This interview took place on September 23, 2008, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at

Disclosure: Dr. Siegel reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


Jerome M. Siegel, PhD, is professor of psychiatry at the University of California, Los Angeles, former president of the Sleep Research Society, and the recipient of Merit and Javits awards from the National Institutes of Health and the Distinguished Scientist award from the Sleep Research Society. His laboratory has made discoveries concerning the role of hypocretin in human narcolepsy and Parkinson’s disease. He has studied the phylogeny of sleep as a clue to sleep function, discovering that the primitive mammal platypus has rapid eye movement sleep and that marine mammals can go without extended periods of sleep for long periods without ill effects.


What is narcolepsy?

Narcolepsy is a disorder characterized by excessive sleepiness. The four classic symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. For diagnostic purposes, excessive daytime sleepiness is usually followed up with a multiple sleep latency test. That is, the patient is given repeated opportunities to go to sleep. Narcoleptics have very short latency to the onset of rapid eye movement (REM) sleep. In clinical practice, persistent sleepiness combined with short latency to the onset of REM sleep is sufficient to diagnose narcolepsy.

What is cataplexy?

Cataplexy is a sudden loss of muscle tone triggered by the sudden onset of strong emotion. The most common trigger for cataplexy is laughter, but in some patients sudden anger and other rapid-onset emotions will trigger it as well. There is a spectrum of intensity of cataplexy. A person might fall to the floor for seconds or even minutes. More typically, there is weakness, such as the jaw or head dropping, which may be transient.

Most cases of narcolepsy with cataplexy are caused by a deficit in the peptide hypocretin (ie, orexin). In autopsy material, patients with narcolepsy with cataplexy showed a 90% loss of hypocretin cells on average. However, most patients with narcolepsy without cataplexy do not have a complete loss of hypocretin in the cerebrospinal fluid. This has lead to the question of whether these two groups, in fact, have the same disease.

Is narcolepsy adequately diagnosed?

Narcolepsy occurs in ~1 in 2,000 people in the United States. It is underdiagnosed. It used to be that >15 years would pass between the onset of symptoms and a correct diagnosis. Though that lag has been reduced, I think many patients with excessive sleepiness are not correctly diagnosed and may just be told that they need to sleep more or that they should get more exercise. Thus, they are not adequately treated. The age of onset is typically in the teens or twenties. In many cases children will not be able to stay awake in school and may be ridiculed for these symptoms. It is very important that they get correctly diagnosed and treated so that their educational and social development are not impaired.

Once narcolepsy manifests, do the intensity and frequency of symptoms change over time?

There is a progression during the year or two after the onset. Typically, the sleepiness presents first and cataplexy comes later. The onset of cataplexy can be delayed by up to 2 years or, in a few cases, more than that. Many patients with narcolepsy with cataplexy report that they have learned to reduce the cataplexy, mostly by avoiding situations that trigger it, such as anything which causes one to laugh. That in itself is quite sad.

However, I am not certain that this cognitive explanation is adequate, because in narcoleptic dogs we see the same progression. That is, the symptoms appear and then as the animal ages, the cataplexy in particular gets more and more infrequent. There is no reason to think that the dogs have any incentive to avoid cataplexy. They are not embarrassed, and the condition does not cause injury or “social” problems. Thus, it appears that with aging there may be some brain reorganization or some normal maturational change that may counter the effect of hypocretin loss on cataplexy. All in all, the general picture is that once the symptoms are established they do not continue to worsen.

Certainly, there is no generalized degeneration leading to other symptoms such as Parkinson’s disease or Alzheimer’s disease. However, a recent article1 showed that Parkinson’s disease patients do have a depletion of hypocretin cells. Though this depletion is not quite as extensive as in narcolepsy, it is still quite severe. This may account for the sleepiness that characterizes Parkinson’s disease, which is quite similar to narcolepsy in many ways. However, it is clear from examining the brains of Parkinson’s disease patients that the cause of the cell loss is not the same as in narcolepsy.

Is narcolepsy related to abnormalities in REM sleep?

In normal REM sleep, several groups of monoaminergic cells become silent. Norepinephrine-, serotonin-, and histamine-containing neurons are inhibited. This is partially responsible for the phenomena of REM sleep. In narcolepsy, these cells are no longer so well coordinated. That is, they do not all stop being active at the same time. Norepinephrine cells become inactive during waking, which never happens in the normal animal. This loss of norepinephrine activity is responsible for the loss of muscle tone in cataplexy. This presumably occurs because of the loss of hypocretin. Normally, hypocretin, an excitatory peptide, keeps the norepinephrine cells active in waking. In the absence of hypocretin, which is the case in narcolepsy, these cell groups can fall silent in waking when strong emotions are triggered. That, then, causes cataplexy.

Have you been able to identify any genetic markers for narcolepsy?

Genetic mutations can cause narcolepsy but that is extremely rare. There are only one or two human cases identified in which there is a mutation in genes synthesizing hypocretin or its receptors. Most narcoleptics do not have such mutations and do not have first-order relatives with narcolepsy. In addition, 87% of identical twins are discordant for narcolepsy, even many years after onset. One identical twin may have narcolepsy but 30 years later the other twin will still be symptom free. However, in the case of some animal models, it is entirely genetic. Two narcoleptic dogs with a mutation that inactivates a hypocretin receptor produce only narcoleptic offspring.

However, there is a genetic risk factor in human narcolepsy, namely, a particular human leukocyte antigen (HLA) subtype called DQB-10602. The HLA system is related to the immune system and mediates tissue compatibility. Most HLA-linked disorders are autoimmune in nature. Ninety-five percent of Caucasian narcoleptics have this particular HLA subtype, whereas in the general population only 20% to 30% have it. Certainly, the HLA subtype by itself is not sufficient to produce the disease. The HLA correlation suggests that narcolepsy may be an autoimmune disease. There is some direct evidence in the postmortem brains of narcoleptics of gliosis in the region of cell loss, which is an indication of prior inflammation. This suggests that something happened at symptom onset that caused these particular cells to be destroyed. In fact, adjacent cells are left untouched. This points to an immune mechanism that would recognize particular cell types, rather than just the destruction of a particular area of the brain as the cause of most human narcolepsy.

Are there any characteristic psychiatric symptoms associated with narcolepsy?

There appears to be a greater incidence of depression in narcolepsy. Although this has not been very well documented or quantified, it has been reported in an anecdotal manner. However, now that we understand that the hypocretin system is the key to this disorder, and we can work with narcoleptic animals, we notice behavioral signs that seem to be similar to depression. For example, it has long been known that narcoleptics tend not to get addicted to various drugs. They very seldom abuse drugs of treatment, such as amphetamines and g-hydroxybutyrate. It has also been documented that mice without hypocretin do not get addicted to agents that produce addiction in normal mice. We know that the hypocretin system connects very strongly to the dopamine system, which has been implicated in addictive behavior and in pleasure. Therefore, the loss of hypocretin may cause depression. This may also be the case of Parkinson’s disease, which has a similar loss of hypocretin cells and similar symptoms of depression.

Should a practitioner who suspects someone might have narcolepsy start treating it or first send the patient to a sleep lab?

I think it is always desirable to go to a sleep lab. The drugs that are prescribed are potential drugs of abuse so it is certainly highly desirable to get objective evidence that the patient has the symptoms that are diagnostic for narcolepsy before prescribing these drugs. Typically, patients will take these drugs for the rest of their lives. In the sleep center, narcolepsy with cataplexy is easily diagnosed. For narcolepsy without cataplexy it is certainly desirable to have the full electroencephalographic workup that can document that the patient has sleep-onset REM periods. Of course, excessive daytime sleepiness is quite common, and other potential causes, particularly sleep apnea, must be ruled out. Another disease category which can look like narcolepsy is idiopathic hypersomnia, where people are just sleepy all the time but do not have cataplexy or REM sleep near sleep onset.

What are the treatments for narcolepsy?

Sleepiness in narcolepsy has traditionally been treated by dextroamphetamine and methamphetamine. Methylphenidate and modafinil are also used. Tricyclic antidepressants are used if cataplexy is a major complaint. More recently, selective serotonin reuptake inhibitors such as fluoxetine have been used. Antidepressants, such as venlafaxine, protriptyline, and imipramine are also commonly used to treat cataplexy. Typically, a narcoleptic will be treated with both anticataplectic drugs and stimulants.

A relatively new drug being used is sodium oxybate (ie, g-hydroxybutyrate). Its mode of action is not well understood but it seems to help both the sleepiness and the cataplexy. It is taken in liquid form, in very large doses of up to approximately 8 grams per night. The patient has to wake up in the middle of the night to take the second half of the dose. It is inconvenient to use but it can be uniquely effective on both symptoms.

The hope is that hypocretin itself or hypocretin agonists will be used as a treatment since that is the underlying deficit. We have shown that hypocretin given to narcoleptic dogs can reverse symptoms. Deadwyler and colleagues2 showed that hypocretin can be administered by nasal inhalation to monkeys that were sleepy. It reversed the sleep deficits very effectively. Potentially, that would be a very useful treatment, but to my knowledge it has not been tested in human narcoleptics. PP


1.    Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson’s disease. Brain. 2007;130(Pt 6):1586-1595.
2.    Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239-14247.


Dr. Hoffman is a child psychiatrist and research fellow in the Albert J. Solnit Integrated Training Program at the Yale Child Study Center at Yale University School of Medicine in New Haven, Connecticut.

Disclosure: Dr. Hoffman previously received the American Academy of Child and Adolescent Psychiatry Pilot Research Award, sponsored by Eli Lilly.

Please direct all correspondence to: Ellen J. Hoffman, MD, Yale Child Study Center, 230 S Frontage Rd, PO Box 207900, New Haven, CT 06520-7900; Tel: 203-785-4659; Fax: 203-785-7560; E-mail:


Focus Points

• Pervasive developmental disorders (PDDs) affect social interaction and communication and are associated with repetitive, stereotyped behaviors.
• Autistic disorder is the most characteristic PDD which involves deficits in these three developmental domains.
• Early identification of PDDs is essential as early intervention improves prognosis.



Pervasive developmental disorders (PDDs), or autism spectrum disorders, are neurodevelopmental disorders resulting in impaired social interaction, verbal and nonverbal communication deficits, and repetitive, stereotyped behaviors and restricted interests. This article reviews the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for the PDDs, which include autistic disorder, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and PDD not otherwise specified, with a focus on autistic disorder, which is most characteristic of the PDDs. In addition, associated clinical and epidemiologic features of the PDDs and comorbidities are discussed. Principal components of the diagnostic evaluation are presented with an emphasis on early identification of these disorders.


Pervasive developmental disorders (PDDs), as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,1 are characterized by dysfunction in three core areas of early childhood development, namely, social interaction; communication and language skills; and behavior, specifically by the presence of stereotyped, repetitive behaviors and restricted activities and interests. Autistic disorder, or autism, which is the most representative type of PDD2 and the most researched to date,3 was first described by Leo Kanner in 1943, who reported many of the principal diagnostic features of children with the disorder.4 These include an “inability to relate” socially or “to convey meaning to others” through language and an “insistence on sameness” in daily routines.4 Kanner posited that these symptoms were “innate,”4 and in fact, our current conceptualization of autism and other PDDs is that these are “complex neurodevelopmental disorders”5 which are highly heritable6 and most likely involve early dysfunction in central nervous system development.3

PDD was introduced as a diagnostic category in the DSM-III7 and has come to be synonymous with autism spectrum disorder (ASD), as both terms refer to disorders affecting a child’s social, communicative, emotional, and cognitive development.2 The terms PDD and ASD are used interchangeably in this article depending on which term was utilized by the referenced study (eg, the DSM-IV-TR utilizes “PDD” while some current research studies prefer “ASD”). In addition to autism, there are four other disorders that are currently classified as PDDs by both the DSM-IV-TR and the International Statistical Classification of Diseases and Health Related Problems, Tenth Revision,8 namely, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder (CDD), and PDD-not otherwise specified (NOS).1,3 While each involves deficits in the same core developmental domains as autism, they are distinguished by the ways in which these domains are affected, along with differences in age of onset, gender distribution, course, and prognosis (Table).1,3,5,6,9-14


This article reviews the diagnostic criteria and associated clinical features of PDDs, with an emphasis on autism itself, as it is the most characteristic of the PDDs2 and the focus of increased research efforts in recent years; this research has led to a greater understanding of the genetics and neurobiology of these disorders.15,16 Both greater public awareness of autism and PDDs and reports of their increasing prevalence (the most recent estimate is one in 166 for all PDDs)9 have contributed to the growing interest in these disorders. While the increased prevalence is likely due in large part to new diagnostic categories and broadening of the diagnostic criteria over the past 50 years,9 these developmental disorders are not uncommon and the importance of early diagnosis and referral for educational and behavioral interventions cannot be overemphasized.3,17 That is, understanding the clinical features, associated medical and genetic aspects, and comorbidities of PDDs, reviewed here, is critical for early identification and intervention, which improve long-term prognosis.5,17

Autistic Disorder

The DSM-IV-TR1 criteria for the diagnosis of autistic disorder include manifestations of dysfunction in social interaction and communication as well as the presence of repetitive, stereotyped behavior. Specifically, there must be a total of at least six impairments in these three areas, and at least two of the six must be deficits in social interaction (Criterion A).1 In addition, delays or dysfunction in either social interaction, language (used in social communication), or symbolic play had to begin before 3 years of age (Criterion B).1 Also, Rett’s disorder or CDD must not be more appropriate diagnoses (Criterion C).1 The Table summarizes the principal clinical features of autism as well as the other PDDs, which are discussed below.

Impairments in social interaction (Criterion A1) may include pronounced deficits in non-verbal social behaviors (eg, lack of eye contact, facial expressions, body posturing, and gesturing), lack of age-appropriate peer relationships, absence of spontaneous attempts to share interests or pleasure with others (eg, not pointing or showing things to others), or “lack of social or emotional reciprocity.”1 That is, children with autism primarily lack joint attention in that they fail to share actively in others’ activities or interests.5 They may behave as if they are unaware of the presence of others, select solitary over social activities, and possibly only interact with parts of people (eg, someone else’s hand, using them “as tools or ‘mechanical’ aids,”1 or as Kanner4 observed, “as if they are objects.” For these reasons, children with autism are sometimes described as being in their “own little world.”5

Deficits in communication (Criterion A2) encompass both verbal and nonverbal disabilities, and thus are closely aligned with social impairments.1 More specifically, these deficits may include delay or absence in spoken language (which is not compensated for by attempts to communicate through gestures or other means); inability to converse appropriately with others, despite the presence of speech; odd, stereotyped, or repetitive uses of language; or the absence of imaginative or pretend play.1 There may be a great deal of variability in the area of communication, ranging from no expressive or receptive language to fluent speech but with semantic or inappropriate social uses of language.5 For example, speech may be monotonous in its tone or involve abnormal pitch, rate, rhythm, or emphasis.1 Language may involve meaningless, stereotyped repetitions of phrases or peculiar uses of words,1 and children may refer to themselves in the second or third person, instead of as “I.”3,4 Echolalia, which can be immediate (repetition of a phrase one has just heard) or delayed (repetition of a phrase heard in the past),18 occurs in up to 75% of individuals with an ASD who are verbal,19 and is a cardinal feature of autism.5 However, not all children with autism demonstrate echolalia. In addition, echolalia can be present in other disorders,18,19 such as dementia, other childhood language disorders, and blindness in children as well as in normal development.18 Additionally, receptive language is marked by difficulties in understanding abstractions (eg, irony, sarcasm), which further impairs social communication.1,5 The hallmark of these deficits in speech and language in autism is that neither is used to perform a social function; that is, as Kanner4 described, in children with autism, “speech is rarely communicative.” Not only communication in the form of receptive and expressive language, but communication via gesturing (eg, pointing, showing) or imitating is also substantially impaired,1,5 underscoring the primacy of social dysfunction in this disorder.

Restricted and stereotyped behavioral patterns (Criterion A3) may include restricted interests that are abnormally intense, rigid adherence to routines or rituals, repetitive motor mannerisms, or preoccupation with the parts of objects.1 Restricted interests are often variable, ranging from cars and trains to numbers and letters, for example, but they are by definition inappropriately intense or odd in their content.5 Children with autism may engage in compulsive behaviors, such as repeatedly lining up objects in a specific way.1,5 They may become overly interested in the moving parts of objects, or engage in repetitive acts such as opening and closing doors.1,5 In addition, slight changes in daily routines can lead to behavioral outbursts.1 Kanner4 described this obsessive rigidity affecting both interests and behavior as an “insistence on sameness.” Motor stereotypes may include hand or finger-flapping, rocking, and spinning,1,5 or there may be nonspecific motor abnormalities such as toe-walking or unusual hand movements or body postures.1 The course of autism is “continuous,”1 though school-age children may show some improvement in social, play, and communicative functioning, which may improve with appropriate intervention.19 Positive prognostic factors include greater language and cognitive abilities.1,20

Although cognitive abnormalities are not part of the DSM-IV-TR criteria for autistic disorder, most children with autism have mental retardation, which can range from mild to profound.1,3 Typically, nonverbal skills are superior to verbal skills, and there tends to be an irregular distribution of cognitive abilities.1,3 Some children with autism, however, may have above-average cognitive skills, such as being able to calculate calendar dates.1,3 At the same time, autism may be associated with conditions that cause mental retardation, such as fragile X syndrome and tuberous sclerosis.3,21 While autism is ~4 times more common in boys than in girls, this varies based on level of cognitive functioning; the male:female ratio is greatest in children with normal cognitive functioning and lowest for children with profound mental retardation.22,23 That is, females with autism are more likely to have more severe mental retardation.1,22,23 Epilepsy and electroencephalograph (EEG) abnormalities without seizures are common in autism and PDDs,1,5,24 and will be discussed further in the “Diagnostic Evaluation and Comorbidities” section of this article. With respect to neurologic abnormalities, macrocephaly, poor motor coordination, and mild hypotonia are more likely in children with ASDs.5 There is evidence that head circumferences are normal at birth, but increase abnormally from 6–12 months, resulting in macrocephaly.5,25 Children with autism may display abnormal responses to sensory stimuli, ranging from hypersensitivity to noise to decreased sensitivity to pain.1,5 In addition, the heritability of autism is >90%, with greater concordance rates in monozygotic versus dizygotic twins, though autism is likely polygenic and involves complex genetics.6

While the DSM-IV-TR specifies that dysfunction must be present prior to 3 years of age for autism to be diagnosed,1 questions have been raised as to how early the diagnosis can be made accurately and to what extent the current diagnostic criteria are applicable to very young children.25 ASDs can be diagnosed at 14 months, but the diagnoses are less stable at early ages.25 In particular, one study of 48 children diagnosed with autism or an ASD by 2 years of age found that diagnostic stability was 68% for autism and 63% for ASDs.26 Diagnosis prior to 30 months of age, lower symptom severity (notably in the area of social functioning), and better cognitive skills predicted less diagnostic stability by 4 years of age.26 Many parents (~80%) observe abnormalities in their child’s development by 2 years of age, most often due to speech and language delays,25 and some parents become aware of problems in the child’s social relatedness from around the time of birth.1 Signs of dysfunction in children 6–12 months of age may include poor eye contact, lack of facial expression, delayed babbling, poor coordination, and hypotonia.25 From 9–14 months of age, children with ASDs may demonstrate delayed receptive and expressive language. They may not point or gesture often or respond to their names being called. They may have repetitive behaviors.25 However, motor mannerisms typically emerge in the preschool years5 and some young children may meet criteria for autism but not the full criteria for repetitive behaviors until around 3 years of age.3 During 20–24 months, children with ASDs may not show interest in other children; they have limited facial expressions, “abnormal prosody” in their speech, and restricted interests in addition to repetitive behaviors.25 Early identification of ASDs is critical, as studies have shown that early interventions led to improvement in social functioning, language, and cognitive abilities.25 (Landa25 provides a comprehensive list of early signs of ASDs from 6–24 months of age.)

While there are early signs of dysfunction within the first year of life in most children with autism, there is evidence of developmental regression in ~20% to 25%,3 with even greater percentages reported.27 That is, following a period of normal or mildly delayed development during the first 1–2 years, these children lose social and communication skills.1,27 Initially, this phenomenon was questioned, as it was based on parental reports,3 though retrospective studies have demonstrated that a subgroup of children with autism experience regression in social and language development.27 In a recent prospective, longitudinal study, Landa and colleagues27 assessed 125 infants between 14 and 36 months of age, most of whom were at high risk for developing autism, as they had siblings with the disorder. The developmental trajectories of toddlers who received an early diagnosis of an ASD (at 14 months of age) were clearly distinct from those of toddlers who were diagnosed later, with respect to sharing positive affect, joint attention, and gesturing (though almost all of the toddlers who were not given an ASD diagnosis at 14 months of age did have signs of “developmental disruption” at that time). Specifically, this study found that the “later-diagnosis” group regressed from being almost indistinguishable from the non-ASD group at 14 months (except that children in the later diagnosis group shifted gaze less frequently from an object to another’s eyes and to the object again [or vice versa] compared to a non-“broader autism phenotype” group), to displaying similar social and communication deficits as the “early-diagnosis” group by 24 months of age (following a period in the later-diagnosis group of slowed language growth, lack of gains in joint attention, and losses in shared positive affect and gesturing).27 Other investigations of early signs of autism, including prospective studies of the high-risk infant siblings of children with ASDs,28,29 indicated that infants and toddlers who are later diagnosed with ASDs demonstrate delays in communication, affect sharing, joint attention, and repetitive behaviors early on, but that signs of autism may not be clinically identifiable or present from birth.16,30

Recent research has focused on characterizing and understanding the mechanisms underlying the social dysfunction in ASDs.31 For example, Klin and colleagues31 utilized eye-tracking technology to compare how individuals with autism view movie scenes involving social situations. These studies showed that adolescents and young adults with autism spent more time looking at others’ mouths and bodies or objects and less time looking at eyes compared to control subjects, and thus they miss social cues.31 Similar findings of a preference for focusing on mouth over eye regions were observed in 2-year-old children with autism compared to children who were either typically developing or developmentally delayed but did not have autism.32 In this study,32 less time spent looking at eyes was associated with greater social impairment. There is also evidence that individuals with ASDs have difficulties in facial recognition and have been found to show decreased activation of the fusiform region and amygdala when perceiving faces.33 In addition, one theory proposed by Baron-Cohen34 is that ASDs may represent a “hyper-systemising” approach to the environment, which may account for resistance to change and poor social functioning in these disorders.16

Asperger’s Disorder

Asperger’s disorder is defined in the DSM-IV-TR as involving the same deficits in social interaction (Criterion A) and stereotyped behavior and restricted interests (Criterion B) as in autistic disorder, but without any language or cognitive delays (Criteria D and E).1 These deficits, particularly in social relatedness, significantly impair the individual’s daily functioning (Criterion C).1 In addition, the DSM-IV-TR specifies that criteria cannot be met for another PDD or schizophrenia (Criterion F).1 Although Asperger’s disorder and autism share diagnostic criteria, there are qualitative differences in the nature of the social dysfunction and repetitive behaviors in the two disorders.11 Unlike autism, individuals with Asperger’s disorder are not necessarily socially withdrawn and are usually interested in interacting with others, but their socially inappropriate or odd style of relating to others (eg, speaking in a formal way as if giving a “monologue”) and difficulty reading social cues cause them to become isolated.10,11 In Asperger’s disorder, restricted interests and rigidity in adhering to rituals are more common than motor mannerisms.10 Individuals with Asperger’s disorder will become experts in a particular circumscribed area of interest, learning a great deal of factual information on this topic often to the exclusion of other types of experience, eg, social activities.10,11 This furthers their social isolation, as they attempt to talk to others about these singular interests as if they are giving a lecture, and for this reason, individuals with Asperger’s disorder are sometimes described as “little professors.”10,11

