Dr. Apter is medical director at Global Medical Institutes LLC and in the Department of Psychology at Princeton University in New Jersey.

Dr. Allen is assistant professor of psychiatry in the Department of Psychiatry at Robert Wood Johnson Medical School at the University of Medicine and Dentistry of New Jersey in Piscataway, New Jersey.

Drs. Woolfok and Comer are professors of psychology in the Department of Psychology at Princeton University in New Jersey.

Acknowledgments: The authors report no financial, academic, or other support of this work. 


 

Abstract

How can we improve our therapeutic armamentarium in psychiatry? The last decade has witnessed an evolution of a new generation of psychopharmacologic agents. As a whole, these new compounds act on more specific receptors and are associated with fewer adverse effects than medications of earlier generations. This article reviews recently approved medications and novel therapeutic mechanisms under investigation in five areas: major depression, anxiety disorders, bipolar disorder, psychotic disorders, and Alzheimer’s disease. Evolving medications available outside the United States or currently under investigation in American clinical trials are discussed.

 

Introduction

The central nervous system drug pipeline is rich, and newer mechanisms of drug action are currently being researched. As novel medications emerge for hypertension and diabetes, so too are they evolving for use in the major disorders treated by psychiatrists. Each therapeutic area under study has developed so that safer and newer drugs are available for depression, anxiety, bipolar, psychotic disorder, and Alzheimer’s disease (AD).

According to a new study1 from Tufts University in Boston, MA, it has been estimated that it now takes an average of 10–15 years of research and development and a cost of $802 million to market a new drug successfully in the United States (US). Relating to such economic realities, and strict Food and Drug Administration (FDA) standards for demonstrating drug safety and efficacy, physicians and scientists have grown accustomed to waiting years for effective medications already available abroad, to be granted FDA approval. On occasion, scant time remaining on patents has prevented drugs from ever becoming available in the US. However, this situation is changing. 

The National Institute of Mental Health, through establishment of its Psychotherapeutic Medication Development Program in 1990, has taken initiatives to stimulate drug discovery, preclinical and clinical drug research, and clinical testing in areas where more effective agents are needed. These areas include disseminating information, providing in vitro testing, and identifying corporate developers. A resulting larger armamentarium of psychopharmacologic agents will certainly require greater efforts for clinicians to remain fully informed and up-to-date, but it will offer new hope for those suffering from psychiatric disorders.

 

Major Depression

Although the efficacy of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) is well documented, the many side effects and potential for lethality in overdose associated with these drugs have been a discouragement for patients and physicians. MAOIs, when combined with tyramine-containing foods or certain medications (ie, demerol, epinephrine, decongestants), have been linked with hypertensive crises. TCAs have been shown to have a high incidence of anticholinergic effects and cardiotoxicity. Because of the drawbacks of MAOIs and TCAs, investigators have developed new antidepressant agents that minimize adverse events.2 Table 1 lists the new antidepressants currently marketed in the US. Research suggests that each of these agents reduces depressive symptomology more effectively than placebo.2-4 Unlike TCAs and MAOIs, most of these agents selectively act on one neurotransmitter system. Venlafaxine and mirtazapine are the exceptions in that they have dual mechanisms of action.

 

Reversible inhibitors of monoamine oxidase A (RIMAs) are a class of antidepressants with an alternative mechanism of action. Unlike MAOIs, which inhibit both monoamine oxidase (MAO)-A and MAO-B activity, RIMAs inhibit only MAO-A activity. By allowing MAO-B to remain active (and deaminate tyramine), RIMAs are thought to act on the isoenzyme (MAO-A, which deaminates noradrenaline, adrenaline, and serotonin) responsible for the antidepressant effect of MAOIs without bringing on hypertensive crises. None of the RIMAs are currently available in the US. However, moclobemide is widely prescribed in Europe. Most clinical trials have shown moclobemide to be as effective as TCAs and more effective than placebo in the treatment of depression.5 Also, moclobemide appears to have a more favorable side-effect profile than do TCAs; it has few anticholinergic effects, minimal sedation effects, and no cardiotoxicity.6

