevertheless, it may be a worthwhile exercise to stop and make some educated guesses about where the field of psychopharmacology will stand 10 years from now—knowing full well that insights and discoveries we cannot predict or anticipate now may pop up to dramatically change the course and direction of clinical psychopharmacology. Thus, the following essay is based on a mixture of best guesses and optimistic hope for change. My predictions will be divided into selective, circumscribed projections of existing promising scientific observations and more mundane political, economic, and societal hopes.

First, the "Star Trek" predictions. I believe that sophisticated functional imaging and molecular genetics will further fuse to advance the field of psychopharmacology. The science of imaging (eg, MRI, functional MRI [fMRI]) has blossomed in recent years, and it is only a matter of time until found and to-be-found correlates of psychotic thinking, mania, depression, dementia, and anxiety can be visualized and can be used to make psychiatric diagnoses and later to treat patients and avoid side effects. Even now, for example, imaging of excess amyloid in Alzheimer disease has been accomplished,¹ and images representing elevated levels of monoamine oxidase-A have been visual-ized in various brain regions in patients with depression,² findings that have implications for treatment with anti-amyloid and monoamine-enhancing drugs, respectively.

Quite possibly, changes such as the hippocampus becoming illuminated during a flashback in a patient with posttraumatic stress disorder (PTSD)³ and the observation that larger fMRI responses to emotionally negative pictures occur in the anterior cingulate cortex in patients whose symptoms respond to venlafaxine may allow predictions of efficacy and outcome. Undoubtedly, development of inexpensive imaging instruments and tech- niques (eg, optical imaging by means of infrared spectroscopy) will determine whether application of imaging technology can occur in everyday clinical practice.

Molecular genetics

It is quite possible that within a decade we will know many of the molecular-genetic underpinnings of our most persistent psychiatric disorders, using whole genome association studies. If these discoveries lead to understanding the genetically determined fundamental metabolic pathways of a given psychiatric disorder (eg, bipolar disorder, autism, schizophrenia, obsessive-compulsive disorder [OCD]), novel drugs and strategies may soon be developed to specifically target a given neurochemical entity, as has occurred, for example, with respect to the ravages of phenylketonuria and the potential treatment of cystic fibrosis.

Psychogenetic studies will also be delving into the molecular and genetic underpinnings of drug efficacy and drug adverse effects, and such knowledge may lead to the selective use of various psychotropic medications. For example, a specific type of dopaminergic D₂ gene has already been associated with the development of tardive dyskinesia⁴ and 2 genetic markers have been related to suicidality induced by citalopam.⁵ Again, whether this information can be used clinically will depend in large part on cost and replication.

Localized brain stimulation

Equally promising are the fledgling efforts to use deep electrode stimulation for such disorders as intractable depression and OCD.⁶ As an extension of this technique, psychotropic drugs could be given via microcatheter to the areas responsive to stimulation, thereby bypassing bothersome peripheral and central side effects.

New targets for drug therapy

There is a growing recognition that core personality characteristics are significantly heritable and that if not causing mental illness, they may underlie vulnerability to it. For example, major components of social phobia are the core personality characteristics of introversion and neuroticism.⁷ Depression has been reliably associated with neuroticism and introversion as well,⁸ and bipolar disorder and substance abuse disorders have been linked to novelty-seeking and impulsivity.⁹ I would predict that soon, pharmacological means will be used clinically to alter these underlying core personality variables and secondarily the disorders they underlie.

As a corollary, I am sure that there will be an upsurge in pharmacological treatment of more characterological styles such as a negative or pessimistic outlook, overreactivity, shyness, bullying, over-conscientiousness, and inability to relate well to others, as well as those behaviors that often trouble society, such as bullying, impulsiveness, and aggressiveness. Good candidates for such treatment can be found among existing psychotropic drugs such as the antidepressants, antipsychotic agents, lithium, and antiepileptics. I would expect that the strategy of focusing on target symptoms, rather than on psychiatric disorders as such, will also become more accepted during the next few years and will be considered to be part of good clinical practice.

New medication developments

Of course, there will be development of novel psychotropic medications as well. Currently, there is evidence that antioxidants (eg, N-acetylcysteine) may be effective in treating bipolar disorder and schizophrenia.¹⁰ The antiestrogen compound tamoxifen may also be helpful in treating mania. If so, it is very likely that a plethora of protein kinase-C inhibitors like tamoxifen will be developed for the treatment of mania.¹¹

A growing body of evidence suggests that centrally acting glutamate-altering and glutamate receptor-altering drugs have potential in the treatment of schizophrenia, and possibly other psychiatric disorders,^12-14 and there is much converging evidence that these compounds will be effective and used clinically in the next decade. Likewise, it is quite possible that the brain's endogenous endocannabinoids, and actual cannabinoids (marijuana and its derivatives),^15-17 as well as centrally acting steroids (eg, neurosteroids such as pregnenolone¹⁸), will be used as antianxiety and/or antidepressant agents, as well as for the addictions and other emotional problems, including eating disorders.

Also, the development of a variety of peptides and peptide antagonists, such as corticotropin-releasing factor antagonists for PTSD, mood disorders, and anxiety¹⁹ and oxytocin for the interpersonal difficulties of autism,²⁰ is occurring, and it is quite likely that some of these will be used widely in the next decade. Similarly, the antiepileptic drug topiramate appears helpful for treating alcoholism, binge eating disorder, and other disorders of impulsiveness,^21,22 and it will probably see even more widespread use.

For Alzheimer disease, recently developed drugs have been focused on decreasing CNS amyloid. Currently, these are being tested in human studies; initial results are at best equivocal. By a decade from now, these drugs will either be proved effective or be gone. Similarly, antilipid statins show promise as anti-Alzheimer agents and their more widespread use will quite possibly occur in the years ahead.²³ This is especially appropriate because the value of cholinesterase inhibitors in Alzheimer disease is seriously being questioned,²⁴ and these drugs will probably fade from widespread use.

Over the coming decade, there undoubtedly will be more direct clinical applications of preclinical information. This will be especially true as gene knockout strategies (taking out specific genes and seeing what happens) and gene replacement techniques allow for dissection of the neurochemistry of animal models of psychiatric disorders. As better animal models of such disorders as bipolar disorder, OCD, schizophrenia, autism, and major depression are developed, the potential for such transfer of information will grow.

Psychotropic use of "medical" drugs

Approximately every decade, a psychotropic use for an existing medical drug is discovered, usually by serendipity or intuitive informed observation. Examples include antipsychot-ics, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), antiepileptic mood stabilizers, and lithium. Discovery of the psychotropic effects of these drugs revolutionized the field of psychopharmacology; indeed, many of today's most useful drugs are derivatives that are fundamentally little different from these unexpectedly discovered agents. To be sure, there are off-label psychiatric uses for old and new medical drugs that are still waiting to be applied. For example, the recent discoveries that scopolamine and ketamine are useful in treating depression represent such applications^25,26; however, manufacturers may fail to develop or market these because they are off patent.

Computers and teleconferencing

In addition to the above pharmacological innovations and discoveries, I believe that our field will be radically transformed by teleconferencing, telebroadcast, and computer applications, used both for psychotherapy and for psychopharmacological monitoring. The rapidly evolving use of video components as a part of computers will become ubiquitous in the coming decade. Patients will be seen, heard, and monitored by techniques that are now developing but are currently used only occasionally in psychiatric practice. It's quite likely that 10 years from now, the obligatory psychopharmacological office visit will be a thing of the past, except under unusual circumstances, superseded by large screen video visualizations.