In contrast to autism, there are no delays in language or cognition early in life in Asperger’s disorder.11 However, speech in individuals with the disorder may be characterized by abnormal prosody, tone, or rate, and may be tangential, circumstantial, or overly verbose, consistent with a lack of attunement to the social uses of language and a focus on the individual’s own interests.10,11 While mental retardation is not common in Asperger’s disorder, there have been cases of mild mental retardation.1 Usually, verbal skills (eg, vocabulary, verbal memory) are superior to non-verbal (eg, fine and gross motor, visual-spatial, visual-motor abilities), as individuals with Asperger’s disorder frequently have motor difficulties such as poor coordination, odd gait, and “clumsiness.”1,11 Asperger’s disorder is often not recognized until a child reaches school age and begins to experience social difficulties with peers, particularly as there is no language delay, the child’s vocabulary can be precocious, and social problems do not emerge at home where their interactions are primarily mediated by adults.1,11

Asperger’s disorder is much more common in males (with male:female ratios estimated at 5:1 to at least 9:1).1,10 While there are few genetic studies of Asperger’s disorder specifically, there is evidence for a family history of the disorder in first-degree relatives.10 In his original description of the disorder, pediatrician Hans Asperger noted that family members of those affected demonstrated similar features.11 Other traits that Asperger reported included decreased facial expressions and gestures, peculiarities in communication, lack of empathy and intellectualization of feelings, and school behavioral problems such as aggression stemming from their social deficits.11 The question of distinguishing Asperger’s disorder and autism diagnostically continues to be a challenge, yet it is clear that social dysfunction in this disorder leads to significant functional impairment.1,11

Rett’s Disorder

Rett’s disorder is characterized by a defined pattern of regression, with respect to social, language, motor, and cognitive development, beginning at ~5–18 months of age.1,12 The DSM-IV-TR diagnostic criteria specify that from birth to 5 months of age, children with Rett’s disorder appear to demonstrate typical development (Criterion A), in that prenatal, perinatal, and psychomotor development seems to be unremarkable and head circumference is normal at birth.1 Retrospectively, however, subtle abnormalities, such as mild hypotonia and atypical or excessive hand movements, have been described during this period.12 A period of developmental regression follows (Criterion B), characterized by deceleration of head growth (between 5–48 months of age); loss of hand skills (between 5–30 months of age) and development of stereotypical hand movements; early loss of social skills, though this improves later; poor coordination of gait or truncal movements; and severe impairment in expressive and receptive language with marked psychomotor retardation.1 Severe or profound mental retardation is often also found in Rett’s disorder.1 Deceleration in head growth may not occur in all children with Rett’s disorder, and regression may not begin until ~18 months of age in some cases.12 Classically defined Rett’s disorder is found only in females, as the disorder has been linked to a gene on the X chromosome that encodes methyl-CpG binding protein-2 (MECP2), which is involved in regulating the expression of other genes during development.12 Mutations in MECP2, which have been reported in 87% of females with classical Rett’s disorder, and 50% of girls with a variant form of the disorder, occur more often on the paternal X chromosome and are thought to be lethal in males, accounting for the predominantly female distribution of the disorder.12 As autistic symptoms occur less often in very young females than in males, Rett’s disorder should be considered diagnostically in females with these symptoms.12 In addition, Rett’s disorder is second to Down’s syndrome as a cause of mental retardation in females.12 Molecular genetic analysis for mutations in MECP2 should be included in the diagnostic evaluation.12

It is important to underscore how the progression of motor and social abnormalities in Rett’s disorder, initially described by physician Andreas Rett in 1966, distinguishes it from other PDDs. Specifically, following the initial period of generally unremarkable development up to ~6 months of age, motor development seems to plateau. Significant developmental delays and neurologic symptoms are present by 15 months of age in ~50% of girls. Ages 1–4 are characterized by rapid loss of social and cognitive abilities, along with speech and hand use. Stereotyped hand movements, consisting of hand-wringing, washing or clasping, and hand-to-mouth movements, are characteristic of Rett’s disorder, and occur almost continuously during the day, interfering with purposeful use of the hands. Ataxia and loss of motor function affect ambulation, such that girls may lose or not develop the ability to walk. Social skills, including interest in others, are also lost during this stage, though in contrast to autism, eye contact is not affected. However, social interaction improves from 2–10 years of age. For this reason, many girls with Rett’s disorder may not demonstrate signs of autism at particular stages of the disorder, notably when they are <6 months of age or >3–5 years of age. Motor symptoms progress to involve spasticity, scoliosis, and rigidity at older ages. Additional features of Rett’s disorder include seizures, which are common, and EEG abnormalities, which are present in almost all cases beginning during the period of regression. Respiratory and sleep problems and bruxism have also been described. There is limited research on the long-term course of Rett’s disorder, and many cases are undiagnosed due to lack of familiarity with this disorder.12

Childhood Disintegrative Disorder

CDD is characterized in the DSM-IV-TR by developmental regression that begins after at least 2 years of what appears to be normal development in the areas of social interaction, communication, play, and adaptive behavior (Criterion A). This is followed by loss of skills prior to 10 years of age in the following areas: receptive and expressive language, social abilities, bowel and bladder control, play, and motor skills (Criterion B). In addition, there is similar dysfunction as that described in autistic disorder in social interaction, communication, or restrictive, repetitive behaviors (at least two of these areas are affected; Criterion C). Another PDD and schizophrenia must not be more appropriate diagnoses (Criterion D). Severe mental retardation is often found in CDD.1

CDD, which is also known as Heller’s syndrome, as it was first described by educator Theodore Heller in 1908, is rare and research on the disorder is limited.1,13 Onset of regression is typically at ~3–5 years of age, and may be rapid (within days to weeks) or gradual (within weeks to months), and occasionally is associated with behavioral changes (eg, agitation, anxiety, irritability).1,13 While CDD may be associated with medical conditions in some cases, such as tuberous sclerosis, metachromatic leukodystrophy, neurolipidoses, and others, this has not been found in most, though a thorough medical and neurologic work-up is recommended.1,13 CDD is characterized by a marked loss of language, social, and even self-help skills, such as toileting, and appears similar to autism following the regression.13 In addition, occurrence of seizures and EEG abnormalities are similar to autism.13 The course is continuous, and in most cases, deterioration reaches a plateau with minimal gains and “a limited recovery”; in a minority of cases, deterioration is progressive.13 CDD appears to be “sporadic,” as cases of the disorder occurring in families have not been identified, though genetic studies are limited and there may be genetic or gene-environment etiologies that have yet to be identified.13

Pervasive Developmental Disorder-Not Otherwise Specified

The DSM-IV-TR describes PDD-NOS as “a severe and pervasive impairment in the development of reciprocal social interaction” that is associated with nonverbal or verbal communication deficits or stereotyped behaviors and interests, but the specific criteria for another PDD are not met.1 The disorder cannot be due to schizophrenia or schizotypal or avoidant personality disorders.1 In addition, the DSM-IV-TR includes “atypical autism” in this category, which refers to cases that do not meet full diagnostic criteria for autistic disorder, as symptoms are “atypical” or “subthreshold,” or age of onset may be delayed.1,14 That is, PDD-NOS refers to cases primarily involving social deficits1,5,14 where symptoms are fewer or less severe than in autistic or Asperger’s disorders and do not meet criteria for Rett’s disorder or CDD,14 though the criteria for PDD-NOS are vaguely defined.5,14 As Towbin14 states, it “is likely that PDD-NOS is not just one condition.” Genetics and family studies indicate that there is an association between PDD-NOS and autism, as siblings of individuals with autism are equally likely to be diagnosed with either PDD-NOS or autism.14 At the same time, ~33% of the first-degree relatives of individuals with an ASD may be part of what has been called the “broader autism phenotype,” which describes individuals who may have similar features to ASDs but are not impaired functionally and do not meet the criteria for an ASD.35 The concept of functional impairment distinguishes PDD-NOS from the broader phenotype, yet further research is required to make the diagnostic criteria more specific and to characterize further “endophenotypes” such as differences in cognitive abilities, face recognition, or eye tracking, within this category.14

Diagnostic Evaluation and Comorbidities

Early identification of ASD symptoms and signs (eg, lack of social smile; poor eye contact; no babbling, pointing, or gesturing by 12 months of age; no spoken words by 16–18 months of age or two-word phrases by 2 years of age; atypical play behavior; loss of language or social skills) by primary care physicians (PCPs) and early referral to a multidisciplinary team (including a child psychiatrist and psychologist, pediatric neurologist, neuropsychologist, and developmental pediatrician) are critical in the diagnosis of ASDs, as recent evidence has shown that early intervention improves prognosis.5,17 For this reason, in 2007, the American Academy of Pediatrics published a “Surveillance and Screening Algorithm” for ASDs that recommends universal surveillance (ie, obtaining a developmental history, addressing parental concerns, assessing risk factors) and screening at preventive visits.17 While there is no conclusive test or biologic marker for ASDs, there are numerous screening and diagnostic tools that may be utilized to assist in the evaluation of children who may have an ASD.5,17 Among the available screening tools are the “level 1” tests, which can be administered at primary care visits, including the Checklist for Autism in Toddlers (CHAT; parent report/clinician observation; 18–24+ months of age),36-38 which is characterized by low sensitivity but high specificity, and the modified CHAT (parent report; 16–48 months of age),39 which is more sensitive.5,17,22 “Level 2” screening tools, which aid in distinguishing between ASDs and other developmental disabilities, include the Autism Behavior Checklist (interviewer completes; ≥18 months of age)40 and the Childhood Autism Rating Scale (trained interviewer completes; >2 years of age).17,41 The “gold standard” diagnostic tests for ASDs are the Autism Diagnostic Interview-Revised,42 which is a semi-structured, standardized interview for parents, and the Autism Diagnostic Observation Schedule,43 which is a “structured observation” of the patient, both of which require formal training to administer.5 PCPs are advised to refer children for a comprehensive evaluation as early as possible when there are concerns regarding the child’s development or if there is a positive result on a screening test, and to be particularly “vigilant” in monitoring at-risk siblings of children with ASDs,17 as the risk of a younger sibling of a child with autism having the disorder has been reported as >15%.44

The initial evaluation of any child who may have an ASD should include vision and hearing exams, as disabilities in these areas may mimic characteristics of ASDs.5,17 That is, while lack of eye contact or response to one’s name being called may occur in autism, these signs may instead be indicative of impairments in vision or hearing, respectively.17 In addition, lead testing is recommended due to pica.17 It is also important to be aware that autism is associated with numerous genetic syndromes, which occur in individuals with autism at various rates, including fragile X syndrome (~2%), tuberous sclerosis (0% to 4%; 8% to 14% of patients with autism and epilepsy), Down syndrome (0% to ~17%), and Angelman syndrome (~1%), among others.21 For this reason, high-resolution karyotype and fragile X testing is recommended in children with an ASD and mental retardation; dysmophic features; or a family history of fragile X, mental retardation, or dysmorphic features.5,17 Testing for MECP2 mutations (Rett’s disorder) and fluorescence in situ hybridization for chromosome 15q (Angelman and Prader-Willi syndromes) should also be considered.5 In addition, epilepsy is common in ASDs, with prevalence ranging from 5% to 40%,5,24 and all seizure types have been described, though seizures are more likely to occur in individuals with ASDs and mental retardation.24 EEGs are clearly indicated in children with clinical signs of seizures and in children who have language regression (as Landau-Kleffner syndrome is characterized by language regression between 4–7 years of age and EEG abnormalities),5,17,24 though some clinicians recommend performing EEGs in all children with autism.5 Metabolic and imaging studies are recommended when there is a specific clinical indication.5,17 Other medical problems that have been reported to occur often in or to be associated with autism include disturbances in sleep, gastrointestinal symptoms, dietary restrictions, and allergies and immunologic abnormalities.5,45

Behavioral and affective symptoms that may also occur in patients with ASDs include attentional difficulties, hyperactivity, obsessive-compulsive symptoms, tics, mood lability, anxiety, and depression.3 For this reason, it is important to consider other psychiatric conditions that may co-occur with ASDs. Although the DSM-IV-TR states that attention-deficit/hyperactivity disorder (ADHD) and autistic disorder cannot be co-diagnosed, Reiersen and Todd46 reported that there is evidence that some patients with autism may meet criteria for ADHD, which is associated with greater behavioral and social impairment, and that in less severe ASD cases the ADHD symptoms may be the chief complaint that leads to the clinical presentation. Forty-one percent to 78% of children with an ASD have ADHD symptoms in clinic studies.46 At the same time, attentional difficulties may be due to the developmental and cognitive deficits in autism, and may not indicate the presence of ADHD as a distinct disorder.3 Nonetheless, Reiersen and Todd46 argued that there are instances where the two disorders co-occur, and that evaluation should include assessment of both ASD and ADHD symptomatology when present. In addition, a recent study47 found that 70% of 11–14-year-old children with an ASD in a population-derived sample, most of whom were boys, met criteria for at least one other psychiatric disorder, based on parent interviews, including anxiety disorders (~42%, which included a high rate of “social anxiety disorder”; the authors note that this may be due to the social deficits of ASDs, or may represent social anxiety in these individuals), ADHD (~28%), and oppositional-defiant disorder (~28%). These studies underscore the importance of evaluating the full range of psychiatric symptoms that may occur in patients with ASDs.


The PDDs, as described in the DSM-IV-TR, are disorders that affect the core developmental domains of social interaction and verbal and nonverbal communication, and involve repetitive, stereotyped behaviors and restricted interests. These disorders, which are also referred to as the ASDs, include autistic disorder (which is the most paradigmatic of the PDDs), Asperger’s disorder, Rett’s disorder, CDD, and PDD-NOS. In addition, cognitive development is often affected in these disorders, although there is a range across disorders, and there may be associated neurologic signs (eg, motor symptoms, EEG abnormalities). Some of the disorders (Rett’s disorder, CDD, the regressive type of autistic disorder) are characterized by developmental regression, that is, loss of acquired skills. While the etiology of these disorders is unknown, there is evidence of heritability in most of these disorders. Given that the PDDs as a group are not uncommon, early identification and referral of patients with these disorders cannot be overemphasized, as early intervention improves long-term prognosis. PP


1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Volkmar FR, Paul R, Klin A, Cohen D. Section 1: diagnosis and classification. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:1-3.
3.    Volkmar FR, Klin A. Chapter 1: issues in the classification of autism and related conditions. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:5-41.
4.    Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943;2:217-250.
5.    Spence SJ, Sharifi P, Wiznitzer M. Autism spectrum disorder: screening, diagnosis, and medical evaluation. Semin Pediatr Neurol. 2004;11(3):186-195.
6.    Gupta AR, State M. Recent advances in the genetics of autism. Biol Psychiatry. 2007;61(4):429-437.
7.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
8.    International Statistical Classification of Diseases and Health Related Problems. 10th rev. 2nd ed. Geneva, Switzerland: World Health Organization; 2004.
9.    Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66(suppl 10):3-8.
10. Woodbury-Smith MR, Volkmar FR. Asperger syndrome. Eur Child Adolesc Psychiatry. 2008 Jun 18. [Epub ahead of print].
11.    Klin A, McPartland J, Volkmar FR. Chapter 4: Asperger syndrome. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:88-125.
12.    Van Acker R, Loncola JA, Van Acker EY. Chapter 5: Rett syndrome: a pervasive developmental disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:126-164.
13.    Volkmar FR, Koenig K, State M. Chapter 3: childhood disintegrative disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:70-87.
14.    Towbin KE. Chapter 6: pervasive developmental disorder not otherwise specified. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:165-200.
15.    Abrahams BS, Geshwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9(5):341-355.
16.    Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child. 2008;93(6):518-523.
17.    Johnson CP, Myers SM, Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007;120(5):1183-1213.
18.    Tager-Flusberg H, Paul R, Lord C. Chapter 12: language and communication in autism. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:335-364.
19.    Loveland KA, Tunali-Kotoski B. Chapter 9: the school-age child with an autism spectrum disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:247-287.
20. Howlin P. Chapter 7: outcomes in autism spectrum disorders. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:201-220.
21.    Zafeiriou DI, Ververi A, Vargiami E. Childhood autism and associated comorbidities. Brain Dev. 2007;29(5):257-272.
22.    Volkmar FR, Lord C, Bailey A, et al. Autism and pervasive developmental disorders. J Child Psychol Psychiatry. 2004;45(1):135-170.
23.    Lord C, Schopler E, Revicki D. Sex differences in autism. J Autism Dev Disord. 1982;12(4):317-330.
24.    Canitano R. Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry. 2007;16(1):61-64.
25. Landa RJ. Diagnosis of autism spectrum disorders in the first 3 years of life. Nat Clin Pract Neurol. 2008;4(3):138-147.
26.    Turner LM, Stone WL. Variability in outcome for children with an ASD diagnosis at age 2. J Child Psychol Psychiatry. 2007;48(8):793-802.
27.    Landa RJ, Holman KC, Garrett-Mayer E. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007;64(7):853-864.
28.    Yirmiya N, Gamliel I, Pilowsky T, Feldman R, Baron-Cohen S, Sigman M. The development of siblings of children with autism at 4 and 14 months: social engagement, communication, and cognition. J Child Psychol Psychiatry. 2006;47(5):511-523.
29.    Bryson SE, Zwaigenbaum L, Brian J, et al. A prospective case series of high-risk infants who developed autism. J Autism Dev Disord. 2007;37(1):12-24.
30. Yirmiya N, Ozonoff S. The very early autism phenotype. J Autism Dev Disord. 2007;37:1-11.
31.    Klin A, Jones W, Schultz R, et al. Defining and quantifying the social phenotype in autism. Am J Psychiatry. 2002;159(6):895-908.
32.    Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946-954.
33. Schultz RT. Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int J Dev Neurosci. 2005;23(2-3):125-141.
34. Baron-Cohen S. Two new theories of autism: hyper-systemising and assortative mating. Arch Dis Child. 2006;91(1):2-5.
35.    Steyaert JG, De La Marche W. What’s new in autism? Eur J Pediatr. 2008;167(10):1091-1101.
36.    Baron-Cohen S, Allen J, Gillberg C. Can autism be detected at 18 months? The needle, the haystack, and the CHAT. Br J Psychiatry. 1992;161:839-843.
37.    Baron-Cohen S, Cox A, Baird G, et al. Psychological markers in the detection of autism in infancy in a large population. Br J Psychiatry. 1996;168(2):158-163.
38.    Baird G, Charman T, Baron-Cohen S, et al. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry. 2000;39(6):694-702.
39.    Robins DL, Fein D, Barton ML, Green JA. The modified checklist for autism in toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord. 2001;31(2):131-144.
40.    Krug DA, Arick J, Almond P. Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. J Child Psychol Psychiatry. 1980;21(3):221-229.
41.    Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: childhood autism rating scale (CARS). J Autism Dev Disord. 1980;10(1):91-103.
42.    Lord C, Rutter ML, Le Couteur A. The autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659-685.
43.    Lord C, Risi S, Lembrecht L, et al. The autism diagnostic observation schedule–generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30(3):205-223.
44.    Sutclilffe JS. Insights into the pathogenesis of autism. Science. 2008;321(5886):208-209.
45. Filipek PA. Chapter 20: medical aspects of autism. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:534-578.
46. Reiersen A, Todd RD. Co-occurrence of ADHD and autism spectrum disorders: phenomenology and treatment. Expert Rev Neurotherapeutics. 2008;8(4):657-669.
47.    Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008;47(8):921-929.


Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


This column continues a series reviewing the interface between dermatology and psychiatry. Dermatologists and primary care physicians frequently encounter important psychiatric issues affecting diagnosis and management of patients with dermatologic complaints. Psychological factors affect many dermatologic conditions, including atopic dermatitis, psoriasis, alopecia areata, urticaria and angioedema, and acne vulgaris. Some dermatologic conditions are best considered as idiopathic functional disorders, such as idiopathic pruritus, which can be generalized or focal (eg, pruritus ani, vulvae, and scroti). Some primary psychiatric disorders present with primarily physical symptoms to dermatologists, including body dysmorphic disorder (BDD) and delusional disorder, somatic type (eg, delusions of parasitosis, delusions of a foul body odor). Indeed, most patients with delusions of parasitosis or BDD avoid seeing psychiatrists or other mental health professionals, and resist referral. Dermatologists also see patients with compulsive behaviors that may be part of obsessive-compulsive disorder, or that stand alone, eg, trichotillomania, psychogenic excoriation, and onychophagia. Factitious skin disorders include factitious dermatitis (also called dermatitis artefacta) and psychogenic purpura. Another important aspect of the interface between psychiatry and dermatology is the range of dermatologic adverse reactions to psychotropic drugs. More detailed coverage of these topics can be found elsewhere.1,2 The first part of the series focused on atopic dermatitis and psoriasis,3 and the second reviewed alopecia areata, urticaria, and angioedema.4 This third installment reviews acne vulgaris and chronic idiopathic pruritus.

Acne Vulgaris

Acne vulgaris, a common skin disease affecting sebaceous glands with sebum blocking hair follicles, is characterized by a variety of lesions, including comedones, inflammatory papules, pustules, and nodules. The face and upper neck are the most common sites, but the chest, back, and shoulders may also be involved. Most cases of acne vulgaris develop in early adolescence, affecting 85% of teenagers, and it frequently continues into adulthood. During adolescence, the frequency of acne increases with age and pubertal development. In girls, the commencement of menstruation is associated with increased frequency of acne. Perhaps this explains why adolescent girls may be more vulnerable than boys to the negative psychological effects of acne.5 The course of acne vulgaris is usually self-limited, with gradual improvement and spontaneous disappearance after several years, but it may persist into the thirties and forties. Possible complications include development of pitted or hypertrophic scars as well as psychological adverse effects, discussed below. Although women are more likely than men to have persistent acne, it tends to be more severe in men.1,2

Although the cause of acne vulgaris is unknown, many factors are probably involved in its pathogenesis, including genetics, inflammation, skin flora, hormonal activity, and stress. The relationship with stress has long been observed, but there are few prospective studies. One study6 reported that patients with acne may experience worsening of the disease during academic examinations. While there is a significant association between psychological stress and severity of acne, it does not appear to be mediated by increased sebum production.7 A variety of neuroendocrine mediators may be involved in the precipitation or aggravation of acne by stress, including adrenal steroids, corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y, insulin-like growth factor, and calcitonin gene-related peptide.1,2,8 It has also been long recognized that lithium can cause or aggravate acne,9 and there have been case reports of acne resulting from aripiprazole,10 lamotrogine,11 valproate,12 and other anticonvulsants, as well as the atypical tricyclic antidepressant amineptine13 (not available in the United States).

Severe acne is associated with increased depression, anxiety, poor self-image, and poor self-esteem.1,2 Not surprisingly, psychiatric symptoms are more common in more severe acne and in the later stages of puberty.14 A cross-sectional study15 of approximately 10,000 teenagers in New Zealand found that “problem acne” was associated with an increased risk of depressive symptoms (odds ratio 2.04), anxiety (odds ratio 2.3), and suicide attempts (odds ratio 1.83). The association of acne with suicide attempts remained after controlling for depressive symptoms and anxiety (odds ratio 1.5). One study16 has estimated the incidence of suicidal ideation in patients with acne as 7.1%. However, psychiatric comorbidity may even occur with milder acne. A Turkish study17 found that patients with acne were at increased risk for anxiety and depression compared to the normal population, irrespective of the degree of severity.