Selective noradrenaline reuptake inhibitors (NRIs) represent another pharmacologic approach to the treatment of depression. Unlike the noradrenaline TCAs, NRIs act preferentially at noradrenergic sites. Reboxetine is an NRI that inhibits presynaptic uptake of norepinephrine. It has not been approved for use in the US, but is marketed in Europe. Reboxetine has been shown to be as beneficial as imipramine6 and fluoxetine7 in reducing depression in adults. Some investigators have found that reboxetine enhances the social functioning of severely depressed adults more effectively than fluoxetine.7 The incidence of adverse events experienced by patients taking reboxetine appears to be lower than that of patients taking imipramine and comparable to that of patients taking fluoxetine.8 Duloxetine is a specific serotonin and norepinephrine (NE) reuptake inhibitor similar in action to venlafaxine, with a dual and balanced reuptake inhibition of serotonin and NE. The agent causes minimal raised blood pressure and has less titration than venlafaxine. Duloxetine also appears to have an excellent efficacy and safety profile.

Hypericum perforatum (St. John’s wort) is an herbal remedy with few side effects, used in the treatment of depression. Studies9 suggest that it is equally effective as TCAs and more effective than placebo in treating mild to moderate depression. Various mechanisms for hypericum perforatum’s mechanism of action have been proposed, including serotonin reuptake inhibition, decreased serotonin receptor expression, inhibition of benzodiazepine binding, and inhibition of MAO. In Germany, hypericum perforatum is used widely. In the US, concerns have been raised regarding the standardization and quality control of commercial preparations of the drug. Also, the long-term efficacy of hypericum perforatum has not yet been examined adequately. Currently, large-scale trials of the drug are being conducted—a recent study from the National Institute of Mental Health showed no efficacy.

Another new approach to the treatment of depression involves neuropeptides. Substance P, an undecapeptide, appears to be distributed throughout the limbic system and has been associated with monoamine-containing circuits. Substance P, along with neurokinin (NK) A and NK B have been found to bind preferentially to NK1, NK2 and NK3 receptors. Recent evidence suggests that NK1 antagonists may have antidepressant actions,10 and two positive studies have been presented at the American College of Neuropsychopharmacology from Merck Pharmaceuticals.11

The newest class of antidepressants under investigation are the selective serotonin reuptake inhibitor (SSRI) enantiomers. Fluoxetine is a racemic mixture of the enantiomers R-fluoxetine and S-fluoxetine. In theory, R-fluoxetine may have a more rapid onset of action and produce fewer side effects than racemic fluoxetine. Also, escitalopram, the s-enantiomer of citalopram that is currently under investigation, has been submitted for FDA approval. Escitalopram may have a faster onset of action and fewer side effects than the racemic citalopram. Other novel therapeutic approaches involve corticotropin-releasing factor  (CRF) antagonists, especially CRF1, vagal nerve stimulation, and even mifepristone, in psychotic depression.

In summary, the last decade of the 20th century witnessed substantial progress in the pharmacologic treatment of depression. New medications effectively reduce symptoms of depression and coincide with fewer adverse events than the TCAs and MAOIs. Ongoing research aims to develop antidepressant agents that benefit a greater proportion of patients and coincide with fewer side effects than the current agents.

 

Anxiety Disorders

Various classes of medications have proven effective in the treatment of anxiety disorders. Prior to the introduction of SSRIs, benzodiazepines and TCAs were the first-line agents for panic disorder, obsessive-compulsive disorder (OCD), and generalized anxiety disorder (GAD). Activating the benzodiazepine γ-aminobuyric acid (GABA) receptor complex, benzodiazepines have been considered by many to be the treatment of choice because of their rapid onset of action. The disadvantages of benzodiazepines include the potential for drowsiness, cognitive impairment, and physical dependency. TCAs have demonstrated efficacy in treating anxiety, yet their numerous side effects and delayed onset of action limit their appeal. Within the last decade, SSRIs have replaced the older generation medications in treatment of many anxiety disorders. The favorable side-effect profile and nonaddictive nature of SSRIs allow for their long-term use, which is essential for many patients suffering from anxiety disorders. Another advantage of SSRIs is their efficacy with both anxious and depressive symptomology since many patients experience both sets of symptoms simultaneously.

