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.

Making best use of what we have

Many advances in the field of psychopharmacology are also likely to come not from dramatic technological developments but from recognition of what is currently in front of our eyes but is missing from our clinical activities. The recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)²⁷ and British Cost Utility of the Latest Antipsychotics and Schizophrenia Study (CUtLASS)²⁸ have taught us that, at best, only one third of schizophrenic patients continued to take an assigned antipsychotic drug over an 18-month period, with only minor differences existing between the older and newer antipsychotic drugs. Even more significant, in the CATIE study, about half the subjects dropped out of treatment completely, thus becoming more vulnerable to relapse and rehospitalization.

Patients often cease drug treatment in spite of effectiveness or minor side effects. Along with education and interpersonal techniques to enhance adherence, there are also physical means now existing and to be developed to better ensure that patients take their necessary psychotropic medications. Longer-acting medication preparations, including injectable haloperidol, fluphenazine, risperidone, and naltrexone exist. However, at present, none of these medications are widely used, although their relapse prevention effectiveness is relatively high. This lack of use is probably in large part because of an aversion to intramuscular administration and the fact that adverse effects cannot be rapidly controlled.

I would expect that within the next decade, oral preparations of a variety of psychotropic medications with actions lasting from months to a year will become available. Alternatively, delivery devices for psychotropic medications (similar to insulin pumps or implants) will be developed that can be inactivated or removed, paralleling development of long-acting male and female contraceptives.^29,30

A key to the use of long-acting preparations is the development of methods to rapidly and easily terminate ineffective drug activity and/or adverse effects. In the years ahead, I would anticipate having drugs and techniques that can selectively and rapidly antagonize a given psychotropic drug's effects or its adverse effects. For example, immunological techniques, administration of antidotes that bind to the drug and inactivate it, or similar treatments might be used.

In addition, there will be progress in the development of treatment for specific vexing psychotropic adverse effects, such as tardive dyskinesia, sexual side effects, agranulocytosis, and the metabolic syndrome (the last almost certainly will be found to cause strokes, myocardial infarctions, and death over the next decade, thus causing a tremendous shock to the psychiatric treatment community).

Generally, the pharmaceutical industry and government have focused more on developing new drugs and refining old ones to eliminate side effects than on developing antidotes to the side effects of existing drugs. An alternative strategy would be to work on developing antidotes to the side effects of existing drugs, a parallel to anticholinergics for parkinsonian symptoms. For example, current potential antidotes for the metabolic syndrome are the use of the antihyperglycemic agent metformin³¹ and the use of antilipid statins.

Furthermore, we now know that older antipsychotic and antidepressant drugs may be similar to newer medications in efficacy, effectiveness, adherence and, ultimately, desirability. Such knowledge may lead to a revi- talization of the use of much less expensive older medications such as the conventional antipsychotics and TCAs, a direction that obviously will be countered by pharmaceutical industry marketing efforts.

Funding new drug development

Of course, an alternative to refining the use of current or older drugs will be the development of new psychotropic drugs, which, it is hoped, will show improvement in effectiveness and in adverse effects. Such efforts are obviously occurring inside and outside the pharmaceutical industry, as already described.

However, if current pharmaceutical industry practices continue, we will more often have slight refinements of "me too" drugs rather than important innovations that require more risk. With government funding and supplements to the pharmaceutical industry, such as currently are given to develop avian influenza vaccines, more risky and innovative work on psychotropic drug development could occur more often.

Thus, how fast the field of clinical psychopharmacology will advance will, in large part, depend on government funding of investigators who are willing to explore novel areas and take risks. NIMH does have an innovative project program, and with luck this will be greatly expanded. In the coming decade, large allocations of funds should be earmarked to enhance practical, promising ideas and innovations.

Legal, regulatory, and insurance issues

We can only hope that the vulnerability of practitioners to lawsuits, especially for psychopharmacological adverse effects and off-label applica- tions, will become minimized. Along the same lines, the chilling and feared implications of using a drug with a black box warning might give way to positions based more on true risk-benefit ratios and less on medical-legal issues, a need recently made crystal clear with respect to thepossible increase in adolescent suicides since SSRI antidepressant use in adolescents was "black boxed."³²

At least for very difficult or intractable disorders and cases, the FDA might move toward approving medications based on provisional information, such as sequential single-blind studies and short-term placebo/ active crossover design studies, and might be less rigid in relying on expensive randomized, parallel-design controlled trials that require a large number of cases. Another positive step would be for the FDA to soften its attitude toward importing psychotropic drugs not currently available in the United States, such as the MAOI moclobemide, which does not interact with other drugs and foods to cause hypertensive crises, and to use data from other countries in determining efficacy for potential drugs.

In one respect, it is almost certain that the practice of psychopharmacology will change radically: more and more psychotropic medications will become available in pharmacies without a prescription, with medication decisions thus shifting to patients and away from physicians.