Acne can substantially interfere with social and occupational functioning and result in impairment in quality of life (QOL). There are numerous available rating scales for quantifying QOL in patients with acne.18 Acne negatively affects quality of life, and there is not always a correlation between the severity of acne and its impact on QOL. The magnitude of anxiety and depression is proportional to degree of impairment of QOL due to acne.17 Acne patients with greater social sensitivity experience poorer QOL compared to other patients with the same severity of acne.19 Anger, similarly, is associated with poorer QOL and less satisfaction with treatment, independent of other variables.20

Successful treatment of acne with isotretinoin leads to reduction in anxiety and depression and significant improvement in self-image.1,2 However, patients’ perceptions of the results of treatment for acne can differ from their physician’s judgment, with more pessimistic self-assessment in those with emotional distress.21

Anecdotal reports of depression, suicidal ideation, suicide attempts, and suicide with the use of isotretinoin for treatment of acne vulgaris were widely reported in the media and led the US Food and Drug Administration to expand the label warning to include that “accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.”22 However, a recent systematic review23 of nine controlled trials found that rates of depression among isotretinoin users were similar to the rates in oral antibiotic control groups, ranging from 1% to 11%. Trials that compared depression before and after isotretinoin treatment did not show a statistically significant increase in depression symptoms or diagnoses. Some even found a trend toward reduction in depressive symptoms after isotretinoin therapy, particularly in patients with higher pretreatment depression scores. Similar reductions have been reported in uncontrolled trials.24 Another recent study25 in Canada using a retrospective case-crossover design found that, the relative risk for those exposed to isotretinoin of developing a depression diagnosis was 2.68 (95% CI=1.10–6.48), after adjusting for confounders. In contrast, another Canadian group26 recently reported a prospective controlled cohort study that concluded that isotretinoin does not appear to be associated with the development of depression. The literature to date has not proven a causative association between isotretinoin use and depression or suicidal behavior. Interpretation of the literature is complicated both by important methodologic limitations in many of the studies and by the association of acne itself with depression, anxiety, and possibly suicidal behavior.

The FDA and isotretinoin’s manufacturer subsequently added a warning regarding the possible development of aggressive and/or violent behavior to the psychiatric disorder warning section of the package insert previously focused on depression and suicidality. While there have been reports of several cases of manic psychosis in association with isotretinoin treatment,27 large population-based cohort studies have found no evidence that use of isotretinoin is associated with an increased risk for psychosis.28

One may ask how clinicians should proceed, given the FDA’s black box warning and the case reports suggesting an association between isotretinoin and depression and suicide, yet an overall lack of support for these associations in the more rigorous observational and epidemiologic studies. It is prudent to continue to prescribe isotretinoin to treat severe acne, while at the same time educating patients (and the parents of minor patients) of the importance of actively monitoring for depressive symptoms; if symptoms appear, referral to a psychiatrist and discontinuation of isotretinoin should be considered. In addition, patients should be cautioned not to self-medicate for depression with St. John’s Wort both because it is ineffective and because its metabolic interaction with hormonal contraceptives may reduce their effectiveness.

Numerous reports attest to the benefits of a wide variety of psychiatric and psychological treatments for acne, including paroxetine,29 olanzapine,30 relaxation techniques, hypnosis, cognitive-behavioral therapy, and biofeedback,31,32 but no controlled clinical trials except for one.33

Chronic Idiopathic Pruritus

Pruritus, or itchiness, is a common symptom of dermatologic diseases, several systemic diseases (eg, hepatic or renal failure, HIV), and advanced age,1,2 but the cause in chronic pruritus is often not identifiable. Such idiopathic pruritus is typically experienced on a daily basis, especially at night and in the evening, resulting in mostly having difficulty falling asleep. Generalized idiopathic pruritus mainly involves the legs, arms, and back. The most common focal presentations of idiopathic pruritus are pruritus ani, vulvae, and scroti. Idiopathic pruritus may be described as crawling, tickling, stinging, or burning.34,35 In one study,34 idiopathic pruritus patients described the itching as unbearable (73%), bothersome (72%), annoying (67%) and/or worrisome (45%). The pathophysiology of pruritus is not well understood, and it is unclear why it is worse at night.36 While psychiatric symptoms are common in idiopathic pruritus, and idiopathic pruritus is common in psychiatric patients, idiopathic pruritus should be considered as a functional disorder rather than a psychogenic one. New onset of unexplained pruritus should lead to evaluation for occult medical disease before considering it to be idiopathic pruritus.

Recent stressful life events, and degree of anxiety and/or depressive symptoms have been correlated with an increased ability to experience itching.1,2 In a study37 of 100 psychiatric inpatients, idiopathic pruritus was reported by 42% of the subjects, 34% of the men, and 58% of the women, with increased prevalence in those without adequate social support and in those without regular employment. It is not surprising that depression is common in patients with idiopathic pruritus, especially given the chronicity and sleep disturbance.38

For focal idiopathic pruritus (eg, pruritus ani, vulvae, and scroti), topical treatments are used. For both generalized and focal idiopathic pruritus, the most commonly prescribed oral medications are antihistamines, which usually provide some short-term relief. Tricyclic antidepressants, especially doxepin, can relieve chronic idiopathic pruritus. Paroxetine has also been reported to be helpful.39 Opiate receptor antagonists and anticonvulsants (gabapentin, pregabalin, carbamazepine) have also been suggested as possible remedies.40 Behavioral treatment, such as habit-reversal training and cognitive-behavioral therapy, may also be helpful in interrupting the itch-scratch cycle,1,2 and there is one case report of the benefits of hypnosis.41 PP



1. Arnold L. Dermatology. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:629-646.
2. Arnold L. Dermatology. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:629-646.
3. Levenson JL. Psychiatric issues in dermatology, part 1: atopic dermatitis and psoriasis. Primary Psychiatry. 2008;15(7):35-38.
4. Levenson JL. Psychiatric issues in dermatology, part 2: alopecia areata, urticaria and angioedema. Primary Psychiatry. 2008;15(9):31-34.
5. Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne vulgaris in adolescents. Int J Dermatol. 2000;39(5):354-357.
6. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol. 2003;139(7):897-900.
7. Yosipovitch G, Tang M, Dawn AG, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol. 2007;87(2):135-139.
8. Zouboulis CC, Böhm M. Neuroendocrine regulation of sebocytes—a pathogenetic link between stress and acne. Exp Dermatol. 2004;13(suppl 4):31-35.
9. Yeung CK, Chan HH. Cutaneous adverse effects of lithium: epidemiology and management. Am J Clin Dermatol. 2004;5(1):3-8.
10. Mishra B, Praharaj SK, Prakash R, Sinha VK. Aripiprazole-induced acneiform eruption. Gen Hosp Psychiatry. 2008;30(5):479-481
11. Nielsen JN, Licht RW, Fogh K. Two cases of acneiform eruption associated with lamotrigine. J Clin Psychiatry. 2004;65(12):1720-1722.
12. de Vries L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia. 2007;48(3):470-477.
13. De Gálvez Aranda MV, Sánchez PS, Alonso Corral MJ, Bosch García RJ, Gallardo MA, Herrera Ceballos E. Acneiform eruption caused by amineptine. A case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15(4):337-339.
14. Kilkenny M, Stathakis V, Hibbert ME, Patton G, Caust J, Bowes G. Acne in Victorian adolescents: associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health. 1997;33(5):430-433.
15. Purvis D, Robinson E, Merry S, Watson P. Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students. J Paediatr Child Health. 2006;42(12):793-796.
16. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54(3):420-426.
17. Yazici K, Baz K, Yazici AE, et al. Disease-specific quality of life is associated with anxiety and depression in patients with acne. J Eur Acad Dermatol Venereol. 2004;18(4):435-439.
18. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006;7(2):99-106.
19. Krejci-Manwaring J, Kerchner K, Feldman SR, Rapp DA, Rapp SR. Social sensitivity and acne: the role of personality in negative social consequences and quality of life. Int J Psychiatry Med. 2006;36(1):121-130.
20. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol. 2004;151(1):183-189.
21. Jones-Caballero M, Pedrosa E, Peñas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309-314.
22. FDA Approved Drug Products. Available at: Accessed September 24, 2008.
23. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2007;26(4):210-220.
24. Kaymak Y, Kalay M, Ilter N, Taner E. Incidence of depression related to isotretinoin treatment in 100 acne vulgaris patients. Psychol Rep. 2006;99(3):897-906.
25. Azoulay L, Blais L, Koren G, LeLorier J, Bérard A. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry. 2008;69(4):526-532.
26. Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol. 2007;14(2):e227-e233.
27. Barak Y, Wohl Y, Greenberg Y, et al. Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol. 2005;20(1):39-41. Erratum in: Int Clin Psychopharmacol. 2005;20(3):182.
28. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136(10):1231-1236.
29. Moussavian H. Improvement of acne in depressed patients treated with paroxetine. J Am Acad Child Adolesc Psychiatry. 2001;40(5):505-506.
30. Gupta MA, Gupta AK. Olanzapine may be an effective adjunctive therapy in the management of acne excoriée: a case report. J Cutan Med Surg. 2001;5(1):25-27.
31. Shenefelt PD. Using hypnosis to facilitate resolution of psychogenic excoriations in acne excoriée. Am J Clin Hypn. 2004;46(3):239-245.
32. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther. 2003;16(2):114-122.
33. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of acne vulgaris by biofeedback relaxation and cognitive imagery. J Psychosom Res. 1983;27(3):185-191.
34. T-J Goon A, Yosipovitch G, Chan YH, Goh CL. Clinical characteristics of generalized idiopathic pruritus in patients from a tertiary referral center in Singapore. Int J Dermatol. 2007;46(10):1023-1026.
35. Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147(1):32-36.
36. Patel T, Ishiuji Y, Yosipovitch G. Nocturnal itch: why do we itch at night? Acta Derm Venereol. 2007;87(4):295-298.
37. Kretzmer GE, Gelkopf M, Kretzmer G, Melamed Y. Idiopathic pruritus in psychiatric inpatients: an explorative study. Gen Hosp Psychiatry. 2008;30(4):344-348.
38. Sheehan-Dare RA, Henderson MJ, Cotterill JA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol. 1990;123(6):769-774.
39. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage. 2003;26(6):1105-1112.
40. Lynde CB, Kraft JN, Lynde CW. Novel agents for intractable itch. Skin Therapy Lett. 2008;13(1):6-9.
41. Rucklidge JJ, Saunders D. Hypnosis in a case of long-standing idiopathic itch. Psychosom Med. 1999;61(3):355-358.


This interview took place on September 24, 2008, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at

Disclosure: Dr. Perkins is a consultant to Dainippon Sumitomo Pharma Co., Ltd; is on the speaker’s bureaus of AstraZeneca and Eli Lilly; and receives grant support from Janssen.


Dr. Perkins is professor of psychiatry in the Department of Psychiatry at the University of North Carolina (UNC) School of Medicine in Chapel Hill. She is medical director of Outreach and Support Intervention Services at UNC Hospitals and the UNC-Chapel Hill School of Medicine. Dr. Perkins’ research emphasizes treatment of the prodromal period and early intervention of the first episode of schizophrenia. Currently investigating pharmacologic and psychotherapeutic treatments for psychosis, she focuses on managing side effects of atypical antipsychotics and the weight gain mechanism in patients taking psychotropic medications. In addition, Dr. Perkins is investigating the genetic basis of schizophrenia.


How has the pathogenesis of schizophrenia evolved in the last century?

It is known that both gene and environment contribute to schizophrenia risk. For example. when an identical twin has schizophrenia, his or her counterpart has a 50% chance of having schizophrenia as well.1 This compares to the population risk of .01%. It is also likely that genetic or environmental risk factors act by changing when and how much protein is made.2

In addition, some forms of schizophrenia are likely neurodevelopmental disorders, meaning that the brains of some people who developed schizophrenia may have developed differently from those unaffected with schizophrenia. It may also be that an environmental event is needed to trigger the disorder in an at-risk person.3 There is also strong evidence that neurocircuits involving the front of the brain, especially the prefrontal cortex, are involved in schizophrenia. Much work needs to be conducted, however, to determine the underlying causes of schizophrenia.

It has been found that schizophrenia is a heterogeneous disorder similar to pneumonia; it is likely that there are hundreds of independent causes to schizophrenia. Such heterogeneity makes it challenging to further decipher the pathogenesis of schizophrenia.

How do parents influence their children having schizophrenia?

One epidemiologic finding is that schizophrenia risk is associated with higher paternal age at the time of conception.  We do not know the reason for this association, but I could speculate that perhaps it is because men make sperm throughout their life, and as they age genetic mistakes may accumulate in the germ line, including variations in the number of copies of genomic regions as well as point mutations. New evidence suggests that the genetic risk of schizophrenia may be due to de novo mutations in the patient.4,5 This may explain why approximately 70% of people who develop schizophrenia do not have a relative with the disorder.6

Is there anything specific about viruses implicated in early development that might be associated with schizophrenia?

There is a wealth of epidemiologic research showing increased risk in individuals who had certain prenatal environmental exposures. An example is maternal starvation where the risk of schizophrenia in offspring doubles.7 While data show most people whose mothers starved did not develop schizophrenia, there is still a small group that may have a biologic vulnerability. Some leading hypotheses suggest it is micro nutrium, meaning some critical nutrients (eg, vitamins D or B) were not received in utero. The second epidemiologic observation involves the fetus’ exposure to an infectious disease process in utero. As a result of this exposure, risk of schizophrenia in adulthood increases by 2–3 fold. Research on that relationship has tried to determine whether it is brain infection with the virus or the maternal immune response that affects brain development, increasing later risk of schizophrenia. Numerous animal models point to the immune maternal response. For example, if there is an infection or something provoking the maternal immune response, then antibodies, cytokines, or other aspects of the immune system response cross the placenta, enter the fetus, and affect brain development. Epidemiologic studies also find that maternal exposure to a traumatic event during pregnancy is associated with an increased risk of schizophrenia. One mechanistic theory involves stress hormones affecting brain development in utero, making a person vulnerable to schizophrenia in adulthood.

There have been studies investigating viral exposures in childhood  and later risk of schizophrenia. For example,  one recent population-based epidemiologic study8 found that childhood cytomegalovirus in the central nervous system was associated with a 16-fold increase in schizophrenia risk.

Is there a connection with gene expression?

One percent of a genome codes for a protein. Until recently, the remaining 99% was considered “junk deoxyribonucleic acid (DNA).” There was no explanation for its function; junk DNA was considered an evolutionary relic. However, in the past 5 years, it has been found that ≥50% of DNA is transcribed into ribonucleic acid (RNA), but this RNA is not translated into protein. Instead, this RNA regulates when and how much of the protein-coding genes are expressed. Numerous post-mortem studies of schizophrenia find altered levels of specific RNAs or proteins, suggesting that some process regulating the expression of a protein is impaired. There is no firm evidence of what regulatory processes might be altered, but research is now focusing on the variety of factors that impact protein expression.

Is there evidence that antipsychotics used earlier are neuroprotective?

Eighty-five percent of patients with schizophrenia will report prodromal symptoms; for example, they may report having weird ideas, illusions, or transient hallucinations (eg, hearing clicking noises, someone calling their name when no one was around). In the prodromal stage of psychosis, people may also complain of increased distractability, problems in school, and social problems. Researchers have been looking at the kinds of symptoms that can help distinguish people at highest increased vulnerability to schizophrenia. The best predictors of psychosis risk appear to be altered thought process (eg, ideas of reference) and abnormal perceptions (eg, illusions or brief hallucinations) that also interfere with social or vocational function.

Current estimates are that approximately 35% to 40% of people experiencing these “clinical high-risk” symptoms will develop a psychotic disorder within 2 years.9 Note that most people who are experiencing these “psychosis-like” symptoms do not go on to develop a psychotic disorder. Some (approximately 20%) will remit; here the symptoms may have been the result of a rough time or a glitch in adolescent brain development that self-corrected. Other times the person was experiencing early symptoms of anxiety disorders, depression, or a personality disorder, but not schizophrenia.

There is great interest in improving the ability to predict risk. One factor that has emerged is functional impairment. The more severe the symptoms, the more they significantly interfere with function. Environmental factors, such as marijuana use or severe stress may further increase psychosis vulnerability. However, more research is required to appropriately identify symptoms before prevention is possible. Studies10-12 examined people experiencing prodromal symptoms who have investigated an antipsychotic, an antipsychotic plus psychotherapy, or psychotherapy alone. In these studies, all interventions were equally successful in preventing psychosis, meaning both pharmacologic and psychotherapeutic interventions could benefit patients.

When the clinician is faced with an adolescent or young adult having clinical high risk symptoms and also struggling in school, treatment decisions are complicated by the fact that most (>50%) will not develop a psychotic illness. While preventative antipsychotic treatment may benefit the approximately 40% who are truly in the earliest stages of illness, antipsychotics are not appropriate for the other 60% of patients. These patients would be unnecessarily exposed to the risks of antipsychotics, such as metabolic or neurologic side effects. In addition, the clinical trials find that patients who are clinically at risk for psychosis are only protected from psychosis while they are taking the antipsychotic. When the antipsychotic is discontinued, the patients continue to be at high risk, and eventually 35% to 40% will develop a psychotic disorder. I think treating clinical high-risk symptoms with an antipsychotic is premature and should only be used when a patient is suffering severe functional impairment. Psychotherapy, however, is a relatively benign and effective treatment. Clinicians should consider some form of psychotherapy, especially a cognitive-behavioral type to help people cope with symptoms, manage stress, and deal with life issues conducive to stress.

Do atypical antipsychotics cause less risk of tardive dyskinesia than the older treatments?

Despite the ongoing debate on this issue, I think they do. In the early part of my career, only typical antipsychotics were available. Tardive dyskinesia was not at all unusual. In my clinical practice tardive dyskinesia is unusual.  Many medical or nursing students rotating through inpatient and outpatient settings will not see a single case of tardive dyskinesia.

Studies on tardive dyskinesia risk are difficult to conduct. Unmedicated people with schizophrenia will develop dyskinetic movements that are indistinguishable from tardive dyskinesia. While dyskinetic movements are not necessarily caused by antipsychotics, there is clear evidence showing antipsychotics increase the risk of developing those movements. In order to understand the difference between the two treatments, patients may have to be followed for several years. Unfortunately, studies of that length are almost impossible to conduct. The reinterpretation of short-term clinical studies suggest that tardive dyskinesia happens less often  with patients treated with atypical antipsychotics. Tardive dyskinesia can certainly emerge in people treated with atypical antipsychotics, but it appears less likely than in patients treated with typical antipsychotics.

Why do antipsychotics tend to cause weight gain and metabolic syndrome?

These adverse effects are seen mostly with newer antipsychotics. For example, patients taking quetiapine, olanzapine, or risperidone have increased risk of weight gain while aripiprazole or ziprasidone might not cause weight gain (at least in adults). In children, there is some increased risk of weight gain and metabolic syndrome with ziprasidone.

There are three possible mechanisms that could explain weight gain and metabolic syndrome in antipsychotic treatment patients. First, the patient’s appetite might increase once starting the antipsychotic. Second, patients using sedative drugs experience increased sleep time, resulting in a decrease in the amount of calories spent in a 24-hour period. Decreased activity is conducive to weight gain. Third, there may be changes in metabolism—for example, how readily a person may tap into fat stores.

I advise patients to exercise regularly and go on a low carbohydrate diet such as the American Diabetic Association diet or the Atkins diet. I have had patients who were able to follow that kind of diet and lose weight associated with antipsychotics. However, weight loss and behavioral change is a difficult task to accomplish, even for people who have schizophrenia. In addition to lifestyle changes, there is emerging evidence from clinical trials13 that metformin may attenuate or even reverse antipsychotic-related weight gain. In addition, there are clinical trials13 suggesting similar benefits from topirimate and amantadine.

Are there developing treatments that may benefit people who are not being treated effectively?

We are learning more about how to best use available treatments. Most clinical trials with antipsychotics were conducted by pharmaceutical industries. As the studies are highly regulated, the data are valid. However, the problem with industry-sponsored studies is that they are initially designed in favor of the company’s drugs. For example, if there is a drug that could cause weight gain, the researchers might not weigh people in the study. There is a fundamental problem with depending on the people who may profit from the drug conducting all of the studies with that drug.

The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study14 involved the atypical antipsychotics that were FDA approved at the time, namely risperidone, quetiapine, and olanzapine. Ziprasidone was added once it was approved by the Food and Drug Administration. Perphenazine was chosen as a typical antipsychotic comparator because the researchers wanted a drug that was unfamiliar and not used. The outcome measure in the CATIE study was all-cause treatment discontinuation. This was picked because it was thought to reflect both clinicians’ and patients’ judgment on how well a medication was working. If a patient experiences enough benefit from a medication and the side effects are not too troublesome, he or she is willing to continue using it. However, if the benefits seem negligible or the side effects are too much relative to the benefit, the patient will stop taking that medication. This was a novel outcome measure that is still somewhat controversial, but it was chosen as a measure of overall effectiveness. The study was large; it randomized 1,400 patients from the United States. Unlike most pharmaceutical industry studies, the CATIE study did not restrict inclusion to those patients who are very healthy, who do not use street drugs, and/or who do not require treatment with other medications, making the findings generalizable to routine clinical practice.

Overall, the study found that 74% of patients discontinued treatment prior to the end of the 18-month study. The time to discontinuation was significantly longer for olanzapine compared to risperidone and quetiapine, and was longer at a trend level compared to perphenazine- and ziprasidone-treated patients. However, olanzapine-treated patients were more likely to gain weight and have lipid abnormalities, so that the improved effectiveness came at the price of more severe side effects. One of the surprising findings of the CATIE study was how well the typical antipsychotic perphenzine peformed compared to the other antipsychotics, especially since other studies had shown that other typical antipsychotics, like haloperidol and chlorpromazine, were not as efficacious as the atypical antipsychotics. Perphenazine prescribing has increased since the publication of the CATIE study.

 What can also be concluded from the CATIE study is that none of the study drugs are optimal, and that treatment discontinuation rates overall are very high. There are now efforts to develop better strategies to improve medication treatment adherence, both with schizophrenia as well as other chronic diseases. Only approximately 50% of patients being treated for chronic illness are compliant with that treatment by 1 year,15 and the reasons for poor adherence are similar in schizophrenia and other chronic disease. We know that there will be a low rate of treatment adherence if a clinician simply writes a prescription and hands that prescription to the patient. A different kind of therapeutic model is needed.

There is growing evidence of a “concordance” model of care, where the patient’s experience of the illness and how treatment affects his or her life is taken into consideration. The clinician may engage in a negotiation with the patient until both agree with the treatment plan. However, it is important to note that even the best-intended patient will likely have difficulties in complying long term. It is difficult to remember to take a medication every day. To be successful, patients usually need to actively work on medication adherence, and the clinician can help. For example, the clinician can keep the medication regimin as simple as possible and also encourage the use of “cognitive adaptive strategies,” where patients develop environmental cues, like pill boxes or alarms to help with adherence.16 The lessons from the CATIE study reveal more than just the need for a new drug. Better ways to use available medication and optimize treatment are needed as well.

There may be breakthrough drugs on the horizon, however. There is a recent clinical trial of a drug that is a selective agonist at certain glutamate receptors (mGluR2 and mGluR3), but that does not affect dopamine receptors. The first published clinical trial17 is promising, and this new drug, at this point called “LY2140023,” may open up a new strategy for treating schizophrenia. Other promising areas include drugs targeting nicotinic receptors. PP


1.    Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait—evidence from a meta-analysis of twin studies. Arch Gen Psych. 2003;60(12):1187-1192.
2.    Perkins et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27.
3.    Lewis DA, González-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008;33(1):141-165.
4.    Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455(7210):232-236.
5.    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237-241.
6.    Mortensen PB, Pedersen CB, Westergaard T, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340(8):603-608.
7.    Penner JD, Brown AS. Prenatal infectious and nutritional factors and risk of adult schizophrenia. Expert Rev Neurother. 2007;7(7):797-805.
8.    Dalman C, Allebeck P, Gunnell D, et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008;165(1):59-65.
9.    Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65(1):28-37.
10.    Morrison AP, French P, Parker S, et al. Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk. Schizophr Bull. 2007;33(3):682-687.
11.    Phillips LJ, McGorry PD, Yuen HP, et al. Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis. Schizophr Res. 2007;96(1-3):25-33.
12.    McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-799.
13.    Baptista T, ElFakih Y, Uzcátegui E, et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs. 2008;22(6):477-495.
14.    Lieberman JA, Stroup TS, McEvoy JP, al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
15.    Adherence to Long Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
16.    Velligan DI, Diamond PM, Mintz J, et al. The use of individually tailored environmental supports to improve medication adherence and outcomes in schizophrenia. Schizophr Bull. 2008;34(3):483-493.
17. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13(9):1102-1107.