The pharmacologic treatment of social phobia has recently received considerable attention. Although only paroxetine has received FDA approval for this indication,12 the other SSRIs (ie, fluvoxamine, sertraline, fluoxetine, and citalopram) have appeared efficacious in treating social phobia.13-15 Two other new psychotropics appear to be effective for, and well tolerated by, socially phobic patients. They are moclobemide, the RIMA presented earlier,16 and gabapentin, a new anticonvulsant described in the section on bipolar disorder.17

The past 10 years of research has supported the use of many new pharmacologic agents for the anxiety disorders. Promising anxiolytics in the pipeline include long-acting or patch formulations of 5-HT1A agonists, glutamate agonists, GABA modulators (such as pagaclone and pregabalin), drugs acting at the benzodiazepine site without dependency potential, substance P antagonists, and the SSRI enantiomers. Finally, a recent meta-analysis suggests that kava extract, piper methysticum, may be an effective anxiolytic.18

 

Bipolar Disorder

Although lithium is considered the drug of choice for bipolar disorder, in the past 17 years, research has found that many bipolar patients find it unsatisfactory.19 Only 40% to 50% of bipolar patients respond to lithium. Nonresponders include patients with rapid-cycling or mixed episodes as well as those who are unable to tolerate lithium’s adverse events. Unfortunately, lithium’s therapeutic range falls very close to its toxic range.

Over the past 10 years, numerous new treatments for bipolar disorder have been developed. Each of these treatments was initially designed and/or approved for epilepsy. Valproate and carbamazepine were the first two anticonvulsants to be used for bipolar disorder. Valproate has FDA approval for the treatment of acute mania and is widely used in treating these patients. Controlled clinical trials have shown that valproate more effectively reduces manic symptoms than placebo.20 The drug appears to be as effective as lithium for manic episodes and possibly more effective than lithium for mixed episodes. Carbamazepine has also been proven to reduce manic symptoms more effectively than placebo and about as effectively as lithium in controlled clinical trials.20 Notwithstanding the promising results from controlled trials, a large percentage of patients are inadequately responsive to either valproate or carbamazepine.

The two newest anticonvulsants that have shown initial promise in the treatment of bipolar disorder are lamotrigine and gabapentin. Lamotrigine appears to act by inhibiting the release of excitatory amino acids and by blocking sodium channels. Gabapentin’s mechanism of action, although unknown, may be related to its effect on GABA. Research on the mood-stabilizing effects of lamotrigine is quickly emerging from studies on bipolar depression.21,22 Additional trials are currently being conducted to examine the drug’s efficacy with rapid-cycling bipolar patients. Positive studies23,24 have been presented in bipolar depression and prevention of relapse in bipolar disorder. Gabapentin’s mood-stabilizing properties have been examined only in uncontrolled studies.22 As a whole, the preliminary evidence on both of these agents, when used alone or in combination with other agents, suggests they may benefit bipolar patients. Gabapentin’s low rate of side effects and interactions with other medications are especially encouraging.

Future treatments for bipolar disorder are likely to include newer anticonvulsants and atypical antipsychotics. Pregabalin, a gabapentin analogue, and topiramate, a sulfamate-substituted monosaccharide, are two of the newest agents currently under investigation in the treatment of both neurologic and psychiatric disorders. The atypical antipsychotic, olanzapine, has recently received FDA approval for the treatment of bipolar disorder. Other antipsychotics, such as risperidone, ziprasidone, and quetiapine, are currently under investigation for treating this disorder as well.

 

Psychotic Disorders

Schizophrenia is associated with hallucinations and delusions (positive symptoms) and apathy, anhedonia, and lack of motivation (negative symptoms). In treating the positive symptoms of acute schizophrenia, conventional antipsychotic agents have had unquestionable success. The negative symptoms of schizophrenia have been less responsive to these agents. Conventional antipsychotics show inefficacy, negative symptoms, and many side effects; this may explain the high incidence of treatment noncompliance and, thus, high relapse rate associated with this class of drugs.