Finally and sadly, many-even most-emotionally disturbed persons cannot obtain effective and lasting psychopharmacological treatment because of a lack of health insurance, a virtually nonexistent community mental health system, and a Medicaid/ Medicare system that pays so poorly that mental health care practitioners will not accept its beneficiaries. I would expect that within the coming decade, our system of mental health treatment, as well as health care in general, will be broken badly enough to lead to the institution of a comprehensive health care system, one that will be readily accessible to our citizens. In addition, I believe that already evolving state laws mandating equity for insurance coverage between somatic and emotional disorders will come to fruition, making the wonderful future possibilities for psychopharmacological treatment available to all.

References:

References

1.

deLeon MJ, Mosconi L, Blennow K, et al. Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease.

Ann N Y Acad Sci.

2007;114-135.

2.

Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression.

Arch Gen Psychiatry.

2006;63:1209-1216.

3.

Bremner JD. Neuroimaging in posttraumatic stress disorder and other stress-related disorders.

Neuroimaging Clin N Am.

2007:523-538.

4.

Mo GH, Liao DL, Lai IC, et al. Support for an association of the C939T polymorphism in the human DRD2 gene with tardive dyskinesia in schizophrenia.

Schizophr Res.

2007;97:302-304.

5.

Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression.

Am J Psychiatry.

2007; 164:1530-1538.

6.

Kopell BH, Greenberg BD. Anatomy and physiology of the basal ganglia: implications for DBS in psychiatry.

Neurosci Biobehav Rev.

2007 Aug 7; [Epub ahead of print].

7.

Bienvenu OJ, Hettema JM, Neale MC, et al. Low extraversion and high neuroticism as indices of genetics and environmental risk for social phobia, agoraphobia, and animal phobia.

Am J Psychiatry.

2007; 164:1714-1721.

8.

Janowsky DS, Hong E, Morter S, Howe L. Myers Briggs Type indicator personality profiles in unipolar depressed patients.

World J Biol Psychiatry.

2002; 3:207-215.

9.

Janowsky DS, Morter S, Hong L, Howe L. Myers Briggs Type Indicator and Tridimensional Personality Questionnaire differences between bipolar patients and unipolar depressed patients

. Bipolar Disord.

1999;1:98-108.

10.

Sivrioglu EY, Kirli S, Sipahioglu D, et al. The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: an open-label pilot study.

Prog Neuropsychopharmacol Biol Psychiatry.

2007;31:1493-1499.

11.

Zarate CA Jr, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study.

Bipolar Disord.

2007;9:561-570.

12.

Krivoy A, Weizman A, Laor L, et al. Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: a preliminary study.

Eur J Neuropsychopharmacol

. 2008;18: 117-121.

13.

Witkin JM, Marek GJ, Johnson, BG, Schoepp DD. Metabotropic glutamate receptors in the control of mood disorders.

CNS Neurol Disord Drug Targets.

2007;6:87-100.

14.

Mathew SJ, Keegan K, Smith L. Glutamate modulators as novel interventions for mood disorders.

Rev Bras Psiquiatr.

2005;27:243-248.

15.

Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex.

J Neurosci.

2007;27:11700-11711.

16.

Vinod KY, Hungund BL. Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders.

Expert Opin Ther Targets.

2006;10:203-210.

17.

Basavarajappa BS. The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism.

Mini Rev Med Chem.

2007;7:769-779.

18.

Strous RD, Maayan R, Weizman A. The relevance of neurosteroids to clinical psychiatry: from the laboratory to the bedside.

Eur Neuropsychopharmacol

. 2006;16:155-169.

19.

Nemeroff CB. New direction in the development of antidepressants: the interface of neurobiology and psychiatry.

Hum Psychopharmacol

. 2002;17: S13-S16.

20.

Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention of social cognition in autism.

Biol Psychiatry.

2007;61:498-503.

21.

Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial.

JAMA.

2007;28:1641-1651.

22.

McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study.

Biol Psychiatry.

2007;61:1039-1048.

23.

Kuller LH. Statins and dementia.

Curr Atheroscler Rep

. 2007;9:154-161.

24.

Raschetti R, Albanese E, Vanacore N, Maggini M. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomized trials

. PLoS Med

. 2007;4:e338.

25.

Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial.

Arch Gen Psychiatry.

2006;63:1121-1129.

26.

Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an

N

-methyl-d-aspartate antagonist in treatment-resistant major depression.

Arch

Gen Psychiatry

. 2006;63:856-864.

27.

Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

N Engl J Med.

2005;353:1209-1223.

28.

Jones BB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in Schizophrenia Study (CUtLASS 1).

Arch Gen Psychiatry

. 2006;63:1079-1087.

29.

Chrisman CE, Curtis KM, Mohllajee AP, et al. Effective use of hormonal contraceptives, part II: combined hormonal injectables, progestogen-only injectables and contraceptive implants.

Contraception.

2006;73:125-133.

30.

Anawalt BD, Amory JK, Herbst KL, et al. Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses spermatogenesis without causing weight gain in normal young men: a randomized clinical trial.

J Androl.

2005;26: 405-413.

31.

Baptista T, Rangel N, Fernandez V, et al. Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.

Schizophr Res.

2007;939:99-108.

32.

Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents.

Am J Psychiatry

. 2007;164:1356-1363.