Dr. Ying is director of New York University (NYU) Behavioral Health Programs and clinical assistant professor at NYU School of Medicine in New York City.

Disclosure: Dr. Ying reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the following unapproved medications for depression or bipolar disorder: aprepitant, ketamine, memantine, mifepristone, paliperidone, and riluzole.

Please direct all correspondence to: Patrick Ying, MD, Director, NYU Behavioral Health Programs, Clinical Assistant Professor, NYU School of Medicine, Faculty Practice Tower, 530 First Ave, #7D, New York, NY 10016; Tel: 212-774-1459; Fax: 212-263-7460; E-mail:


Focus Points

• In the last few years, the only medications approved for mood disorders are existing medications or derivatives of them.
• New medications for mood disorders rely on both the existing monoaminergic and novel mechanisms of action.
• Medications that work on tachykinins, glutamate, and the hypothalamic-pituitary-adrenal axis are being investigated.
• Newer mechanisms of action may allow for improved efficacy, tolerability, and speed of response.



There remains a significant need for new treatments for mood disorders. In the last 2 years, only one new drug has been approved for the treatment of major depressive disorder, desvenlafaxine; during this time, the other medications approved for the treatment of depression or bipolar disorder have been atypical antipsychotics that have already been approved for the treatment of schizophrenia. There are, however, numerous medications in development for the treatment of mood disorders. Agomelatine is an agonist at melatonin (MT)1 and MT2 receptors and a serotonin (5-HT)2C antagonist in Phase III trials. Vilazodone, which is undergoing a Phase III clinical trial, is a selective serotonin reuptake inhibitor which also has 5-HT1A agonist properties. Triple reuptake inhibitors which selectively inhibit reuptake of serotonin, norepinephrine, and dopamine are also being developed. There are also medications in development whose mechanism of action does not depend on directly affecting monoaminergic function. Glucocorticoid receptor antagonists and corticotropin releasing factor-1 antagonists, which seek to modulate the hypothalamic-pituitary-adrenal axis, are being explored for efficacy in the treatment of unipolar depression. Agents that modify the glutamatergic system, such as riluzole and ketamine, are being explored for treatment of bipolar and unipolar depression. This article reviews the rationale and evidence for these proposed agents in the treatment of mood disorders.


There remains an acute need for new, effective treatments for mood disorders. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study1 reported a cumulative 67% remission rate after four treatment steps. However, not only did approximately 33% of patients not achieve remission, but patients who went into remission during the third or fourth treatment step had relapse rates of 41% to 50%.1 Likewise, the Systematic Treatment Enhancement Program for Bipolar Disorder2 indicated that only 58.5% of patients experiencing a manic, mixed, or depressive episode achieved symptom-free recovery in up to 2 years of follow up, and of those who did, 48.5% of these individuals experienced recurrences.2 These two National Institute of Mental Health (NIMH)-funded studies, which sought to deliver “best practice” care to “real world” patients, provide an effective snapshot of effectiveness of current medications for mood disorders.

Some authors suggest that there has been no truly revolutionary drug for the treatment of mood disorders for numerous decades. Recent Food and Drug Administration approvals for bipolar disorder and unipolar depression have been for compounds that have already been approved for other disorders or reformulations or metabolites of already available medications. However, the pharmacologic treatment of mood disorders remains an area of intense and exciting research. Multiple approaches that appear promising are being investigated, some of which hold the promise of extending existing paradigms of mood disorder psychopharmacology.3-5

Atypical Antipsychotics

Atypical antipsychotics continue to expand their indications for bipolar disorder. Quetiapine has received approval for maintenance treatment of bipolar disorder as an adjunct to lithium or divalproex. Applications have been made to the FDA for the extended-release version quetiapine for treatment indications for manic and depressed episodes of bipolar disorder, and for unipolar depression. (The steps for FDA approval are defined in the Table.6) Aripiprazole has received expanded indications for the acute treatment of manic or mixed episodes in pediatric patients. Perhaps the most notable FDA indication is the approval of aripiprazole as an augmentation agent for the treatment of unipolar depression. This represents the first indication of an atypical antipsychotic for unipolar depression. Curiously, two large studies7 were unable to demonstrate aripiprazole’s effectiveness as monotherapy for bipolar depression.


Two large randomized placebo-controlled trials8,9 demonstrated aripiprazole’s efficacy as augmentation treatment in unipolar depression. Both studies started with a screening phase, where patients were determined to be in a major depressive episode for at least 8 weeks, had between 1–3 adequate antidepressant trials for which they had a <50% response, and had a Hamilton Rating Scale for Depression (HAM-D)17 score of >18. If patients met these criteria, they entered an 8-week prospective treatment phase. Patients received single-blind treatment; escitalopram, paroxetine, sertraline, fluoxetine, or venlafaxine; and an adjunctive placebo. Antidepressant choice was based on the investigator’s clinical assessement. After 8 weeks, if patients did not respond, they entered a randomized double-blind study phase where they received aripiprazole or a placebo in addition to the antidepressant selected by the investigator. Doses started at 5 mg, were increased to 10 mg if tolerated, and could be lowered to 2 mg if not tolerated. Investigators could also increase the dose by 5 mg/week to 20 mg/week if there was no response. Patients in both studies had significant drops in the Montgomery Åsberg Depression Rating Scale (MADRS) total score, the primary outcome measure. Separation from placebo began at week 2 in both studies. Remission rate at 6 weeks was statistically significant for both studies at 25.4% to 26.0% versus 15.2% to 15.7% for placebo. The average dose of aripiprazole was 11.1–11.8 mg, somewhat below the dose for bipolar disorder and schizophrenia.8,9


Desvenlafaxine was approved in 2008 for treatment of major depressive disorder (MDD). It is the major active metabolite of venlafaxine, and like venlafaxine is a serotonin norepinephrine reuptake inhibitor. Desvenlafaxine has a greater effect on norepinephrine reuptake relative to its effect on serotonin reuptake compared to venlafaxine, although it is similar to venlafaxine in that it continues to have a greater effect on serotonin reuptake than norepinephrine reuptake overall. Desvenlafaxine is not predominately metabolized by the cytochrome P450 (CYP) system and is eliminated primarily by phase II metabolism; as a result, it has lower potential for drug interactions, especially with the CYP 2D6 pathway. It is suggested that a potential advantage of desvenlafaxine over venlafaxine is greater predictability with regard to the ratio of inhibition of norepinephrine reuptake to serotonin reuptake. Since venlafaxine is converted to desvenlafaxine by CYP 2D6, patients who are taking 2D6 inhibitors or who are genetically poor metabolizers will have a greater ratio of venlafaxine to desvenlafaxine and, therefore, comparatively less norepinephrine reuptake compared to serotonin reuptake.10

Efficacy has been demonstrated by four fixed-dose double-blind placebo controlled studies.11-14 Two studies11,12 examined 50 mg and 100 mg doses, while one study13 examined 100 mg, 200 mg, and 400 mg doses. The last study14 examined 200 mg and 400 mg doses. Desvenlafaxine demonstrated superiority over placebo in all four studies in terms of decrease in HAM-D17 scores, although in one study did not separate from placebo at the 100 mg dose. Overall, there was no statistically significant  improvement in efficacy at doses >50 mg and these higher doses were associated with higher dropout rates and more adverse events; as a result, the recommended dose is 50 mg.15 In one published study11 with the recommended 50-mg dose, the remission rate was 34%, significantly greater than for placebo group, 24%; in the other study,12 while the response rate at 50 mg dose was significantly greater than placebo, 65% to 50%, the remission rate did not significantly separate from placebo, 37% to 29%.

Desvenlafaxine appears to be well tolerated. The most common adverse events leading to discontinuation are nausea (4%), dizziness (2%), headache (2%), and vomiting (2%). Nausea was reported by 22% of patients taking 50 mg, and this increases in dose dependent fashion to where 41% of patients taking 400 mg report nausea.15 As with the other serotonergic antidepressants, the caveats regarding the risk of combination with monoamine oxidase inhibitors (MAOIs) apply. Serotonergic antidepressants are frequently associated with weight gain and sexual dysfunction. In premarketing studies,15 decreased libido, delayed ejaculation, and erectile dysfunction were noted in men, especially at higher doses, whereas in women only anorgasmia was notable at the 400 mg dose. However, with regard to weight gain, patients lost an average 0.4–1.1 kg in short-term studies,15 In one long-term study,15 there was no difference in mean weight change between patients who were on desvenlafaxine or placebo for 6 months. Like venlafaxine, desvenlafaxine is associated with sustained elevations in blood pressure. Venlafaxine is associated with elevations at higher doses; however, desvenlafaxine is associated with sustained diastolic hypertension at all doses. Curiously, there is no clear dose response relationship. The incidence of sustained hypertension is 1.3% at a dose of 50 mg of desvenlafaxine, 0.7% at 100 mg, 1.1% at 200 mg, 2.3% at 400 mg, and 0.5% for placebo. Venlafaxine is known to have significant discontinuation syndrome related to its short half-life and serotonergic action. Desvenlafaxine’s half-life is approximately 11 hours, and it is also associated with a discontinuation syndrome. Since desvenlafaxine comes in an extended-release tablet that is not recommended to be cut or split, the recommendation is to taper the medication by increasing the interval between doses.15

The clinical utility of desvenlafaxine over its parent compound remains an open question. The decrease in potential drug-drug interaction is an incremental benefit. However, it is not clear that desvenlafaxine’s greater ratio of norepinephrine to serotonin reuptake inhibition compared to venlafaxine is clinically meaningful with regards to efficacy or tolerability.

With the relative dearth of novel agents for mood disorders, it is worth surveying drugs that are in development. There are >50 drugs in phases I, II, or III clinical trials for depression and bipolar disorder.16 What follows is not a comprehensive survey, but rather an overview of compounds that may be close to an approval decision or have a novel mechanism of action.

New Atypical Antipsychotics

The success of atypical antipsychotics in mood disorders will lead to newer atypical antipsychotics to be tried in mood disorders as well. Paliperidone, the active metabolite of risperidone and recently approved for schizophrenia, is in phase III trials for the treatment of manic and mixed episodes. Asenapine, a serotonin (5-HT2)/dopamine-2 antagonist, has been submitted to the FDA for approval for both mania and schizophrenia. Bifreprunox, a dopamine partial agonist, which received a non-approvable letter for a schizophrenia indication, is in phase III trials for bipolar depression.16


Agomelatine, a melatonergic agonist at melatonin (MT)1 and MT2 receptors and a 5-HT2C antagonist, is in phase III clinical trials in the United States for the treatment of MDD. Blockade of 5-HT2C receptors on gamma-aminobutyric acid interneurons is thought to result in the increase of norepinephrine and dopamine in the prefrontal cortex. In addition, its activity at the MT1 and MT2 receptors is thought to have positive effects on sleep promotion and the regulation of circadian rhythms.17 Efficacy of agomelatine in MDD was demonstrated in three published double-blind, placebo controlled trials.18-20 The first trial18 involved 711 depressed patients with either MDD or bipolar type II, comparing 1 mg, 5 mg, and 25 mg of agomelatine to 20 mg of paroxetine and placebo. Both the 25 mg agomelatine group and the paroxetine group showed statistically significant decreases in HAM-D scores. Both groups had significantly more remitters than the placebo group—30.5% for 25 mg agomelatine and 25.7% for the paroxetine group—compared to 15.7% for placebo.18 Two additional trials,19,20 which featured flexible dosing starting at 25 mg and going to 50 mg after 2 weeks of nonresponse, also showed significant improvement in HAM-D scores and response rates after 6 weeks. All three trials performed subanalyses that showed significant improvement in severely depressed patients with HAM-D scores >25.21

Agomelatine appears to be well tolerated. In all three studies18-20 mentioned above, agomelatine did not have significantly more adverse events than placebo. Separate studies found that agomelatine compares favorably to venlafaxine with regards to sexual dysfunction22 and was also not associated with discontinuation symptoms.23 Notably, in a 24-week relapse prevention study,6 patients on agomelatine did not have significant changes in sexual functioning, weight, cardiovascular effects, or laboratory studies.

Agomelatine has initially been rejected by regulatory agencies in the European Union on efficacy grounds, particularly in long-term studies, although efforts to gain approval continue in Europe and the US. Although not appearing to have significant efficacy advantages, agomelatine would appear to have significant advantages in tolerability, especially with regards to weight gain and sexual dysfunction.


Vilazodone, a selective serotonin reuptake inhibitor (SSRI), also has partial agonist properties at the 5-HT1 receptor. It is undergoing a Phase III clinical trial for the treatment of depression. Partial agonism at 5-HT1 is thought to enhance the action of SSRIs, perhaps by accelerating the desensitization of somatodendritic autoreceptors. This has been borne out clinically by studies indicating the effectiveness of buspirone, a 5-HT1 partial agonist, in the augmentation of SSRI treatment, most notably in the STAR*D trial. In addition, there is thought that activity at the 5-HT1 receptor can mitigate sexual side effects of SSRIs. There is also some evidence that buspirone is effective in treating sexual dysfunction brought on by SSRIs, although it is somewhat equivocal. In one 8-week, double-blind, placebo-controlled study24 of 410 patients, vilazodone had significant decreases in HAM-D and MADRS scores beginning at week 1. Vilazodone also had a significantly higher percentage of responders and remitters. Principal adverse events include diarrhea, nausea, and somnolence. Sexual dysfunction was examined using the Arizona Sexual Experiences Scale, and no significant differences were noted between treatment and placebo group. Furthermore, the investigators identified a genetic biomarker which identifies patients that had significantly more improvement after 8 weeks of vilazodone treatment. Patients with the biomarker and treated with vilazodone had significantly more improvement compared to patients without the biomarker and treated with vilazodone as well as patients treated with placebo regardless if they had the biomarker.24

Triple Reuptake Inhibitors

The monoaminergic hypothesis of depression underlies existing antidepressants and the preceding compounds. All existing antidepressants are thought to modify mood based on effects on serotonin, norepinephrine, or dopamine. However, the majority of antidepressants only have significant effects on serotonin and norepinephrine. Substantial evidence exists linking the importance of dopaminergic pathways to depression. In particular, anhedonia and lack of motivation are thought to be connected to dopaminergic deficits. Of existing antidepressants, bupropion is thought to work by increasing levels of dopamine and norepinephrine; only the MAOIs, which carry significant drug interactions and have tolerability issues, are thought to increase all three neurotransmitters. Triple reuptake inhibitors, compounds that add blockade of the dopamine transporter to actions blocking serotonin and norepinephrine, seek to increase level of all three neurotransmitters while maintaining the tolerability found in SSRIs or serotonin norepinephrine reuptake inhibitors.25

Triple reuptake inhibitors have been referred to as “broad spectrum,” being able to target a wide range of symptoms that have been associated with either serotonergic, noradrenergic, or dopaminergic deficits. Theoretically, such an agent might have a more rapid onset of action and higher remission rates. There are proposed tolerability advantages as well. Dopaminergic activity might serve to attenuate serotonergic-mediated sexual dysfunction and weight gain.26 However, dopaminergic agents, with their effects on reward pathways, may have abuse liability. Dopamine transporter drugs that produced >50% dopamine transporter blockade within 15 minutes were reinforcing.27

Numerous triple reuptake inhibitors have shown promise in animal models of depression and have progressed to clinical trials. DOV 21,947 has completed eight Phase I trials and is now recruiting for Phase II clinical trials for the treatment of MDD. DOV 21,947 is an enantiomer of DOV 216,303 which has also been developed as a triple reuptake inhibitor, although patent life concerns have halted development. Results of a double-blind Phase I study with DOV 216,303 showed significant decreases in HAM-D scores after 2 weeks of treatment. The study was limited by the lack of a placebo arm and the short time frame. The length of the study was limited by the amount of safety data at the time. Instead of a placebo arm, there was an active comparator arm using citalopram 20 mg BID, which also showed significant decrease in HAM-D scores in the same time period.28 Another triple reuptake inhibitor, GSK 372475, is also in phase II trials for depression. A third, SEP 225289, has started phase I clinical trials.15 Conceptually, triple reuptake inhibitors are quite appealing and are the natural extension of the monoaminergic hypothesis of depression, although questions remain about what the most effective balance of neurotransmitter action would be.

Novel Mechanisms of Action: Beyond Monoamines

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in patients with mood disorders have been explored since the 1950s. Under normal circumstances, in response to stress, the hypothalamus releases corticotrophin releasing factor which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH) which, in turn, stimulates the adrenal glands to produce cortisol. High levels of cortisol produce negative feedback on corticotropin releasing factor (CRF) which ultimately leads to cortisol levels returning to normal. However, in depressed patients, this regulatory mechanism does not function properly. Depressed patients are found to have elevated cortisol levels, exaggerated adrenal responses to ACTH, and fail to suppress cortisol secretion when given the synthetic glucocorticoid dexamethasone. Chronic high levels of cortisol are thought to contribute to hippocampal volume loss and possibly neurocognitive symptoms of depression. Furthermore, successful treatment of depression leads to normalization of cortisol levels and regulation of the HPA axis. It is hypothesized that modulating the HPA axis and correcting cortisol levels will result in improvement of depressive symptoms and improved neurocognitive function.29

Numerous strategies have been employed to regulate the HPA axis in the treatment of depression. Steroid synthesis inhibitors such as ketoconazole, metyrapone, or aminogluthemide have been studied with mixed results.30 In particular, two approaches are being actively pursued as treatments for mood disorders, namely, glucocorticoid receptor antagonists and CRF-1 receptor antagonists.

Mifepristone is a glucocorticoid receptor-2 antagonist and progesterone receptor, which is approved by the FDA for termination of early pregnancy. There have been multiple published studies examining it’s efficacy in depression with psychosis. Early open-label studies demonstrated rapid and durable responses in patients after only 4–6 days of treatment with mifepristone 600 mg.31 In a large double-blind, placebo-controlled study32 of >200 patients, 58.1% of patients receiving mifepristone 600 mg achieved at 50% reduction in the Brief Psychiatric Rating Scale-Positive Symptoms Subscale in 1 week and maintained it until the fourth week compared to 38.1% in the placebo arm. However, there were no significant differences in HAM-D scores between the mifepristone and placebo group. Although three Phase III clinical trials for mifepristone have failed to demonstrate efficacy versus placebo for depression with psychosis, trials continue to examine higher doses of 1,200 mg. Two other glucocorticoid receptor-2 antagonists are in phase II trials, ORG 34517 and ORG 34850.15

Numerous CRF-1 receptor antagonists have been developed for depression and anxiety disorders. In an open-label study of 20 patients, patients who received R121919 40–80 mg had significant decreases in HAM-D and Beck Depression inventory scores over 30 days. Sleep electroencephalogram studies indicated reversal of sleep architecture changes associated with depression. However, development was halted when drug-induced reversible increases in liver enzymes were detected in a safety study, although this was thought to be unrelated to its principal method of action.33 Despite this setback, the exploration of CRF-1 receptor antagonists for the treatment of depression and anxiety disorders remains extremely active. Pexacerfont is currently in Phase III clinical trials and three other compounds are in phase I or phase II clinical trials.15,16


Substance P, neurokinin A, and neurokinin B are the three most common tachykinins. Tachykinins are short 11–13 amino acid-long peptide neurotransmitters sharing a common C-terminal sequence. Tachykinins exert their effect through G-protein-mediated receptors called neurokinin (NK)1, NK2, and NK3.34 Substance P preferentially binds NK1, neurokinin A preferentially binds NK2, and neurokinin B prefererentially binds NK3, although all three have agonist effects at all three receptors. Tachykinins—especially substance P—became of interest as targets for potential psychiatric medications, as these neuropeptides and their receptors are found in areas of the brain involved in stress, fear, and emotional response (amygdala, hippocampus, hypothalamus and frontal cortex) and closely overlap serotonergic and noradrenergic neurons.35

Antagonists to NK1 and NK2 receptors have been found to have antidepressant effects in animal models and have progressed to clinical trials. In particular, NK1 antagonists have been explored as potential treatments for depression for a number of years.  However, results with numerous compounds have been disappointing.35

Aprepitant (MK-836) had shown promise in two early studies.36,37 In the first,37 MK-836 showed superior efficacy to placebo and equal efficacy to paroxetine with improved tolerability, and had been hailed as a potential breakthrough drug. Only somnolence was found to be a more common adverse event than placebo; weight gain, sexual dysfunction, nausea or vomiting were not significant problems.37  In an another study36 in which both aprepitant and fluoxetine failed to separate from placebo, a post hoc analysis indicated the antidepressant efficacy of aprepitant in a subgroup of severely depressed patients. However, an analysis38 of five clinical trials representing over 750 patients failed to show efficacy versus placebo. Furthermore, using paroxetine 20 mg as an active comparator, investigators were able to replicate paroxetine’s efficacy versus placebo in the same studies.38  Finally, positron emission tomography studies indicate that the doses used in these clinical studies would result in 95% occupancy of NK1 receptors.38

A similar compound, with higher brain penetration and oral bioavailability, L-759274 was also studied. A double-blind placebo-controlled study39 of >162 patients demonstrated superiority to placebo in patients with depression with melancholic features, although a dose-finding trial40 has failed to show separation from placebo. Development on these two compounds for mood disorders has been halted, although aprepitant has been approved for the adjunctive treatment of chemotherapy-induced emesis. Nevertheless, many NK-1 antagonists are still being developed for depression and anxiety.16

Saredutant is a NK-2 receptor antagonist that had progressed to the point that an application for approval for depression seemed to be forthcoming. However, efficacy results were also somewhat equivocal. Of four unpublished phase III studies only two demonstrated statistically significant results compared to placebo.3 Subsequently, a long-term study.41 which compared the ability of saredutant to prevent relapse in patients who had already responded to saredutant for 3 months failed to show superiority to placebo. As a result, approval application will rest on the results of studies currently running on saredutant in combination with  citalopram and paroxetine.

Glutamate and Mood Disorders

Glutamate is the principal excitatory neurotransmitter in the brain. A growing body of research implicates abnormal glutamatergic function with an important role in the pathophysiology of mood disorders. A proposed mechanism for the mood stabilizing and antidepressant effects of lamotrigine is the inhibition of glutamate release through its effect on sodium channels. A number of compounds that modulate the glutamatergic system have been examined for the treatment of mood disorders.42

Riluzole is the only FDA-approved medication for amyotropic lateral sclerosis. It has multiple mechanisms of action which include inhibition of glutamate release through sodium channels, similar to that of lamotrigine, and the enhancement of glutamate reuptake.43 Two open-label studies44,45 have been performed in unipolar depression, and one open-label study46 in bipolar depression. The first study44 used riluzole 100–200 mg as monotherapy for unipolar depression for 19 patients. All patients had to be unresponsive to one medication trial and 53% were unresponsive to at least two trials from two different classes; 68% of the patients completed the 6-week trial. Response rates on the MADRS were 32% for all patients and 46% for completers. Remission rates were 21% for all patients and 31% for completers. In another study,45 riluzole 100 mg was used as an augmentation strategy in unipolar depression for patients who had a HAM-D24 score >21 despite being on a stable dose of medication for at least 6 weeks. After 6 weeks, the average HAM-D score was reduced 36%; significant decreases were noted in week 1. Forty percent of the 10 patients who completed the 6 weeks had responded and 30% were in remission. Patients who responded seemed to respond rapidly in the first week and held durable responses for months. Another open-label study46 looked at riluzole in addition to lithium for bipolar depression. The response and remission rate at week 8 was 50%. Notably, four patients who had remitted had failed to respond to lamotrigine in the past. Two of these patients remitted, while one had a partial response and one had no response. The NIMH is sponsoring a Phase II trial in unipolar and bipolar depression. Riluzole, while available, can cost upwards of $1,000/month. It has an extended patent due to orphan drug status, which expires in 2013.