A new era of antipsychotic treatment began with the release of the first atypical antipsychotic, clozapine, in 1990. Clozapine was demonstrated to be more effective than standard antipsychotics, especially with treatment-resistant schizophrenics, without causing tardive dyskinesia.25,26 The risk of agranulocytosis that is associated with clozapine prohibits its use as a first-line treatment. Nevertheless, a number of other second-generation antipsychotics that do not pose a risk of agranulocytosis, have received FDA approval since 1990 (Table 2). Controlled clinical trials suggest that these second-generation antipsychotics have two advantages over the earlier medications. First, atypical antipsychotics produce significantly fewer extrapyramidal adverse events than conventional neuroleptics.27-31 Second, the new agents seem to ameliorate the negative as well as the positive symptoms of schizophrenia.27-31 The primary clinical differences among these new agents are listed in Table 2.

 

The mechanism of action of atypical antipsychotics also differs from that of conventional antipsychotics. The new agents selectively block dopamine receptors and serotonin receptors with minimal effect on muscarinic or cholinergic receptors. Specifically, these agents tend to have high 5-HT2 and D2 receptor affinity ratios. In addition, they bind to a range of receptors, including 5- HT1A, D1, and D4 with varying degrees of intensity.

Other new antipsychotics with diverse mechanisms of action are in developmental stages. Aripiprazole is a presynaptic dopamine agonist and a postsynaptic D2 antagonist. Iloperidone and perospirone are serotonin-dopamine antagonists. Amisulpride is a selective D2/D3 receptor antagonist. Lastly, metabotropic glutamate receptor agonists are under investigation for treating psychosis.

The turn of the century marks an exciting era in the treatment of schizophrenia, with changes that parallel that of SSRI use in the treatment of depression. It is likely that some of these atypical antipsychotics will become first-line treatments because of their efficacy for both positive and negative symptoms of schizophrenia. Also, their superior side-effect profile, as compared with the side-effect profiles of conventional agents, may facilitate patient compliance, and thus, reduce relapse rates. Research has yet to confirm whether any of the new compounds will achieve the efficacy of clozapine in refractory patients. However, studies are under way to examine this.

 

Alzheimer’s Disease

AD is a prevalent progressive illness affecting memory and cognitive functioning. The incidence of senile dementia of the Alzheimer’s type (SDAT) is expected to reach 20 million by the year 2050. Currently, approximately 4 million Americans are diagnosed with SDAT. The cost of SDAT to society is approximately $90 billion annually, a figure that includes average nursing home rates ($36,000 per year) and average in-home costs ($18,000 per year) for these patients.

AD pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Also, AD has been associated with a substantial decrease in cholinergic function. Evidence of acetylcholine (ACh) deficiency has been supported by various lines of research. Postmortem samples of AD patients have shown shortages of the cholinergic enzyme, choline acetyltransferase, and acetylcholinesterase.32 Drugs that block ACh have been shown to cause memory deficits in elderly patients.33 In addition, improvement in cognitive functioning has been observed with the use of cholinergic drugs and via stimulation of muscarinic and nicotinic cholinergic receptors.

Acetylcholinesterase inhibitors, the first agents developed for treating SDAT, have been studied extensively. These agents delay degradation of acetylcholine and, thus, potentiate cholinergic neurotransmission. Although cholinergic treatment probably does not alter the progression of neurodegeneration, it improves symptomatology, delays institutionalization, and reduces the costs of SDAT.34 Tacrine35 was the first inhibitor approved by the FDA in 1993. Initial enthusiasm for tacrine, the first cholinesterase inhibitor approved by the FDA in 1993,35 quickly waned because of the drug’s hepatotoxic effects and need for QID dosing. In 1996, donepezil gained FDA approval and became the drug of choice for SDAT. Donepezil’s favorable side-effect profile and once-per-day dosing appeal to both patients and physicians.36

A number of other cholinesterase inhibitors have been studied extensively. Rivastigmine, recently approved by the FDA, appears to be highly effective and lacks drug-drug interactions—perhaps because it does not interact with P456.37 Galanthamine has received FDA approval for marketing in the US.38 Metrifonate and eptastigmine, although extensively studied, have been withdrawn from consideration by the FDA because of reported adverse effects.