The N-methyl-D-aspartate excitotoxic amino acid (NMDA) receptor is a subtype of glutamate receptor and has been the subject of investigation regarding depression. Ketamine, a general anesthetic which is also known as a “club drug,” is an NMDA receptor antagonist. Two randomized, double-blind, crossover studies47,48 have been published. In both studies, patients were randomized to receive either a single subanesthetic (0.5 mg/kg) infusion of ketamine over 40 minutes or a saline solution. At least 1 week later, the patient would receive the infusion that they did not receive the first time. Significant decreases in depression occurred within 110 minutes after infusion, which persisted for 1 week. In one study,48 71% of patients receiving ketamine were responders after 1 day and 35% were responders after 1 week. No patients in the placebo group showed a response at any time.47,48

The ketamine studies are notable if only for the speed of response and proof of concept. However, the need for intravenous infusion and ketamine’s notoriety as a potential drug of abuse may limit its ultimate utility as an antidepressant. Memantine is a low-affinty NMDA antagonist used for the treatment of Alzheimer’s disease. Compared to ketamine, it does not have psychotomimetic properties, is well tolerated, and is orally bioavailable. However, double-blind placebo-controlled study49 of 32 subjects with bipolar depression showed no treatment effect at doses of memantine 20 mg/day.


The need for new treatments in the pharmacotherapy of mood disorders remains. New medications, some of which continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine and some of which employ novel mechanisms of action hold the potential to improve the treatment of patients. Novel mechanisms of action include modifying the HPA axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy. PP


1.    Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry. 2006;163(11):1864-1866.
2.    Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163(2):217-224.
3.    Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008;33(9):2300.
4.    Norman TR, Burrows GD. Emerging treatments for major depression. Expert Rev Neurother. 2007;7(2):203-213.
5.    Holtzheimer PE 3rd, Nemeroff CB. Advances in the treatment of depression. NeuroRx. 2006;3(1):42-56.
6.    The New Drug Approval Process. Available at: Accessed November 6, 2008.
7.    Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28(1):13-20.
8.    Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):843-853.
9.    Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(2):156-165.
10.    Stahl S. Antidepressants. In: Stahl S. Stahl’s Essential Psychopharmacology, Neuroscientific Basis and Practical Applications. 3rd ed. New York, NY: Cambridge University Press; 2008:549-550.
11.    Boyer P, Montgomery S, Lepola U, et al. Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial. Int Clin Psychopharmacol. 2008;23(5):243-253.
12.    Liebowitz MR, Manley AL, Padmanabhan SK, Ganguly R, Tummala R, Tourian KA. Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. Curr Med Res Opin. 2008;24(7):1877-1890.
13.    DeMartinis NA, Yeung PP, Entsuah R, Manley AL. A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder J Clin Psychiatry. 2007;68(5):677-688.
14.    Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-347.
15.    Pristiq [package insert]. Madison, NJ: Wyeth-Ayerst. September 2008.
16.    Future treatments for depression, anxiety, sleep disorders, psychosis, and ADHD. Available at: Accessed October 24, 2008.
17.    San L, Arranz B. Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry. 2008;23(6):396-402.
18.    Lôo H, Hale A, D’haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239-247.
19.    Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16(2):93-100.
20.    Olié JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10(5):661-673.
21.    Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol. 2007;22(5):283-291.
22.    Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28(3):329-333.
23. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol. 2004;19(5):271-280.
24.    Rickels K, Athanasiou M, Robinson, D, Gibertini, M, Whalen H, Reed CR. Vilazodone: evidence for efficacy and tolerability in the treatment of major depressive disorder. Poster presented at: the Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington, DC.
25.    Liang Y, Richelson E. Triple reuptake inhibitors: next-generation antidepressants. Primary Psychiatry. 2008;15(4):50-56.
26.    Skolnick P, Basile AS. Triple reuptake inhibitors (“broad spectrum” antidepressants). CNS Neurol Disord Drug Targets. 2007;6(2):141-149.
27.    Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005;57(6):640-646.
28.    Skolnick P, Krieter P, Tizzano J, et al. Preclinical and clinical pharmacology of DOV 216,303, a “triple” reuptake inhibitor. CNS Drug Rev. 2006;12(2):123-134.
29.    Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008;(1):CD005168.
30.    Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis. Neurochem Res. 2008;33(4):691-707.
31.    Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychotic [corrected] disorders. Eur J Pharmacol. 2008;583(2-3):358-364.
32.    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60(12):1343-1349.
33.    Ising M, Holsboer F. CRH-sub-1 receptor antagonists for the treatment of depression and anxiety. Exp Clin Psychopharmacol. 2007;15(6):519-528.
34.    Rupniak NM, Kramer MS. Substance P and related tachykinins. In: Davis K, Charney D, Coyle J, Nemeroff C, Neuropsychopharmacology, the 5th Generation of Progress. New York, NY: Lippincott, Williams and Wilkins; 2002:169-176.
35.    Hafizi S, Chandra P, Cowen J. Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations. Br J Psychiatry. 2007;191:282-284.
36.    Herpfer I, Lieb K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs. 2005;19(4):275-293.
37.    Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281(5383):1640-1645.
38.    Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59(3):216-223.
39.    Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology. 2004;29(2):385-392.
40.    Krishnan KR. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry. 2002;63(suppl 11):25-29.
41.    sanofi-aventis press release, July 31, 2008. Available at:  Accessed November 6, 2008.
42.    Kugaya A, Sanacora G. Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 2005;10(10):808-819.
43.    Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761-786.
44.    Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
45.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
46.    Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430-432.
47.    Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
48.    Zarate CA Jr, 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(8):856-864.
49.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.


Dr. Peselow is research professor at New York University (NYU) School of Medicine in New York City. Dr. Malavade is clinical assistant professor of psychiatry at NYU School of Medicine and house staff of Out-Patient Services at Bellevue Private Hospital in New York City. Dr. Lowe is clinical assistant professor of psychiatry at NYU School of Medicine. Dr. Glick is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in California.

Disclosure: Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer. Dr. Malavade is a consultant to and on the speaker’s bureau of Eli Lilly. Dr. Lowe reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Glick is a consultant to Bristol-Myers Squibb, Janssen, Lunbeck, Organon, Pfizer, Shire, Solvay, and Vanda; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen, Pfizer, and Shire; receives research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, Shire, and Solvay; and owns stock in Forest as well as Johnson and Johnson.

Please direct all correspondence to: Eric D. Peselow, MD, Research Professor, School of Medicine, Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016-8304; Tel: 917-376-6755; Fax: 718-763-1677; E-mail:


Focus Points

• Numerous agents throughout history have been used to treat mental illness.
• Orthomolecular psychiatrists have thought that vitamins and amino acids have helped with respect to mental illness in part as a result of their effects on neurotransmitter systems.
• Herbal medications are agents derived from natural products that can be bought over the counter without Food and Drug Administration regulation.
• Herbal medications include Sam-e, inositol, and St. John’s wort, among others.


Throughout history numerous medications and unique treatments have been tried to diminish the frequency and severity of psychiatric symptoms. Some discovered by serendipity, such as lithium, chlorpromazine, monoamine oxidase inhibitors, and tricyclic antidepressants, have been efficacious and continue to be mainstays of psychiatric treatment. Others, such as insulin coma therapy, chemical convulsive therapies, and continuous sleep therapy, have passed into history. However, due to the fact that Food and Drug Administration-approved drugs have side effects and are efficacious no more than 66% of the time, there has been a need for patients and physicians to attempt to find other agents. This article discusses current orthomolecular agents (amino acids) and herbal agents (Ginkgo biloba, St. John’s wort) and assesses their current utility in treating psychiatric illness.

Introduction: Treatments of Historic Significance

Biological therapies for the treatment of mental disorders have been available since the dawn of civilization. Herbs, potions, and other treatments for emotional disturbance date back thousands of years. In the 20th century, many new pharmacologic and other biological therapies have been developed to treat psychiatric disorders. Some treatments, such as insulin coma therapy, have not survived. It remains to be seen whether newer interventions, described below, will become important tools in modern psychiatric practice or will be quickly dispatched to the vaults of history.

Historic Drugs


Fenfluramine, which in 1997 was available for use in decreasing appetite, was presumed to exert its effects through a serotonergic mechanism; however, it was not a stimulant. In 1987, d-fenfluramine, one of its isomers, was introduced in the United States after having been available in Europe for some time and was widely used alone or in combination with phentermine as “fen-phen” in obesity programs. d-Fenfluramine turned out to be associated with changes in the heart valves and with occasionally fatal pulmonary hypertension and was withdrawn from the US market.1,2

Chemical Convulsive Therapies

Convulsive therapies for the treatment of serious psychiatric disorders date back hundreds of years, with the Swiss physician Paracelsus reportedly giving camphor by mouth to induce seizures and to treat lunacy in the 16th century. Several European manuscripts from the 1700s describe the benefits of camphor-induced seizures for the treatment of mania and other forms of insanity. These manuscripts were largely forgotten until the work of Ladislas von Meduna in the 1930s. Von Meduna had experimented with intramuscular (IM) camphor monobromide, caffeine, strychnine, brucine, and other compounds in the treatment of schizophrenia.

The two most common convulsant therapies used for the treatment of dementia praecox were pentylenetetrazol and hexafluorodiethyl ether. Pentylenetetrazol was reliable and was more soluble than many other compounds and also had a quicker onset of action. These latter two agents were inhaled as vaporizers, and both produced convulsions; they were essentially introduced as substitutes for electroconvulsive therapy (ECT). Von Meduna typically used an initial 5 mL dose of a 10% solution of pentylenetetrazol, followed by additional doses every minute if convulsions were not achieved.3-5

The major drawbacks of these chemical convulsions is that seizures sometimes did not occur and patients would experience significant preictal discomfort, including nausea and anxiety, and, thus, would tend to decline further treatment. In the late 1930s and early 1940s, chemical convulsive therapy was replaced by the considerably more reliable ECT, which has greater safety and ease of administration.4

Coma-Inducing Therapies

Insulin coma therapy emerged at approximately the same time in the 1930s as ECT. In 1933, Manfred Sakel observed that dementia praecox patients who went into a coma tended to come out of the coma less symptomatic, exhibiting less severe psychotic symptoms. The treatment involved using incrementally higher doses of IM insulin until the patient became comatose. Comas were initially terminated with glucagon after approximately 15 minutes, but an attempt was made to increase subsequent comas to a maximum of 60 minutes. Patients often required ≥60 treatments before results were observed. Complications, including arrhythmias and laryngeal spasms, were not uncommon, and insulin coma therapy had a fatality rate of at least 1% and, in some samples, considerably higher. The danger of the procedure and a controlled study6 in 1962 that suggested that it was no more effective than a similar period of unconsciousness induced by barbiturates hastened the demise of the procedure. The risk of death (caused by irreversibility of the coma) and intellectual impairment led to a general abandonment of this treatment in the US.

However, some patients clearly appeared to respond to insulin coma therapy who did not respond to other available treatments. Insulin coma treatment had its best results in the treatment of the excited paranoid and catatonic patient.7

Variations of insulin coma therapy included atropine coma therapy used briefly in the 1950s. Atropine in doses of as low as 15 mg/day IM and as high as 200 mg/day was given to induce comas lasting 6–8 hours. If the patient did not wake up spontaneously, the coma was aborted by IM physostigmine. The patient would take warm and cold showers on awakening. Scopolamine, which has actions similar to atropine, was used in a like manner between 5 mg/day and 100 mg/day and was administered as much as 6 times/week.

As with insulin coma therapy, atropine coma therapy was said to be effective for the treatment of schizophrenia and mania. The most serious complications were hyperthermia (which were treated aggressively with ice packs) and rhabdomyolysis. By the late 1950s, coma therapies had been all but abandoned for safer treatments, including ECT and effective antipsychotics.8

Continuous Sleep Therapy

Continuous sleep therapy was introduced by Klaesi in 1920. It continued in use through the 1930s and 1940s. It involved therapies that altered consciousness for extended periods by seizure or coma, as these were thought to be effective in the treatment of psychosis. Even earlier, psychosis was treated by inducing a state of continuous sleep by giving barbiturates, chloral hydrate, or paraldehyde to induce sleep for 20 hours/day. This was repeated for periods ranging from 10 days to 3 weeks. There were brief interruptions from the sleep to allow the patient to eat and to use the bathroom. Complications of barbiturate-induced continuous sleep included allergic reactions, seizures and delirium on withdrawal, and respiratory depression ending in death. Later, the combination of chlorpromazine with benzodiazepines and other hypnotics was used to keep patients asleep for therapeutic purposes. Electrosleep therapy was introduced by Giljarowski in Russia in 1942, whereby a low level of electric current passed through electrodes applied to the patient’s head produced sleep. This was done for 1–2 hours/day for as long as 3 days. Although there are some reports of improvement in anxiety states, obsessive-compulsive disorder (OCD), and schizophrenia, no controlled data are available to support these claims for these treatments. Given the significant morbidity and clear lack of efficacy of this method, it was largely abandoned in the US by the 1960s.9

Hallucinogen Therapy

Many cultures have used hallucinogens, including mescaline, psilocybin, and ergots, for thousands of years to gain spiritual and personal insight. These agents had been used experimentally through the early 1950s. Lysergic acid diethylamide (LSD) was synthesized in the 1930s and was marketed to psychiatrists and other practitioners in the late 1940s under the trade name Desylid as a tool for understanding psychosis and for facilitating psychotherapy. The model psychosis produced by LSD was used to see if it could illuminate the understanding of the schizophrenic process. Using LSD reportedly helped patients capture repressed memories and deal with anxiety, and it allowed patients to gain insight through an analysis of the primary process induced by the hallucinogen. Oral doses of 150–250 mg were administered occasionally by psychiatrists throughout the 1950s and early 1960s to facilitate psychotherapy with some patients.10,11 In the 1960s, Timothy Leary advocated the widespread use of hallucinogens, but the drugs were outlawed as class I controlled substances in 1965.

Although, overall, these agents are no longer used for therapeutic purposes in this country, LSD has fulfilled part of its early promise as a probe for psychosis. More recent understanding of the pharmacology of LSD and its affinity to serotonin (5-HT)2 receptors has supported the interest in developing 5-HT–dopamine antagonists (atypical antipsychotics) with the 5-HT2 receptor-blocking properties. Advocates in the 21st century suggest there may be a role for hallucinogens in psychiatry.12

Detoxification Therapies

The notion that some mental disorders may be related to a toxin of some sort is old. Various methods have been used to combat potential toxins suspected to be included in the etiology of psychosis. In 1949, Kielholz13 suggested that an endotoxin in the blood caused catatonic schizophrenia. More recent attempts to deal with suspected toxins include the use of blood transfusions in the 1940s and 1950s and hemodialysis in the 1970s. In 1977, Wegemaker and Cade14 began to hemodialyze patients with schizophrenia with the hope of removing toxic polypeptides from their blood to alleviate symptoms. A few case reports15,16 in the late 1970s suggested that hemodialysis was an effective short-term and maintenance treatment in some schizophrenic patients. Patients were dialyzed daily until improvement was seen and were then maintained with dialysis every 2–8 weeks. Several patients were said to recover with hemodialysis and to relapse when the treatments were stopped. The investigators presumed that a leucine-containing endorphin was the responsible toxin, but they (and other investigators) were unable to replicate their initial findings. To date, it is believed that the previously mentioned treatments are of no appreciable value. Thus, the hemodialysis joined blood transfusions and other detoxification therapies in the annals of psychiatric history.

Unconventional Treatments: Will They Become Standard in the Future or Will They Fade into History?

Orthomolecular Psychiatry

Some physicians practice holistic medicine with the idea that physical and emotional illness can be caused by deficiencies in naturally occurring substances. It is their belief that these patients can be treated with organic preparations, including vitamins, minerals, amino acids, and, perhaps, herbs and roots. For psychiatric symptoms, practitioners subscribe to the belief that biochemical derangements exist that can be treated with large quantities of agents that compensate for the disorder. Agents used include the B vitamins, lecithin, vitamin C, tryptophan, phenylalanine, and folic acid.

Megavitamin therapy was introduced into psychiatry in 1952 by Osmond and Smythies17 and Hoffer and colleagues.18 Their hypothesis was that faulty adrenalin metabolism in schizophrenia caused the production or inadequate removal of highly toxic methylated biogenic amines. These amines were thought to be the basis for symptoms such as hallucinations. Treatment with large doses of vitamins, such as nicotinic acid, which is converted in the body to nicotinamide, is thought to be instrumental in causing demethylation of such biogenic amines, making them nontoxic and thus reducing psychotic symptoms.

In 1968, Pauling coined the term orthomolecular to refer to the connection between the mind and nutrition.19 Research articles19 were compiled supporting the notion that taking many times the recommended minimum daily dose of vitamins is useful in the treatment of schizophrenia and other psychiatric disorders. Pauling20 suggested that large (mega) doses of vitamin C (ascorbic acid) combined with niacin, pyridoxine (vitamin B6), and folic acid (vitamin B12) were effective in the treatment of mental illness.

Although some severe vitamin deficiencies may result in syndromes with a psychiatric component (eg, niacin deficiency resulting in pellagra), empirical data and an American Psychiatric Association task force have failed to find evidence supporting the notion that schizophrenia and other disorders respond to vitamin therapies. However, that is not to say that vitamins and amino acids are of no importance in preserving mental health. Evidence indicates that severe vitamin deficiencies can result in psychiatric symptoms and that amino acid supplements may be pharmacologically useful in the treatment of some disorders. These are briefly reviewed in the following sections.

Thiamine, Vitamin B12, and Folate

In industrialized societies, severe vitamin deficiencies are rarely encountered, except in certain populations. Those who are elderly, alcohol dependent, or chronically ill or who have certain types of gastrointestinal surgery are at greatest risk. Among the forms of vitamin deficiency most commonly encountered in the emergency room is acute thiamine depletion from alcohol dependence. Thiamine deficiency is seen in patients who have beriberi. Although the chronic forms of thiamine deficiency that lead to beriberi are rarely seen in the Western world, the fulminant depletion of already low stores of thiamine results in Wernicke’s encephalopathy and Korsakoff’s syndrome. Wernicke’s encephalopathy21 classically presents with the triad of ataxia, ophthalmoplegia, and mental confusion, but confusion and a staggering gait are perhaps most common. Although Wernicke’s encephalopathy is an acute process, Korsakoff’s syndrome22 may be the permanent residue of this encephalopathy. Patients with Korsakoff’s syndrome exhibit a well-circumscribed retrograde and anterograde amnesia that results from destruction of the mammillary bodies, and psychotic symptoms are also reported. Wernicke’s encephalopathy is a medical emergency that responds to acute treatment with 50 mg of thiamine intravenously followed by 250-mg IM injections daily until a normal diet is attained. The treatment of uncomplicated acute thiamine deficiencies usually involves 100 mg given orally 1–3 times per day. Thiamine deficiency is also seen in peripheral neuritis associated with pellagra, and should be considered in alcoholic patients with altered sensorium. Dietary sources of thiamine include legumes, pork, beef, whole grains, fresh vegetables, and yeast. Complete dietary abstinence can lead to a disease state in 3 weeks.23

Vitamin B12 deficiency or pernicious anemia is often seen in elderly adults, patients with gastric surgery, and malnourished depressed patients.24 Vitamin B12 is used in the treatment of pernicious anemia; vitamin B12 deficiency; or increased vitamin B12 requirements due to pregnancy, hemorrhage, malignancy, thyrotoxicosis, or liver or kidney disease.25 In addition, anticonvulsants may decrease the absorption of vitamin B12. The most typical psychiatric presentations include apathy, malaise, depressed mood, confusion, and memory deficits. Vitamin B12 concentrations of 150 mg/mL of serum are sometimes associated with these symptoms. Vitamin B12 deficiency is a more common cause of reversible dementia and is typically assessed in dementia evaluations. The treatment of pernicious anemia usually involves daily IM injections of 1,000 mg of vitamin B12 for approximately 1 week, followed by maintenance doses of 1,000 mg every 1–2 months.26

Folic acid is used in the treatment of megaloblastic and macrocytic anemias due to folate deficiency.27 Folate deficiency has been associated with depression and dementia. Other psychiatric symptoms occasionally associated with folic acid deficiency include paranoia, psychosis, agitation, and confusion.28-30 The relationship of folate to depression has been debated over the years. Folate deficiency may be the consequence of anorexia in depressed patients and may also contribute to depression by interfering with the synthesis of norepinephrine and 5-HT. Folate deficiency has been associated with anticonvulsant use (particularly phenytoin, primidone, and phenobarbital) and the sex steroids, including oral contraceptives and estrogen replacement. Perhaps the most common cause of folate deficiency is the malnourishment associated with alcoholism. Many folate deficiencies respond to folate 1 mg/day orally; however, some more severe forms may require dosages of 5 mg as much as three times a day. Dietary supplements of folic acid are often necessary to prevent neural tube defects in pregnant women, particularly those taking anticonvulsants.31

Amino Acids

Amino acids provide the substrate for neurotransmitters and have been used as adjunctive agents in the treatment of depression and sleep. L-Tryptophan was used for many years in the US and elsewhere to treat insomnia and to augment standard antidepressants. L-Tryptophan, the precursor to 5-HT, must be obtained from the diet.

It was believed that, after oral administration of L-tryptophan, free and protein-bound L-tryptophan increase rapidly, and the free fraction is transported into the central nervous system (CNS). It is hypothesized that CNS levels of tryptophan may stimulate 5-HT synthesis and may reverse the depressive episode. Mendels and colleagues32 did not confirm these findings.

L-Tryptophan had been used for many years combined with antidepressants or lithium to decrease response time and had been reported as a reasonable adjunct in converting partial antidepressant responders to full responders.33

Combination treatments of monoamine oxidase inhibitors plus tryptophan have suggested antidepressant efficacy. L-Tryptophan was also noted to be effective when added to clomipramine but did not seem to be effective when added to tricyclic antidepressants (TCAs).

Patients who respond to serotoninergic antidepressants may rapidly relapse into depression on a diet that is deficient in L-tryptophan. Interestingly, patients who respond to more noradrenergic antidepressants appear less vulnerable to relapse with an L-tryptophan–free diet.

The immediate precursor of 5-HT, 5-hydroxytryptophan, has been shown efficacious in two studies34,35 as an augmenter to chlorimipramine. Numerous small studies36 have suggested that, although tryptophan or 5-hydroxytrptophan did have some effect on augmenting antidepressants, it had little antidepressant effect of its own.37

L-Tryptophan was also used as an over-the-counter (OTC) treatment of insomnia in the US. Numerous studies38 suggested that L-tryptophan in doses of 1–6 g before bedtime decreased sleep latency. L-Tryptophan has been unavailable in the US since 1989 because of its association with the eosinophilia-myalgia syndrome, which may have been secondary to an impurity resulting from the processing of the compound. Before this finding, it was believed that, with the exception of rare nausea or the exacerbation of psoriasis, L-tryptophan was well tolerated.

Another amino acid that has been examined as an augmentor to antidepressants is phenylalanine. Phenylalanine is converted to tyrosine as a catecholamine precursor. Phenylalanine has been added to selegiline successfully in the treatment of some patients with refractory major depressive disorder (MDD). However, Mann and colleagues39 noted minimal improvement in depressive symptoms with phenylalanine alone. Tyrosine has been investigated as an augmentor to TCAs and may also have some mild antidepressant activity itself.

Conclusions Regarding Orthomolecular Agents

The above agents are frequently used and promoted for overall mental and physical health. How useful they will prove remains to be seen.

Herbal Agents

Natural medications are medications that are derived from natural products, and are not approved by the US Food and Drug Administration for their proposed indication. In the US, the public spends approximately $4 billion on supplements with little or no data on what to expect.40 Consumers often believe that because a remedy is “natural” it is, therefore, safe. Moreover, since these remedies are most often purchased OTC, there is no clear mechanism for reports of toxicity to reach those who use them.40

Herbal agents used in mood disorders include omega-3 fatty acids, St. John’s Wort, S-Adenosylmethionine (SAMe) and inositol.

Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated lipids which are cardioprotective.41 The most promising data, however, are in the treatment of both bipolar disorder and unipolar depression; positive studies42-45 have been reported in each of these domains. Psychotropically active doses are generally thought to be in the range of 1–2 g/day, with dose-related gastrointestinal distress being the major side effect. There is also a theoretical risk of increased bleeding, so concomitant use with high-dose nonsteroidal anti-inflammatory drugs or anticoagulants is not recommended.

St. John’s Wort

St. John’s Wort (Hypericum perforatum L.) is one of the biggest-selling natural medications on the market. There have been 27 studies46 looking at St. John’s Wort versus placebo. In MDD there is thought to be minimal benefit; in non-MDD or milder depression there is thought to be possible benefit. St. John’s Wort versus standard antidepressants (TCAs and selective serotonin reuptake inhibitors yield similar efficacy.47 Suggested doses range from 900–1,800 mg/day depending on the preparation, and adverse effects include dry mouth, dizziness, constipation, and phototoxicity. Care should be taken in patients with bipolar disorder due to the possibility of a switch to mania. St. John’s Wort may reduce the therapeutic activity of numerous common medications, including warfarin, cyclosporine, oral contraceptives, theophylline, digoxin, and indinavir.


SAMe is an essential methyl group transfers. It is the principal methyl donor in the one-carbon cycle with SAMe levels depending on levels of the vitamins folate and B12. SAMe is involved in the methylation of neurotransmitters.

SAMe has been shown to elevate mood in depressed patients in doses of between 300–1,600 mg/day. Studies48,49 support antidepressant efficacy of SAMe when compared with placebo and TCAs. Potential adverse effects are relatively minor and include anxiety, agitation, insomnia, dry mouth, bowel changes, and anorexia. Sweating, dizziness, palpitations, and headaches have also been reported.


Inositol is a natural isomer of glucose that is present in common foods. Inositol has been found in various small studies50-53 to be effective in the treatment of depression, panic disorder, OCD, and possibly bipolar depression. Effective doses are thought to be in the range of 12–18 g/day. Adverse effects are generally mild and include gastrointestinal upset, headache, dizziness, sedation, and insomnia.

Herbal Agents Used for Anxiety Disorders: Melatonin, Valerian, and Kava


Melatonin is a hormone derived from 5-HT and manufactured in the pineal gland. It is actually commercially available, as supplies are derived synthetically or from hog pineal glands. It is useful for individuals who travel across several time zones, as it can help rest one’s biological clock by reorganizing one’s circadian rhythm.

Melatonin is a popular OTC hormone used by many Americans on a regular basis for insomnia, and anecdotal reports54 suggest that melatonin can reduce the insomnia associated with jet lag. The hormone is released naturally by the pineal gland early in the sleep cycle and appears to contribute to natural sleep cycles. A number of small, brief studies55 melatonin can act as a hypnotic in doses of 0.2 mg and 5.0 mg at night, although other placebo-controlled studies55 have disagreed on the efficacy of melatonin versus placebo in doses ranging from 0.5 mg to 10.0 mg/day. Some uncontrolled reports55 suggest that melatonin has mild antidepressant effects. However, because of its reciprocal relationship to beta-adrenergic receptor activity, it may worsen depression in some patients.

High doses may cause daytime somnolence and confusion. The drug can interact with the hypothalamic-pituitary-adrenal axis and thymus and can cause immunosuppression; thus, it must be used cautiously with steroids. The long-term effects of melatonin use are unknown and the efficacy of melatonin has been inconclusive at this time given the widespread use of the drug. Indeed, a recent study by Spitzer and colleagues56 showed no significant differences between melatonin and placebo (dose range from 0.5–5.0 mg) in the treatment of jet lag.


Valerian (Valeriana officinalis) is a flowering plant extract that has been used to promote sleep and to reduce anxiety for over 2,000 years. Valerian was thought to be better than placebo in six of seven double-blind studies57 of insomnia (though Valerian has an odor which may have compromised the blind). The onset of action is slow, taking 2–3 weeks to have an effect. Sedative effects are dose-related with usual dosages in the range of 450–600 mg approximately 2 hours before bedtime. In anxiety disorders, there have only been open studies.58 Adverse effects, including blurry vision, gastrointestinal symptoms, headache, and a mild hangover seem to be uncommon.


In treating anxiety, kava has been effective in seven double blind studies.1 A meta analysis of three of thes studies59 has shown that kava is superior to placebo on the Hamilton Rating Scale for Anxiety. The suggested dose is 60–120 mgday. Major side effects include gastrointestinal upset, headaches, and dizziness. Toxic reactions, including ataxia, hair loss, respiratory problems, yellowing of the skin, and vision problems, have been seen at high doses or with prolonged use. There have also been more than 70 published reports60 of severe hepatotoxicity worldwide. Overall, worldwide there have been 11 cases of liver transplants and four deaths associated with Kava.60 Kava has been banned in the European Union and Canada and has an FDA advisory in the US.

Herbal Agents Used for Cognitive Disorders and Dementia

Ginkgo biloba has been used in Chinese medicine for thousands of years. This natural medication comes from the seed of the Gingko tree and has generally been used for the treatment of impaired cognition and affective symptoms in dementing illnesses; however, there may be a role in the management of antidepressant-induced sexual dysfunction.

The suggested dose of ginkgo biloba is 120–240 mg/day with a minimum 8-week course of treatment. However, it may take up to 1 year to appreciate the full benefit. Since ginkgo has been shown to inhibit platelet-activating factor and has been associated with increased bleeding risk (though results are mixed), it should probably be avoided in those at high risk of bleeding.61 Other noted side effects include headache, gastrointestinal distress, headache, seizures in epileptics, and dizziness. With regard to dementia, the data is inconsistent and the cholinesterase inhibitors and memantine are preferred.62


Dehydroepiandrosterone (DHEA), a precursor hormone for estrogens and androgens, is available OTC. It is an abundantly produced adrenal steroid that has been evaluated as a treatment for psychiatric disorders since the 1950s.

Recent years have seen an interest in DHEA for improving cognition, depression, sex drive, and general well-being in elderly adults. Some reports63,64 suggest that DHEA in doses of 50–100 mg/day increases the sense of physical and social well-being in women 40–70 years of age. Reports also exist65 of androgenic effects, including irreversible hirsutism, hair loss, voice deepening, and other undesirable sequelae. In addition, DHEA has at least a theoretical potential of enhancing tumor growth in people with latent, hormone-sensitive malignancies, such as prostate, cervical, and breast cancers. Despite its significant popularity, there is a dearth of controlled data on the safety or efficacy of DHEA.

DHEA has become popular as an OTC drug that can enhance quality of life. Because of the fact that it is reputed to diminish fat, to increase muscle mass, to increase libido, to increase sense of well-being, and to decrease depression, as well as to prevent various diseases (heart disease, cancer, diabetes, Parkinson’s disease, and Alzheimer’s disease), it is highly used. A recent double-blind depression study66 showed some efficacy in the treatment of depression.

Conclusion: Herbal Medication

One out of every three people in the US will use at least one form of alternative medication. It is important to note that the FDA has no established definition for an herbal supplement. Although traditionally used as drugs, herbal products are generally unable to pass the stringent requirements imposed by the FDA for new molecular entities, such as new medications.

The Dietary Supplement Health and Education Act of 1994 prohibits the FDA from the regulation of dietary supplements as food additives.

An estimated 70% of patients do not inform their doctors about the use of alternative therapies, causing 15 million Americans to be at risk for potential drug-dietary supplement interaction. Many of these therapies may prove to be a valuable addition to the armamentarium of treatments available to psychiatrists in the future.

Overall, the jury is still out. Whether these agents will prove to be safe and effective and used appropriately for psychiatric indications or whether they will pass into history remains to be seen. PP


1.    Weissman NJ. Appetite suppressants and valvular heart disease. Am J Med Sci. 2001;321(4):285-291.
2.    Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581-588.
3.    Bennett AE. Metrazol convulsive shock therapy in affective psychoses. A follow-up of results obtained in 61 depressive and 9 manic cases. American Journal of Mental Science. 1939;198:695-701.
4.    Ziskind E, Somerfeld-Ziskind L. Metrazol and electric convulsive therapy of the affective psychoses. Archives of Neurological Psychiatry. 1945;53:212-217.
5.    Impastato D. Electric and chemical convulsive therapy in psychiatry (SCC modified EST. Metrazol and Indoklon convulsive therapy). Dis Nerv Syst. 1961;22:91-96.
6. Freund JD. The place of insulin coma therapy in modern psychiatry. J Neuropsychiatr. 1962;3:246-250.
7.    Fink M, Shaw R, Gross G, Coleman FS. Comparative study of chlorpromazine and insulin coma in the therapy of psychosis. JAMA. 1958;166(15):1846-1850.
8.    Rinkel M, Himwich HE. Insulin Treatment in Psychiatry. New York, NY: Philosophical Library; 1959.
9.    Clapp JS, Loomis EA. Continuous sleep treatment; observations on the use of prolonged, deep, continuous narcosis in mental disorders. Am J Psychiatry. 1950;106(11):821-829.
10.    Sandison RA, Whitelaw JD. Further studies in the therapeutic value of lysergic acid diethylamide in mental illness. J Ment Sci. 1957;103(431):332-343.
11.    Cutner M. Analytic work with LSD 25. Psychiatr Q. 1959;33:715-757.
12.    Morris K. Research on psychedelics moves into the mainstream. Lancet. 2008;371(9623):1491-1492.
13.    Kielholz P, Labhardt F. Treatment of mental disorders with chlorpromazine. J Clin Exp Psychopathol. 1956;17(1):38-44.
14.    Wagemaker H Jr, Cade R. The use of hemodialysis in chronic schizophrenia. Am J Psychiatry. 1977;134(6):684-685.
15.    Wagemaker H. The effect of hemodialysis on fifteen chronic, process schizophrenics. Artif Organs. 1978;2(2):205-206.
16.    Fischler M, Emrich HM, Kissling W, von Zerssen D, Riedhammer H, Edel HH. Hemodialysis in schizophrenia. Results in three chronic cases. Arch Psychiatr Nervenkr. 1979;227(3):207-212.
17.    Osmond H, Smythies J. Schizophrenia: a new approach. J Ment Sci. 1952;98(411):309-315.
18.    Hoffer A, Osmond H, Smythies J. Schizophrenia: a new approach. II. Result of a year’s research. J Ment Sci. 1954;100(418):29-45.
19.    Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825):265-271.
20.    Pauling L. Molecular basis of biological specificity. Nature. 1974 Apr 26;248(5451):769-71.
21.    Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 6th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2005:113.
22.    Langlais PJ. Cognitive deficits in alcoholis Wernicke-Korsakoff syndrome. Alcohol Health Res World. 1995;19:116-117.
23.    Lonsdale D. A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(E) and its Derivatives. New York, NY: Oxford University Press; 2006.
24.    Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 2000;19:357-377.
25.    Svenson J. Neurologic disease and vitamin B12 deficiency. Am J Emerg Med. 2007;25(8):987.
26.    Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.
27.    Kamen B. Folate and antifolate pharmacology. Semin Oncol. 1997;24(5 suppl 18):S18-30-S18-39.
28.    Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369(9557):208-216.
29.    Morris DW, Trivedi MH, Rush AJ. Folate and unipolar depression. J Altern Complement Med. 2008;14(3):277-285.
30.    Mischoulon D, Raab MF. The role of folate in depression and dementia. J Clin Psychiatry. 2007;68(suppl 10):28-33.
31.    Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet. 1997;350(9092):1666-1669.
32.    Mendels J, Stinnett J, Burns D, Frazer A. Amine precursors and depression. Arch Gen Psychiatry. 1975;32(1):22-30.
33.    VanPraag HM, Korf J. 5-Hydroxytryptophan as an antidepressant. The predictive value of the probenecid test. J Nerv Ment Dis. 1974;158(5):331-337.
34.    Kahn RS, Westenberg HG, Verhoeven WM, Gispen-de Wied CC, Kamerbeek WD. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol. 1987;2(1):33-45.
35.    Nardini M, De Stefano R, Iannuccelli M, Borghesi R, Battistini N. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. Int J Clin Pharmacol Res. 1983;3(4):239-250.
36.    van Praag HM Serotonin precursors in the treatment of depression. Adv Biochem Psychopharmacol. 1982;34:259-286.
37.    Carroll BJ, Mowbray RM, Davies B. L-Tryptophan in depression. Lancet. 1970;1(7658):1228.
38.    Hartmann E. Effects of L-tryptophan on sleepiness and on sleep. J Psychiatr Res. 1982;17(2):107-113.
39.    Mann J, Peselow ED, Snyderman S, Gershon S. D-Phenylalanine in endogenous depression. Am J Psychiatry. 1980;137(12):1611-1612.
40.    Mischoulon D, Nierenberg AA. Natural medications in psychiatry. In: Stern TA, Herman JB, eds. Psychiatry Update and Board Preparation. 2nd ed. New York, NY: McGraw-Hill; 2004:399-408.
41.    Harris WS, Reid KJ, Sands SA, Spertus JA. Blood omega-3 and trans fatty acids in middle-aged acute coronary syndrome patients. Am J Cardiol. 2007;99(2):154-158.
42.    Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry. 2006;67(12):1954-1967.
43.    Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr. 1995;62(1):1-9.
44.    Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56(5):407-412.
45.    Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477-479.
46.    Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448.
47.    Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression: an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313(7052):253-258.
48.    Spillmann M, Fava M. S-adenosyl-methionine (ademethionine) in psychiatric disorders. CNS Drugs. 1996;6:416-425.
49.    Papakostas GI, Alpert JE, Fava M. S-Adenosyl methionine in depression: a comprehensive review of the literature. Curr Psychiatry Rep. 2003;5(6):460-466.
50.    Benjamin J, Agam G, Levine J, et al. Inositol treatment in psychiatry. Psychopharmacol Bull. 1995;31(1):167-175.
51.    Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21(3):335-339.
52.    Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996;153(9):1219-1221.
53.    Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotri-gine, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210-216.
54.    Bjorvatn B, Pallesen S. A practical approach to circadian rhythm sleep disorders. Sleep Med Rev. 2008 Oct 7. [Epub ahead of print]
55.    Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms. 1997;12(6):644-650.
56.    Zhdanova IV, Tucci V. Melatonin, circadian rhythms, and sleep. Curr Treat Options Neurol. 2003;5(3):225-229.
57.    Bent S, Padula A, Moore D, et al. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119(12):1005-1012.
58.    Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in generalized anxiety disorder: a randomized placebo-controlled pilot study. Phytother Res. 2002;16(7):650-654.
59.    Singh YN, Singh NN. Kava (Piper methysticum) is derived from a root originating in the Polynesian Islands, where it is used as a social and ceremonial herb Therapeutic potential of kava in the treatment of anxiety disorders. CNS Drugs. 2002;16(11):731-743.
60.    Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing products—United States, Germany, and Switzerland, 1999-2002. JAMA. 2003;289(1):36-37.
61.    Bent S, Goldberg H, Padula A, Avins AL. Spontaneous bleeding associated with Ginkgo biloba: a case report and systematic review of the literature. J Gen Intern Med. 2005;20(7):657-661.
62.    Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia: North American EGb Study Group. JAMA. 1997;278(16):1327-1332.
63.    Wolkowitz OM, Reus VI, Roberts E, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry. 1997;41(3):311-318.
64.    Bloch M, Schmidt PJ, Danaceau MA, et al. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry. 1999;45(12):1533-1541.
65.    Chang AY, Ghayee HK, Auchus RJ. Dehydroepiandrosterone replacement therapy–panacea, snake oil, or a bit of both? Nat Clin Pract Endocrinol Metab. 2008;4(8):442-443.
66.    Wolkowitz OM, Reus VI, Keebler A, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999;156(4):646-649.


Needs Assessment: Serotonin reuptake inhibitors and benzodiazepines are currently the mainstays of treatment for anxiety disorders. However, a significant number of patients do not fully respond to these drugs, and benzodiazepines are associated with unwanted side effects. This article updates clinicians with recent research findings of established and novel agents for the treatment of anxiety disorders.   

Learning Objectives:
•  Understand the need for new medication treatment of anxiety disorders
•  Identify types of established drugs that may be helpful in anxiety disorders
•  Identify novel agents that show efficacy in anxiety disorders

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):50-56


Dr. Choy is in private practice, is staff psychiatrist at the University of California, Irvine (UCI) Counseling Center, and is assistant clinical professor of psychiatry at the UCI Department of Psychiatry and Human Behavior. Dr. Schneier is associate professor of clinical psychiatry at Columbia University College of Physicians and Surgeons and research psychiatrist at the Anxiety Disorders Clinic at the New York State Psychiatric Institute in New York City.

Disclosures: Dr. Choy reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Schneier is on the Scientific Advisory Board of Jazz and has received grant support from Forest and Pfizer.

Off-Label Disclosure: This article includes discussion of the following unapproved medications for anxiety disorders: haloperidol, risperidone, quetiapine, olanzapine, divalproex, topiramate, levetiracetam, tiagabine, lamotrigine, gabapentin, pregabalin, abercarnil, ocinaplon, gepirone, flesinoxan, lesopitron, ondansetron, deramciclane, D-cycloserine, LY354740, and LY544344.

Please direct all correspondence to: Yujuan Choy, MD, 4199 Campus Drive, Suite 550, Irvine, California 92612; Tel: 949-725-2951; Fax: 949-612-1569; E-mail:


Serotonin reuptake inhibitors and benzodiazepines are currently the mainstays of treatment for anxiety disorders. Recent advances in novel anxiolytic agents with mechanisms of action at the gamma-aminobutyric acid-ergic, serotonergic, and glutamatergic systems have garnered a great deal of interest as alternative treatment options. There has also been considerable research in expanding the indications of established agents, including antipsychotics and anticonvulsants, as monotherapy or adjunctive treatment. This article updates clinicians with the findings of recent controlled trials that examine the efficacy of novel drug treatments of anxiety disorders.


Serotonin reuptake inhibitors (SRIs) are currently the first-line pharmacotherapy for most anxiety disorders, including obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), panic disorder, and social anxiety disorder (SAD). However, a significant number of patients do not fully respond to an adequate trial of an SRI. For example, at least 40% to 60% of OCD patients still exhibit symptoms after treatment.1 Benzodiazepines are widely used for panic disorder, GAD, and SAD, but they are associated with unwanted cognitive side effects, a withdrawal syndrome, and potential for abuse. Use of tricyclic antidepressants and monoamine oxidase inhibitors is limited by their adverse side effect profiles. As a result, there has been a growing interest in evaluating anxiolytic properties of established drugs (eg, antipsychotics and anticonvulsants) and of novel agents that modify the gamma-aminobutyric acid (GABA)-ergic, serotonergic, and glutamatergic receptor complexes. This article reviews published controlled studies that examine the efficacy of established and new drugs for the treatment of anxiety disorders. Most of the agents mentioned are not Food and Drug Administration approved for anxiety disorders, with the exception of duloxetine (approved for GAD) and fluvoxamine controlled release (CR; approved for OCD and SAD).

Literature Search Method

A search of MEDLINE from January 2004 to March 2008 was conducted using the search terms: phobic disorders, anxiety disorders, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and panic disorder. Each of these disorders were combined with the terms for the antidepressants (duloxetine,  fluovoxamine), antipsychotics (haloperidol, risperidone, quetiapine, olanzapine, ziprasidone, aripiprazole), antiepileptics (anticonvulsants, divalproex, carbamazepine, phenytoin, topiramate, levetiracetam, tiagabine, lamotrigine, gabapentin, pregabalin) and novel agents (abercarnil, ocinaplon, gepirone, flesinoxan, lesopitron, ondansetron, deramciclane, D-cycloserine, LY354740, LY544344). For agents that yielded controlled studies, and selected agents that did not yield studies (eg, haloperidol, lamotrigine), a repeat search was conducted for articles from 1990–2004. Only controlled trials in adults (≥18 years of age) that have a placebo group or another active agent (ie, active comparison trial) and published in English were included.

For most of the studies, the response rate is based on the clinician’s ratings of  much or very much improvement in the Clinical Global Impression (CGI) scale (ie, CGI response rate). Response rate can also be measured by the proportion of treatment responders based on the primary outcome measure, which is usually a scale specific to the particular disorder studied. For example, response rate for GAD can alternatively be measured by the number of patients who achieved a 50% decrease in the Hamilton Rating Scale for Anxiety (HAM-A). Response rate for OCD is commonly measured by the number of patients who achieved a 25% or 35% decrease in the Yale-Brown Obsessive Compulsive Scale. For consistency across the studies, the CGI response rate was reported when available. When there were inconsistencies in the response rate as measured by the CGI versus the primary outcome measures, this was noted in the article.


Numerous controlled trials have examined the efficacy of antipsychotics in treatment-resistant anxiety disorders, most often as an adjunct to SRI treatment. The best-established findings are for OCD, showing that 30% to 50% of OCD patients respond to antipsychotic augmentation, with better results for haloperidol and risperidone. Response can be apparent within 4 weeks. Treatment responses from other antipsychotics, such as quetiapine and olanzapine, have been inconsistent for OCD. For other anxiety disorders, including PTSD and SAD, there is limited evidence for the efficacy of antipsychotic treatments, with studies limited by small sample sizes and high placebo response rates.


Haloperidol appears to be an effective adjunct for treatment-resistant OCD based on a small controlled study2 of 34 patients. In this study, the addition of haloperidol to fluvoxamine over 4 weeks resulted in a 65% response rate, compared to 0% in the placebo group. There were no drop-outs, but 29% of the haloperidol patients required propranolol for akathisia despite prophylactic benztropine.


Three controlled studies showed that risperidone augmentation of SRIs over a period of 6–8 weeks decreased OCD symptoms in treatment-resistant patients, with a response rate of approximately 30% to 50%.3-5 One of the studies did not achieve statistical significance (40% vs. 0% response rate in risperidone and placebo group, respectively), but this might have been limited by the lack of power (n=8 per group).4 The presence of comorbid tic disorder or schizotypal personality disorder did not predict response, even though antipsychotics are considered helpful with these symptoms.3 Those who failed ≥2 medication trials3 or had less insight into their illness4 had poorer treatment outcomes. Interestingly, risperidone was helpful only in treatment-resistant cases. In patients with an initially good response, adding risperidone resulted in a weakened SRI effect.5

Risperidone treatment of PTSD has shown less consistent findings. Three studies reported that risperidone was helpful in alleviating PTSD symptoms in combat-related6 and non-combat-related PTSD,7,8 whether as an adjunct or as monotherapy. Two studies reported negative results.9,10 In these studies, risperidone did not decrease aggressive tendencies although it decreased irritability,9 and it did not decrease global PTSD symptoms or associated psychotic symptoms.10

In GAD, the addition of risperidone in treatment-resistant patients did not improve anxiety symptoms.11,12 One of these studies had a large sample size (n=417).12 

Risperidone was generally well tolerated in anxiety disorder patients at a dosage range of 0.5–4.0 mg/day, with most common side effects of sedation and increased appetite. Akathisia and extrapyramidal symptoms were reported in some studies. Since none of the studies extended use of risperidone beyond 12 weeks, the rate of potential long-term adverse effects such as tardive dyskinesia and weight gain in anxiety disorder patients is unknown. 