Other approaches to slowing degeneration of cholinergic cells in AD patients include the use of muscarinic agents, nicotinic agents, and nerve-growth factor. Muscarinic agonists, such as xanomeline, may delay cognitive deterioration.39 The neuroprotective properties of nicotine have been considered after a study found that smoking was inversely correlated with SDAT.40 Also, nerve-growth factor and other neurotrophins are currently being developed in hopes that they may retard the loss of cholinergic cells. Nerve-growth factor has been shown to increase acetylcholine and prevent cholinergic cell loss and atrophy.41

Evidence suggesting the presence of oxidative damage in AD has prompted research on the use of antioxidants with this population. It has been hypothesized that the increase in MAO-B activity (that is characteristic of AD) may cause an increase in oxidative deamination of monoamines. In turn, hydrogen peroxide and other free radicals may be formed and damage cells. Selegiline, an MAOI-B with antioxidant properties, and α-tocopherol (vitamin E) appear to benefit some AD patients.42 Ongoing research is examining the efficacy of other antioxidants in delaying the progression of SDAT.

Some researchers are examining the relationship between AD and inflammatory processes. Individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs) have fewer cerebral microglia and are less likely to develop SDAT than are individuals who do not take NSAIDs.43,44 Agents with anti-inflammatory properties, including the new COX-2 inhibitors, are being examined for their ability to alter this abnormal inflammatory process. For example, estrogen has received attention for its anti-inflammatory, antioxidant, and antiapoptic effects.45 Despite its initial promise, a recent multisite trial found no evidence that estrogen slows the progression of SDAT.46 Another putative antioxidant and anti-inflammatory agent, ginkgo biloba, has been associated with small improvements in cognitive functioning in AD patients.47

Two of the newest treatment approaches are targeting the amyloid plaques that characterize the brains of AD patients. β- and γ-secretase inhibitors are currently in phase II-A trials with the hope that they will inhibit amyloid plaque formation. Also, a vaccine consisting of AN-1792, a synthetic form of the primary component of amyloid plaques, is now in phase I trials. Immunization with this vaccine may remove existing amyloid plaques and prevent the formation of new plaques.

Another direction for the treatment of SDAT involves N-methyl-D-aspartate (NMDA) antagonists. Preliminary data suggests that NMDA antagonists, such as memantine, may slow cognitive deterioration in AD patients.48

Other potentially important neurotransmitters involved in SDAT include CRF1, somatostatin, NE, 5-HT, dopamine, and GABA. The relationship between these neurotransmitters and the cognitive deficits observed in AD patients has not yet been fully described. Catecholamine abnormalities may contribute to the behavioral disturbances observed in AD patients. A broad range of psychotropic medications (including SSRIs, benzodiazepines, antipsychotics, and anticonvulsants) has been used in the treatment of behavioral disturbances (eg, depression, agitation, aggression, insomnia, psychosis) that may accompany cognitive deficits.

At present, there are two different approaches to the treatment of SDAT under investigation. The use of cholinesterase inhibitors, muscarinic agonists, SSRIs, benzodiazepines, and antipsychotics is directed at symptomatic relief. Structural changes aimed to delay disease progression are being attempted with agents such as antioxidants, NSAIDs, NMDA antagonists, and secretase inhibitors. Future investigators are likely to examine the efficacy of combining these agents to achieve symptomatic and structural benefits.

 

Conclusion

Buoyed by the discovery of better psychotropic drugs, the search to maximize desired effects and minimize side effects in new compounds is in high gear. Appreciation of both the multiple subtypes of receptors and the complicating effects of active metabolites is leading to more sophisticated and specific approaches to drug design and preclinical testing. The last decade of drug development in psychiatry has been very productive for new drug approvals and the next decade will likely offer equal or even greater breakthroughs. The areas discussed (major depression, anxiety disorders, bipolar disorder, psychotic disorders, and AD) give the clinician a glimpse of the potential of newer drugs still in development.   PP

 

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