Four small, controlled studies13-16 have examined the efficacy of quetiapine as an augmenting agent for treatment-resistant OCD. Two studies13,14 reported positive results with response rates of 40%13 and 71%,14 whereas two subsequent studies15,16 showed no difference between quetiapine and placebo. In one of the negative studies,15 there was an unusually high placebo response rate of 47% (compared to 40% in treatment group). Quetiapine was well tolerated with few drop-outs secondary to side effects. Additionally, quetiapine was not shown to be effective as a monotherapy treatment of SAD.17 Approximately 40% of quetiapine patients responded to treatment, compared to 0% in placebo, but this was not statistically significant in a sample of 15 patients.


Olanzapine yielded an approximately 40% response rate in two studies18,19 when used as an adjunct in treatment-refractory OCD patients. Whereas one study18 found significant results with a 46% response to drug versus 0% placebo response rate, the other study19 found equivalent response rates of 41% for drug and placebo.

In the treatment of PTSD, one augmentation study20 also reported a high placebo response rate of 60%, which was equal to that of the olanzapine-treated group. In another study,21 olanzapine resulted in a greater improvement of PTSD-specific symptoms, but there was no significant difference in global response rates between drug and placebo (30% vs. 11%, respectively).

Two studies22,23 showed promising results for olanzapine as an augmentation agent in GAD22 and as monotherapy in SAD.23 In the GAD study, there was a significantly higher rate of CGI responders to adjunctive olanzapine (56%) compared to placebo (8%). However, there was no significant difference in the primary outcome measure (HAM-A). In the SAD study, there was no significant difference in CGI response rates between medication and placebo (43% vs. 0%), but the olanzapine-treated patients had superior outcomes based on the social anxiety-specific scales.

Olanzapine was generally tolerated at doses from 2.5–20 mg/day, but patients complained of weight gain and sedation. 


Antiepileptics have also received considerable attention in the treatment of anxiety disorders, particularly the new-generation anticonvulsants, but with mixed findings. The benzodiazepines, which have anticonvulsant properties, have long been a mainstay of anxiety disorder treatment. Of the other older anticonvulsants, only divalproex has been studied in controlled trials,24 but it did not yield any effect in the treatment of PTSD. Of the new-generation anticonvulsants, topiramate, levetiracetam, and tiagabine have not shown any efficacy in the treatment of anxiety disorders. Topiramate was not effective in the treatment of PTSD whether as a monotherapy25 or as an adjunct to antidepressants and group therapy.26 It was associated with significant cognitive side effects, and the drop-out rate was 55% in one of the studies.26 Likewise, levetiracetam did not demonstrate any efficacv in the treatment of SAD.27 Tiagabine is a selective GABA-reuptake inhibitor28 that was ineffective in two large placebo-controlled trials28,29 for the treatment of PTSD29 and GAD,28 as well as in a small (n=40) active comparison trial for GAD.30

However, several other new-generation anticonvulsants—lamotrigine, gabapentin, and pregabalin—appeared to have some benefit. In a small study31 of 15 patients, lamotrigine was superior to placebo in the treatment of PTSD, with 50% of lamotrigine-treated patients versus 25% of placebo patients responding to treatment. Lamotrigine was well tolerated with mild side effects that included drowsiness, poor concentration, sweating, unsteadiness, forgetfulness, and sexual side effects. 

Gabapentin and pregabalin are structural analogs of GABA, but their mechanism of action is thought to involve selective binding to the alpha-2-delta subunit of voltage-dependent calcium channels in the central nervous system.32 Both drugs are predominately excreted by the kidney, and do not have significant drug-drug interactions.

There are two controlled studies33,34 of gabapentin in the treatment of anxiety disorders. In panic disorder, gabapentin was not effective in reducing panic symptoms. In SAD, gabapentin was more effective than placebo, but the amount of improvement was modest. Patients were still quite symptomatic at endpoint (average Liebowitz Social Anxiety Scale of 60) and only 32% of the patients had a >50% reduction in SAD symptoms. In addition, 38% of the gabapentin-treated patients dropped out of the study because of adverse effects or lack of efficacy. Most common side effects included sedation, dizziness, and dry mouth.

Pregabalin has been approved in Europe as a treatment for GAD. Five large controlled trials35-39 reported that pregabalin was effective in the acute treatment of GAD. Montgomery and colleagues39 noted that one negative study was not published. All of the published studies reported a statistically significant reduction of general anxiety with a 46% to 61% response rate. In addition, one study40 reported that pregabalin was efficacious during a 6-month maintenance treatment of GAD; acute-responders relapsed at a lower rate compared to placebo over a 24-week period (42% vs. 65%, respectively). Pregabalin was also investigated as a treatment of SAD.41 In patients with SAD, pregabalin 600 mg decreased social anxiety symptoms compared to placebo. Common side effects included dizziness, somnolence, headaches, dry mouth, blurry vision, incoordination, ataxia, and weight gain. There were no significant withdrawal symptoms when medication was discontinued.

Novel GABAergic Agents

Currently, benzodiazepines are the only FDA-approved, anxiolytic agents with a GABAergic mechanism of action. Other GABAergic agents have been investigated as potential anxiolytics, but two of these agents failed to show efficacy (tiagabine28-30 and abercarnil42). Another agent (ocinaplon) was effective in decreasing anxiety based on one study.43  Neither abercarnil nor ocinaplon are commercially available at present.

New Indications for SSRI/SNRI Agents

Recently, duloxetine and a controlled-release formulation of fluvoxamine received new FDA indications for anxiety disorders.


Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) that received FDA approval for the treatment of GAD in 2007 based on three large placebo-controlled trials.44-46 A pooled analysis showed a response rate of 51% in duloxetine-treated patients compared to 33% in placebo.47 Response was defined as >50% reduction from baseline in HAM-A total score at endpoint, and remission was defined as a HAM-A total score <7 at endpoint. Remission was achieved in 30% of patients treated with duloxetine. The efficacy of duloxetine appeared to be comparable to that of venlafaxine and SRIs, but no statistical comparison was conducted.46 Duloxetine 60 mg and 120 mg were equally effective, but the higher dose resulted in greater adverse effects.44 Duloxetine was also effective in the treatment of clinically significant pain, with improved GAD symptoms correlating with better pain control.48

The most common side effects included nausea/vomiting, dizziness, sedation, fatigue, sweating, dry mouth, insomnia, constipation, and decreased libido. Discontinuation symptoms were absent in one study,46 but problematic in another study.44

Fluvoxamine Controlled Release

Fluvoxamine CR received FDA approval for the treatment of SAD and OCD in 2008. There are two large placebo-controlled trials in patients with SAD.49,50 One study49 was positive but the response rate was not impressive: 33.9% in fluvoxamine CR versus 16.7% in placebo were considered treatment responders. The other study50 was essentially negative with no difference in response rates between fluvoxamine CR and placebo groups (48% vs. 44%). For those who did respond, continued treatment for an additional 12 weeks resulted in further improvement, but the treated group still was no different from placebo (80% vs. 74%).51

During acute treatment, common side effects included headaches, nausea, somnolence, and insomnia, but there was no notable weight gain or sexual side effects. The incidence of sexual side effects became more prominent when the study was extended to 24 weeks (16% in fluvoxamine CR vs. 5% in placebo). Discontinuation symptoms or drug-drug interactions were not investigated.

There is one large placebo-controlled trial52 of fluvoxamine-CR for the treatment of OCD. Patients treated over a 12-week period with fluvoxamine CR 100–300 mg showed greater improvement in OCD symptoms compared to that of placebo, and significant differences were observed by week 2 of the study. A treatment response was achieved in 44% of fluvoxamine CR-treated patients, compared to 23% in placebo. Side effects were similar to those noted in the SAD studies, including sexual side effects. A higher percentage of fluvoxamine CR patients dropped out because of side effects (19% vs. 6% in placebo).

Other Serotonergic Agents

Drugs that act on different serotonergic receptors have been investigated in the treatment of anxiety disorders.

Given the efficacy of buspirone in the treatment of GAD, other agents with partial or full agonist activity at the serotonin (5-HT)1A receptors have been investigated as a potential non-benzodiazepine anxiolytic. However, these agents—gepirone,53 flesinoxan,54 and lesopitron55—have not been shown to be efficacious and are not currently marketed.

Ondansetron is a selective antagonist at the 5-HT3 subtype of serotonin receptors that is used in the treatment of nausea and vomiting in chemotherapy patients. A low dose of ondansetron (1 mg) was effective in reducing anxiety in GAD patients.56 It was well tolerated with mild side effects, including cold-like symptoms, constipation, and headaches. 

Deramciclane is an unmarketed novel anxiolytic agent with specific antagonism at 5-HT2A/2C receptors. In a recent study,57 deramciclane 60 mg decreased anxiety compared to placebo in patients with GAD. Medication was well tolerated with overall incidents of side effects comparable to placebo. Abrupt discontinuation did not result in withdrawal symptoms.

Glutamatergic Agents

Glutamate is a major mediator of excitatory neurotransmission in the central nervous system. The two major glutamate receptors are ionotropic receptors, which mediate fast synaptic transmission via ion-gated channels and include the N-methyl-d-aspartate (NMDA) receptor group, and metabotropic receptors, which mediate slower synaptic transmission via second messengers such as cyclic adenosine monophosphate. These receptors have recently been targeted for the development of anxiolytic agents. 


D-cycloserine is a partial NMDA receptor agonist that was initially developed as a broad-spectrum antibiotic for tuberculosis. It is unique in that its application to anxiety disorders grew out of animal studies showing that it plays an important role in facilitating extinction of conditioned fear.58 Unlike anxiolytics, D-cycloserine does not appear to directly reduce anxiety symptoms, but instead enhances learning that takes place during therapeutic exposure to feared situations. It has been studied only as an augmentation to behavioral therapy in which it was administered 1–4 hours prior to exposure sessions at doses ranging from 50–500 mg.

In the first clinical study,59 D-cycloserine expedited treatment response in patients with height phobia, and treatment gains were maintained at 1- and 3-month follow-up. Since this trial, a number of other studies in SAD,60,61 spider fear,62 and OCD63-65 have been completed. Two placebo-controlled studies60,61 demonstrated that D-cycloserine was affective in augmenting the effects of 5-sessions of behavioral therapy for public-speaking fears in patients with SAD. Treatment gains were maintained at 1-month follow-up.60 However, D-cycloserine did not affect treatment outcome in participants with subclinical spider fears in which >90% of participants responded to exposure therapy alone.62

In two of three augmentation studies63,64 for OCD, D-cycloserine decreased OCD symptoms relative to pill placebo during mid-treatment, but this positive effect was lost by the end of treatment. In the other OCD study,65 both D-cycloserine and pill-placebo patients responded equally well over time and at treatment endpoint. In these OCD studies, a full course of exposure therapy was given (up to 12 sessions or until a treatment response was achieved), whereas in the previous studies with height phobia and SAD, therapy was comparatively shorter, between 2–5 sessions. This suggests the possibility that prolonged and repeated administration of D-cycloserine during a full course of behavioral therapy may not be as effective as augmentation of an abbreviated course of exposure therapy. Alternatively, OCD may be more resistant to treatment augmentation. Nonetheless, a greater percentage of D-cycloserine patients completed treatment compared to pill placebo patients (93% vs. 65%),63 suggesting that D-cycloserine may increase patient adherence to effective treatment. D-cycloserine was generally well tolerated with mild gastrointestinal distress, dizziness, fatigue, and anxiety. Given the preliminary results, it may be premature to use D-cycloserine in clinical settings at this time. Further controlled trials are still need to establish the efficacy of D-cycloserine augmentation compared to standard cognitive-behavioral therapy alone.

LY354740/ LY544344

LY354740 is a metabotropic glutamate type 2 receptor agonist that negatively inhibits glutamate release and controls the release of GABA and other neurotransmitters.66 In a small controlled study66 of panic disorder patients, this agent performed worse compared to placebo. Interestingly, paroxetine 60 mg also did not fair better than placebo. However, LY354740 was reported to be efficacious in the treatment of GAD in a large placebo-controlled trial,67 and its efficacy was comparable to lorazepam but with better tolerability. More recently, LY544344, a prodrug that increases LY354740 bioavailability, was shown to be effective in the acute treatment of GAD.67 Unfortunately, this trial was prematurely terminated secondary to concerns over convulsions reported in animal studies. In the clinical study, no convulsions were observed, and LY544344 was well tolerated with minimal side effects.


The current interest in and need for new treatments for anxiety disorders has led to a search for expanding the use of established drugs as well as investigation of novel agents that modulate different neurotransmitter systems thought to influence anxiety symptoms. Recently, duloxetine received an FDA indication for GAD, and fluvoxamine CR was approved for OCD and SAD. All other agents discussed in this article are used off-label or have not been marketed. 

Both antipsychotics and anticonvulsants have been considered in the treatment of anxiety disorders. Numerous controlled trials have indicated that treatment-resistant OCD patients may benefit from antipsychotic augmentation, particularly with haloperidol and risperidone. Studies for the antipsychotic treatment of other anxiety disorders have been less encouraging. Risperidone has not been effective in GAD and has limited benefits in PTSD; quetiapine has not been beneficial in SAD; and responses to olanzapine in patients with PTSD, GAD, and SAD have been inconsistent. Of the anticonvulsants studied, there is strong evidence for the efficacy of pregabalin in the acute and possibly maintenance treatment of GAD, and there is limited evidence for the efficacy of gabapentin in SAD and lamotrigine in PTSD.

In the treatment of GAD, the investigative GABAergic agent ocinaplon appeared beneficial, but its counterpart abercarnil was not effective. The novel serotonergic 5-HT1A partial and full agonists either worsened or did not have any effect on anxiety symptoms. Ondansetron appeared to be effective, but findings of the investigative 5-HT2A/2C receptor antagonist (deramciclane) were inconsistent.

Lastly, D-cycloserine showed promising results in enhancing the efficacy of behavioral therapy for height phobia and performance anxiety. However, it did not have any benefit as an augmenting agent during a longer treatment period in patients with OCD. Repeated administration of D-cycloserine may not be as effective as brief administration in enhancing learning and fear extinction during exposure therapy.

A survey of new and recent drugs for the treatment of anxiety disorders leaves much room for further investigation. Although there has been progress in some areas, such as antipsychotic augmentation of treatment-resistant OCD and use of novel agents for GAD, our arsenal of drugs for the treatment of anxiety disorders is currently still limited. Some potential anxiolytic targets that have been long-associated with anxiety in animal models, such as corticotropin releasing factor and neuropeptide Y, have not yet yielded published, controlled efficacy trials. Glutamatergic drugs are another area of active investigation. While we do have effective drug and psychotherapy treatments for each of the anxiety disorders, the field is still waiting for a treatment break-through in the order of magnitude as last seen with the establishment of the SRIs in the 1990s. PP


1.    Pallanti S, Quercioli L. Treatment-refractory obsessive-compulsive disorder: methodological issues, operational definitions and therapeutic lines. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):400-412.
2.    McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH. Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry. 1994;51(4):302-308.
3.    McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57(8):794-801.
4.    Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2003;6(4):397-401.
5.    Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Eur Neuropsychopharmacol. 2005;15(1):69-74.
6.    Bartzokis G, Lu PH, Turner J, Mintz J, Saunders CS. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol Psychiatry. 2005;57(5):474-479.
7.    Reich DB, Winternitz S, Hennen J, Watts T, Stanculescu C. A preliminary study of risperidone in the treatment of posttraumatic stress disorder related to childhood abuse in women. J Clin Psychiatry. 2004;65(12):1601-1606.
8.    Padala PR, Madison J, Monnahan M, et al. Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol. 2006;21(5):275-280.
9.    Monnelly EP, Ciraulo DA, Knapp C, Keane T. Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder. J Clin Psychopharmacol. 2003;23(2):193-196.
10.    Hamner MB, Faldowski RA, Ulmer HG, Frueh BC, Huber MG, Arana GW. Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin Psychopharmacol. 2003;18(1):1-8.
11.    Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66(10):1321-1325.
12.    Pandina GJ, Canuso CM, Turkoz I, Kujawa M, Mahmoud RA. Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial. Psychopharmacol Bull. 2007;40(3):41-57.
13.    Denys D, de Geus F, van Megen HJ, Westenberg HG. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65(8):1040-1048.
14.    Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol. 2002;17(3):115-119.
15.    Carey PD, Vythilingum B, Seedat S, Muller JE, van Ameringen M, Stein DJ. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. BMC Psychiatry. 2005;5:5.
16.    Fineberg NA, Sivakumaran T, Roberts A, Gale T. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol. 2005;20(4):223-226.
17.    Vaishnavi S, Alamy S, Zhang W, Connor KM, Davidson JR. Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1464-1469.
18.    Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry. 2004;65(4):565-568.
19.    Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry. 2004;55(5):553-555.
20.    Butterfield MI, Becker ME, Connor KM, et al. Olanzapine in the treatment of post-traumatic stress disorder: a pilot study. Int Clin Psychopharmacol. 2001;16(4):197-203.
21.    Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002;159(10):1777-1779.
22.    Pollack MH, Simon NM, Zalta AK, et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 2006;59(3):211-215.
23.    Barnett SD, Kramer ML, Casat CD, Connor KM, Davidson JR. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol. 2002;16(4):365-368.
24.    Davis LL, Davidson JR, Ward LC, et al. Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population. J Clin Psychopharmacol. 2008;28(1):84-88.
25.    Tucker P, Trautman RP, Wyatt DB, et al. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(2):201-206.
26.    Lindley SE, Carlson EB, Hill K. A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder. J Clin Psychopharmacol. 2007;27(6):677-681.
27.    Zhang W, Connor KM, Davidson JR. Levetiracetam in social phobia: a placebo controlled pilot study. J Psychopharmacol. 2005;19(5):551-553.
28.    Pollack MH, Roy-Byrne PP, Van Ameringen M, et al. The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin Psychiatry. 2005;66(11):1401-1408.
29.    Davidson JR, Brady K, Mellman TA, Stein MB, Pollack MH. The efficacy and tolerability of tiagabine in adult patients with post-traumatic stress disorder. J Clin Psychopharmacol. 2007;27(1):85-88.
30.    Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry. 2003;64(10):1245-1249.
31.    Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;45(9):1226-1229.
32.    Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs. 2003;12(4):663-672.
33.    Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20(4):467-471.
34.    Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
35.    Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):533-540.
36.    Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;23(3):240-249.
37.    Pohl RB, Feltner DE, Fieve RR, Pande AC. Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol. 2005;25(2):151-158.
38.    Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry. 2005;62(9):1022-1030.
39.    Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771-782.
40.    Feltner D, Wittchen HU, Kavoussi R, et al. Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol. 2008;23(1):18-28.
41.    Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24(2):141-149.
42.    Rickels K, DeMartinis N, Aufdembrinke B. A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. J Clin Psychopharmacol. 2000;20(1):12-18.
43.    Lippa A, Czobor P, Stark J, et al. Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. Proc Natl Acad Sci U S A. 2005;102(20):7380-7385.
44.    Koponen H, Allgulander C, Erickson J, et al. Efficacy of Duloxetine for the Treatment of Generalized Anxiety Disorder: Implications for Primary Care Physicians. Prim Care Companion J Clin Psychiatry. 2007;9(2):100-107.
45.    Rynn M, Russell J, Erickson J, et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety. 2008;25(3):182-189.
46.    Hartford J, Kornstein S, Liebowitz M, et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. Int Clin Psychopharmacol. 2007;22:167-174.
47.    Allgulander C, Hartford J, Russell J, et al. Pharmacotherapy of generalized anxiety disorder: results of duloxetine treatment from a pooled analysis of three clinical trials. Curr Med Res Opin. 2007;23(6):1245-1252.
48.    Russell JM, Weisberg R, Fava M, Hartford JT, Erickson JS, D’Souza DN. Efficacy of duloxetine in the treatment of generalized anxiety disorder in patients with clinically significant pain symptoms. Depress Anxiety. 2008;25(7):E1-E11.
49.    Davidson J, Yaryura-Tobias J, DuPont R, et al. Fluvoxamine-controlled release formulation for the treatment of generalized social anxiety disorder. J Clin Psychopharmacol. 2004;24(2):118-125.
50.    Westenberg HG, Stein DJ, Yang H, Li D, Barbato LM. A double-blind placebo-controlled study of controlled release fluvoxamine for the treatment of generalized social anxiety disorder. J Clin Psychopharmacol. 2004;24(1):49-55.
51.    Stein DJ, Westenberg HG, Yang H, Li D, Barbato LM. Fluvoxamine CR in the long-term treatment of social anxiety disorder: the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial. Int J Neuropsychopharmacol. 2003;6(4):317-323.
52.    Hollander E, Koran LM, Goodman WK, et al. A double-blind, placebo-controlled study of the efficacy and safety of controlled-release fluvoxamine in patients with obsessive-compulsive disorder. J Clin Psychiatry. 2003;64(6):640-647.
53.    Rickels K, Schweizer E, DeMartinis N, Mandos L, Mercer C. Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial. J Clin Psychopharmacol.1997;17(4):272-277.
54.    van Vliet IM, Westenberg HG, den Boer JA. Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder. Psychopharmacology (Berl). 1996;127(2):174-180.
55.    Fresquet A, Sust M, Lloret A, et al. Efficacy and safety of lesopitron in outpatients with generalized anxiety disorder. Ann Pharmacother. 2000;34(2):147-153.
56.    Freeman AM, 3rd, Westphal JR, Norris GT, et al. Efficacy of ondansetron in the treatment of generalized anxiety disorder. Depress Anxiety. 1997;5(3):140-141.
57.    Naukkarinen H, Raassina R, Penttinen J, et al. Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study. Eur Neuropsychopharmacol. 2005;15(6):617-623.
58.    Davis M. Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur J Neurosci. 2002;16(3):395-398.
59.    Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61(11):1136-1144.
60.    Hofmann SG, Meuret AE, Smits JA, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry. 2006;63(3):298-304.
61.    Guastella AJ, Richardson R, Lovibond PF, et al. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry. 2008;63(6):544-549.
62.    Guastella AJ, Dadds MR, Lovibond PF, Mitchell P, Richardson R. A randomized controlled trial of the effect of D-cycloserine on exposure therapy for spider fear. J Psychiatr Res. 2007;41(6):466-471.
63.    Kushner MG, Kim SW, Donahue C, et al. D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol Psychiatry. 2007;62(8):835-838.
64.    Wilhelm S, Buhlmann U, Tolin DF, et al. Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder. Am J Psychiatry. 2008;165(3):335-341.
65.    Storch E, Merlo L, Bengtson M, et al. D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2007;22:230-237.
66.    Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. Int Clin Psychopharmacol. 2005;20(6):291-293.
67.    Dunayevich E, Erickson J, Levine L, et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology. 2008;33(7):1603-1610.


Needs Assessment: Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. It causes a deterioration in patients afflicted. The current agents, though helpful, only diminish the frequency and severity of positive psychotic symptoms by 20% to 30% and have less of an effect on the negative symptoms and the cognitive deterioration. There is a tremendous need to develop novel agents with unique mechanisms of action for the treatment of psychotic disorders.  

Learning Objectives:
• Identify drugs in the pipeline for the treatment of schizophrenia
• Understand the need for new medication treatment of psychotic disorders
• Understand the mechanisms involved in the development of new antipsychotics

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):57-64


Dr. Glick is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in California. Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosures: Dr. Glick is a consultant to Bristol-Myers Squibb, Janssen, Lundbeck, Organon, Pfizer, Shire, Solvay, and Vanda; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen, Pfizer, and Shire; receives research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, Shire, and Solvay; and owns stock in Forest and Johnson and Johnson. Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Off-label disclosure: This article includes discussion of investigational treatments for schizophrenia or psychotic illness.

Please direct all correspondence to: Ira D. Glick, MD, Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University Medical Center, 401 Quarry Rd, Rm 2122, Stanford, CA 94305-5543; Tel: 650-723-3519; Fax: 650-723-2507; E-mail:


Due to the severity caused by schizophrenia, it is important to develop effective treatments. The current antipsychotics, including both typical and atypical, are at best effective only partially effective. Response is usually defined as a 20% to 30% reduction in the positive symptoms (delusions, hallucinations) with a lesser affect on the negative and cognitive symptoms. There has been a tremendous effort to develop newer antipsychotics to improve outcome. This article describes the current antipsychotics in the pipeline being clinically tested. The article also describes preclinical and clinical studies on a variety of agents that affect multiple receptors that are thought to be related to etioilogy.


Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. The conceptualization of psychosis as a “mental illness,” however, has only occurred recently. The development of effective pharmacotherapy began with the development of chlorpromazine in 1952,1 which revolutionized the treatment of schizophrenia. Older agents such as haloperidol and chlorpromazine (first-generation antipsychotics [FGAs]) are very effective for managing the positive symptoms of schizophrenia but display relatively poor long-term efficacy for negative symptoms, mood disturbances, and cognitive deficits. They are also associated with debilitating extrapyramidal symptoms (EPS) and tardive dyskinesia, thus often nullifying their therapeutic effect. There were no new agents approved by the Food and Drug Administration from 1977–1988. However, the introduction of clozapine from Europe in 19892 dispelled the notion that EPS and tardive dyskinesia were inevitable conclusions of antipsychotic therapy.

The FDA approval of clozapine led to a new generation of antipsychotics which seemed to provide a broader range of efficacy (both positive and negative symptoms and less cognitive decline) with a lower risk of EPS and tardive dyskinesia versus the older agents.3 Recent work4 has suggested that the newer agents cause a great risk for the metabolic syndrome—including diabetes, weight gain, and hyperlipidemia—which might be (in the long-run) more problematic than EPS or tardive dyskinesia. Thus, the continuing need for newer, safer, more efficacious antipsychotics continues.

Second-Generation Antipsychotics

The original agents, FGAs or typical antipsychotics, were thought to act by blocking striatal dopamine (D)2 receptors; indeed, the antipsychotic potency was positively correlated with in vitro potency of the D2 receptor.5,6 The evidence for this was that positron emission tomography positively demonstrated that N-methylspiperone (a radiolabeled ligand of the D2 receptor) blocked striatal dopamine receptors.

The second-generation antipsychotics (SGAs) which included risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole were characterized by strong or stronger antagonism for the serotonin (5-HT)2 receptor than for the D2 receptor.6 These newer agents (which also include clozapine) only partially block striatal dopamine receptors and more potently block serotonin receptors in the frontal cortex.

In addition, newer antipsychotics may have more unique actions. They appear to enhance glutamatergic function at the N-methyl-D-aspartate (NMDA) receptor and block the behavioral and physiologic effects of phencyclidine, a non-competitive NMDA receptor antagonist that produces a syndrome in normal individuals that closely mimics schizophrenia.7 In addition, SGAs, while alike, often show differences that may lead one to different mechanistic possibilities. For example, aripiprazole is a high affinity partial agonist of the dopamine receptor. It displays both dopamine agonist and antagonist properties.8 The partial dopamine agonist may thus reduce dopamine synthesis and release by stimulating presynaptic dopamine autoreceptors. They may also diminish the dopaminergic signal at postsynaptic sites by competing with dopamine for postsynaptic receptors.9

Newer Drugs and Strategies in Schizophrenia

A fundamental barrier to the discovery of novel treatments remains that our level of the biologic processes involved in schizophrenia is not sufficient to predict the therapeutic value of novel drug targets. Newer agents usually represent drugs that hit known and validated targets (“me too type drugs”). It is important to note that it is important to look at specific symptoms in schizophrenia. FGAs and SGAs are efficacious in treating the positive symptoms (delusions, hallucinations, thought disorganization, and loose associations), but even here the response rate is 67% to 75% with response being a 20% to 30% reduction in overall symptoms.

However, it is the negative symptoms (alogia, avolition, flat affect, and anhedonia) along with cognitive impairments that contribute disproportionately more to the long-term disability in patients with schizophrenia.10 The negative symptoms lead to particularly poor functional capacity and quality of life. Despite the fact that there was high optimism that the SGAs represented a breakthrough for the treatment of negative symptoms, a complete response has not been shown clinically.4,11 The cognitive impairments are significant in that patients with schizophrenia have been known to have documented problems with attention, working memory, and learning in addition to executive level functions such as abstract thinking and problem solving.12,13 Thus, improved efficacy with negative symptom relief and improvement in cognition remains unsolved.

Dopaminergic Approaches

Of note, all marketed drugs to date have efficacy at the D2 receptor. Many of the drugs in Phases II and III clinical trials have the same mechanism of action as the already available agents, that is, 5-HT2A and D2 antagonism.


Iloperidone, which is currently in placebo-controlled, phase III trials, affects multiple receptor sites. It is an antagonist at D2 and D3 receptors, as well as an antagonist at the 5-HT2A and 5-HT1A receptor site. It has had a long developmental process after being dropped by Novartis due to concerns that the drug may cause cardiac arrhythmias (specifically, it might increase the QT interval of the heartbeat). A study14 in the November 2001 issue of Psychiatric Times noted no cardiac abnormalities in 10 patients receiving 0.5–6.0 mg of iloperidone; however, this is an extraordinarily small sample size, and the study was sponsored by Novartis. In other words, these safety concerns have yet to be resolved in the public domain. However, iloperidone is still in development (currently in phase III FDA clinical trials). Because it acts as an antagonist on many different receptors—including several different classes of dopamine, serotonin, and norepinephrine receptors—it has the potential to alleviate a wide range of symptoms.


Bifeprunox was in phase III clinical trials until recently. It is a partial dopamine agonist/antagonist as well as a serotonin receptor agonist. It is expected that partial dopamine agonist action will have beneficial effects for positive, negative, and cognitive symptoms, while the serotonergic agonist action will help alleviate some side effects and possibly combat depression and anxiety that can accompany schizophrenia treatment. Early results report little to no weight gain, and no cardiac effects or EPS. Efficacy was uncertain, and the company investigating it has discontinued the trials.


Blonanserin [AD 5423] is a combined D and 5-HT receptor antagonist currently undergoing development in Japan with Dainippon Sumitomo Pharmaceutical as a potential antipsychotic. Blonanserin is unrelated structurally to typical antipsychotics or to newer agents such as risperidone. It is hoped that the combination of receptor blockade possessed by blonanserin will be effective against both the positive and negative symptoms of schizophrenia, with a low tendency to cause EPS. Blonanserin is expected to have minimal sedative and hypotensive effects, as its adrenaline receptor-blocking function is weak.

Dainippon is conducting phase III clinical trials with oral formulations (tablet and powder) of the compound in psychotic disorders in the United States.


Ocaperidone is a D2 and 5-HT antagonist. Due to the dual-action mechanism of the drug, early research reports it to have “haloperidol-like effects” on the positive symptoms of schizophrenia, but with a lower incidence of EPS (more like the side-effect profile of risperidone). Neuro3d, the France-based developers of the medication, report that they are nearing the end of phase II clinical trials.


Nemonapride (international nonproprietary name [INN]; tradename Emilace) is a dopamine receptor antagonist approved in Japan for the treatment of schizophrenia. Its mechanism of action is proposed to involve both D2 and D3 antagonism Nemonapride is a substituted benzamide antipsychotic with general antipsychotic properties–with effects on positive and negative symptoms of schizophrenia. The average daily dose of nemonapride was 18 mg/day. Plasma prolactin concentrations are significantly (P<·01) increased.


Perospirone (INN; trade name Lullan) is a neuroleptic in Japan. It is a D and 5-HT2A receptor antagonist. Clinical trials show that EPS tend to occur less often and were generally milder than with haloperidol.


Zuclopenthixol (marketed as Cisordinol, Clopixol, or Acuphase) is a typical antipsychotic neuroleptic of the thioxanthene group. It mainly acts by antagonism of D1 and D2 receptors, though it also has some antihistamine activity. It is produced and marketed by Lundbeck pharmaceutical company. It is available in three forms, namely, zuclopenthixol decanoate (clopixol), a long-acting intramuscular injection; zuclopenthixol acetate (clopixol acuphase), a shorter-acting intramuscular injection; and zuclopenthixol dihydrochloride (clopixol tablets), a tablet taken orally. Side effects, such as EPS and elevated prolactin levels, are similar to many other typical antipsychotics. In addition, the taking the drug may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Zuclopenthixol is available wordwide. None of the findings suggest any clear difference between zuclopenthixol and other typical antipsycotics across a wide range of adverse effects. When compared with the newer generation of drugs, those taking zuclopenthixol were associated with no greater risk of being unchanged or worse compared with those taking risperidone.


Lurasidone is an atypical antipsychotic in Japan. As of 2008, it is undergoing a Phase III clinical trial. Lurasidone blocks D1, D2 and 5-HT2A receptors. It seems to cause fewer EPS than current antipsychotics.


ACP-104, or N-desmethylclozapine, is the major metabolite of clozapine and is being developed by ACADIA as a novel, stand-alone therapy for schizophrenia. It combines an atypical antipsychotic efficacy profile with the added potential benefit of enhanced cognition, thereby addressing one of the major challenges in treating schizophrenia today. ACP-104 combines muscarinic (M)1 agonism, 5-HT2A inverse agonism, and D2 and D3 partial agonism in a single compound and, therefore, uniquely addresses what ACADIA believes are the three most promising target mechanisms for treating schizophrenia. As of this writing it is in phase II clinical trials. Two clinical studies15,16 showed the drug was safe with the major side effects being sleepiness, increased salivation, constipation, and tachycardia. No significant changes were observed in safety parameters such as electrocardiograph measures (including QT/QTc interval) and clinical chemistries. No EPS were observed in the patients. The Phase IIb study of ACP-104 for the treatment of schizophrenia did not meet its primary endpoint of antipsychotic efficacy (improvement in Positive and Negative Syndrome Scale (PANSS) or any of the secondary endpoints). Neither dose of ACP-104 600 mg or 800 mg demonstrated improved efficacy compared to a placebo. The drug’s future is uncertain.


BL-1020 is an orally available gamma-aminobutyric acid-enhanced antipsychotic clinical candidate for the treatment of schizophrenia. It is a dopamine receptor antagonist. Data from preclinical and Phase I studies demonstrated that the compound may retain the efficacy of currently available typical and atypical antipsychotics while achieving a much higher safety profile as evidenced by a lack of metabolic or EPS. In an open-label, multi-center, 6-week trial17 conducted in hospitalized patients with treatment-resistant schizophrenia, BL-1020 showed statistically significant efficacy with minimal side effects. Overall, BL-1020 treatment reduces the PANSS total score by 26.1 points from the baseline (P<.001; baseline=85.6, day 42=58.2). There was a significant (P<.001) improvement in PANSS negative score by 7.1 points when compared to baseline values (baseline=20.5, day 42=13.4). Furthermore, computer-generated imagery results showed that 92.35% of patients improved by at least one category by the end of this part of the study.


RGH-188 (INN; generic cariprazine), discovered by researchers at Gedeon Richter, is a novel antipsychotic which preferentially binds to D3 receptors and acts as a dopamine system stabilizer. It is also a D2 antagonist. A phase II study18 involving 389 schizophrenia patients. evaluating a primary endpoint change from baseline to Week 6 on the PANSS and RGH-188 demonstrated a nominally statistically significant (ie, not adjusted for multiple comparisons) therapeutic effect compared to placebo in the treatment of schizophrenia in the low-dose arm and a numerical improvement compared to placebo in the high dose arm that did not reach nominal statistical significance. RGH-188 was generally well tolerated and overall premature discontinuation rates (all causes including adverse event related) were 47% for patients receiving low dose of RGH-188 up to 4.5mg/day, 46% for patients receiving high dose RGH-188 up to 12 mg/day, and 47% for patients receiving placebo.


ACR-325 is a dopaminergic stabilizer (primarily a dopamine agonist), a new class of compounds with a unique ability to either enhance or inhibit dopamine-controlled functions depending on the initial level of dopaminergic activity. ACR-325 has also demonstrated an ability to strengthen the glutamatergic and noradrenalinergic (agonistic) functions, which is an important aspect in novel treatments of psychosis and motor dysfunctions.

In June 2008 NeuroSearch has completed Phase I evaluation ACR-325 with a highly positive outcome. The results of single- and multiple-dose studies19 in healthy volunteers show that ACR-325 has a linear and predictable pharmacokinetic profile after oral administration. Further, the compound proved very well tolerated at doses and plasma levels exceeding by far the predicted therapeutic levels.


SLV-313 is a combined D2 receptor antagonist and 5-HT1A receptor agonist that may improve efficacy and alleviate some side effects associated with classical antipsychotics. As a full 5-HT1A receptor agonist and full D2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, it represents a potential novel treatment for schizophrenia. A phase I study randomizing patients to fixed doses of 2 mg, 5 mg, and 10 mg is currently underway.


YKP-1358 is a novel 5-HT2A and D2 antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. It is currently undergoing phase I trials.


Asenapine is a 5-HT and D2 antagonist, part of a class of atypical antipsychotics that have typically been more effective than medications that act only at D2 receptors. For example, clozapine, risperidone, and olanzapine all have serotonin-dopamine antagonist properties, and these drugs are popular for their low incidence of side effects (particularly EPS) and their efficacy against both positive and negative symptoms. Early data from previous trials shows good tolerability and superior efficacy when tested against placebo. Schering-Plough Corp. acquired Organon in 2007—now asenapine is currently pending FDA approval for both mania and schizophrenia.

The problem with the above drugs is that they have the same mechanism of action as the already available agents.

Attempts to Look at Various Neurotransmitter Systems to Develop New Antipsychotics

Other Dopamine Strategies: D1, D3, and D4 Receptors

The D1 receptor plays an important role in schizophrenic illness as it is thought to have a role in cognitive dysfunction.20 Chronic blockade of D2 receptors leads to down regulation of D1 receptors in the prefrontal cortex, and this produces severe working memory impairment in non-human primates. Thus, novel compounds targeted at stimulating the D1 receptor may be of great value in treating the cognitive symptoms of schizophrenia. Many drugs have been proposed, such as ZD-3638, a 5-HT2A/D2, D1 agent developed by AstraZeneca in phase II development; BSF-78438 (Abbott); and LE-300 (sanofi-aventis), the latter two in preclinical development.21

The D3 receptor is structurally similar to the D2 receptor and is, thus, a target for drug development. Interestingly, a study evaluating drug-free schizophrenics found elevated levels of D3 receptors with normal D2 receptors. A few agents are being evaluated. A-437203 is undergoing Phase II trials as is SB-773812. BP 4.879a (Bioproject), SB-277011 (GlaxoSmithKline), PD 157533 (Pfizer), U 99194A (Pfizer), and PNU 177864 are in preclinical development. The potential antipsychotic efficacy of D3 receptor antagonists remains unknown at this time but there is some suggestion that D3 receptor antagonists have a role in improving negative symptoms22 and working memory.23

The D4 receptor was initially cloned. It was noted that clozapine had a higher affinity for this receptor than for the D2 receptor, leading to speculation that the D4 receptor might be the receptor responsible for clozapine’s unique enhanced efficacy.24 However, clinical trials have not yet demonstrated any appreciable evidence of efficacy of D4 receptor antagonists in the treatment of schizophrenia.25,26 These clinical failures suggest that selective D4 antagonism alone is not responsible for the unique antipsychotic efficacy of clozapine but it is possible that D4 antagonism along with the action of other neurotransmitter receptors may be important in treating psychosis. There is some suggestion that D4 antagonism may play an important role in impulsivity and working memory.24 Pfizer has three D4 agents in clinical development, namely, PD 165167, PD 172760, and U99363E.

Serotonergic Issues

Since the atypical antipsychotics bind with higher affinity to the 5-HT2A receptors versus dopamine receptors, selective 5-HT2A receptor antagonists have been evaluated as possible antipsychotics.

Eplivanserin: A 5-HT2A/2C Receptor Antagonist

Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Reductions in the PANSS total and negative scores in the group receiving the 5-HT2A/2C antagonist were equal to haloperidol and were significantly larger than those in the group receiving placebo.27

Another 5-HT2A selective antagonist, M100907, though more effective than placebo in two cumulative studies, was not as effective as haloperidol.28

The above studies suggest that although 5-HT2A receptor antagonists have antipsychotic properties, they are not superior to D2 antagonists. It does appear that 5-HT2A receptor antagonists may help with negative symptoms by elevating dopamine in the mesocortical region.29

5-HT1A agonists like clozapine have been suggested to boost dopamine levels in the prefrontal cortex. This may be responsible for clozapine’s efficacy with respect to negative symptoms and cognitive dysfunction in schizophrenics. So far, attemts to develop 5-HT1A agonists have not replicated the clinical efficacy profile of clozapine.30

The 5-HT2C, 5-HT4, and 5-HT6 receptors have also been targets of antipsychotic drug development. Selectively of the 5-HT2C receptor by decreasing dopamine in the mesolimbic and mesocortical region but not the nigrostriatal region suggests it might have antipsychotic efficacy without EPS.29 Since the 5-HT2C receptor antagonism has been shown to cause weight gain, a 5-HT2C receptor agonist may be useful in reducing food intake and weight in patients.31

The 5-HT4 receptor is prominent in the hippocampus, frontal cortex, and amygdala. This receptor is decreased in Alzheimer’s disease and, thus, 5-HT4 receptor agonists may be helpful in schizophrenia with the mechanism of increasing cholinergic transmission in the hippocampus. Thus, there is the possibility that these agents may be helpful in the cognitive dysfunction in schizophrenics.32 The affinity of clozapine and olanzapine on the 5-HT6 receptor, which preclinically improves cholinergic neurotransmission, may help with the neurocognitive deficits in schizophrenia.33

To date, human clinical studies involving the 5-HT1A, 5-HT2C, 5-HT4, and 5-HT6 agents have not been published.

Other Receptors

Alpha-adrenergic receptors may play a role in improving the cognitive functioning for schizophrenics. Indeed, alpha-adrenergic-2 receptor agonists such as clonidine and guanfacine have shown some efficacy in improving cognitive function in schizophrenics when added to standard antipsychotics.34,35 The problem with this is many alpha-adrenergic-2 receptor antagonists are traditional antipsychotics and thus a choice between alpha-adrenergic-2 receptor agonism and antagonism will be challenging.

Cholinergic Agents

Acetylcholine is important in various domains of cognition, including attention, learning, and memory. Cholinergic dysfunction is central to the treatment of Alzheimer’s disease as cholinesterase inhibitors have been shown to slow down the cognitive decline of Alzheimer’s disease and other neurodegenerative disease.36 These agents have been hypothesized to help with respect to cognitive dysfunction in schizophrenia, but the results have been disappointing.37

Muscarinic Acetylcholine Receptors

There are five types of muscarinic receptors (M1–M5), with M1 the most closely linked to schizophrenia. Clozapine and its metabolite N-desmethylclozapine bind to the M1 receptor with N-desmethylclozapine acting as a potent agonist.38

Xanomeline, an agonist at the M1 and M4 receptor with activity at 5-HT1A and 5-HT2A receptors, has shown improvement with active psychotic symptoms in a double-blind, placebo-controlled study39 assessing 10 patients receiving xanomeline versus 10 patients receiving placebo. Patients on xanomeline showed greater improvement on Brief Psychiatric Rating Scale (BPRS) and PANSS scores as well as verbal learning and short-term memory function compared with placebo.

Nicotinic-acetylcholine receptors have shown interest as schizophrenics have been shown to have significantly higher smoking rates than normal control40 and smoking has been shown to improve various measures of cognition while easing the side effects of antipsychotics.40 Considerable efforts are being made to explore the potential use of nicotinic agents in the treatment of schizophrenia.

Glutamate in Schizophrenia

The role of glutamate in schizophrenia is complex. Since phencyclidine and ketamine—both NMDA antagonists—may cause psychotic symptoms as well as worsen cognition and negative symptoms, it has been hypothesized that schizophrenia may be related to NMDA hypofunction.41 However, it is also thought that hyperactivity of the NMDA receptor may alleviate psychosis.

The NMDA receptors are ligand-gated ion channels with both a primary glutamate-binding site and an allosteric glycine-binding site. In view of the fact that a direct agonist to the glutamate-binding site may cause excessive excitation possibly giving rise to seizures, the glycine-binding site on the NMDA receptor has been the focus of much attention in the development of new antipsychotics.

NMDA receptor agonists attaching to the glycine site have been evaluated. These include the amino acids such as glycine, D-cycloserine, D-serine, and D-alanine. These agents have been added to either typical or atypical antipsychotics and show some significant benefits in reducing negative symptoms and cognitive impairment in schizophrenia.42

Other attempts to increase glycine is by inhibiting the glycine transporter. A low-potency glycine transport inhibitor, sarcosine, has been investigated in relation to schizophrenia. Early evidence suggests that intake of sarcosine 2 g/day as add-on therapy to certain antipsychotics43 in schizophrenia gives significant additional reductions in both positive and negative symptomatology as well as the neurocognitive and general psychopathologic symptoms that are common to the illness. This was not found to be the case when sarcosine was added on to clozapine.44 Sarcosine has been tolerated well. It is also under investigation for the possible prevention of schizophrenic illness during the prodromal stage of the disease. It acts as a type 1 glycine transporter inhibitor. It increases glycine concentrations in the brain, thus causing increased NMDA receptor activation and a reduction in symptoms. As such, sarcosine and other glycine transporters might be interesting treatment options and a possible new direction in the treatment of schizophrenia in the future.

Glutamate Receptor

The glutamate receptor family is subdivided into ionotropic receptors and metatropic receptors which activate G-protein coupled intracellular metabolic processes.45 NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate are ionotropic receptors. The NMDA receptor is mainly coupled to the calcium channel while AMPA and kainate are coupled to sodium channels. Allosteric potentiation of the AMPA receptor by a group of compounds known as ampakines may help in alleviating some symptoms of schizophrenia. Indeed, the ampakine CX-516, when added to clozapine, yielded significant improvement in memory and attention,46 although when given as monotherapy it had no benefit.47

Currently, there are eight metabotropic receptors divided into three classes. Group 1, classified as mGLU R 1 and mGLU R 5, uses inositol 3P as its second messenger; Group 2, classified as mGLU R 2 and mGLU R 3, uses cyclic adenosine monophosphate (cAMP) as its second messenger; Group 3, which includes mGLU R 4, mGLU R 6 (mainly confined to the retina), mGLU R 7, and mGLU R 8, also uses cAMP as its second messenger. Selective allosteric modulators of these mGLU R receptors are being examined in schizophrenia.

Neurokinin Receptors

First identified in the 1930s, neurokinins are neurotransmitters found in the substantia nigra and striatum areas of the brain. Unlike most of the neurotransmitters identified to date, they are made from peptides rather than amino acids. They are believed to be involved in the control of movement. Their potential as therapeutic targets for drug development has only recently been suggested, but these receptors are seen as an area of rich research. The neurokinins NK1 and NK3 have been identified as suitable targets for drug development. Several antagonists to these neurokinins are now in development. Talnetant and osanetant are the two NK3 antagonists in development for schizophrenia.

NK1 has been studied with respect to depression but NK3 receptor antagonists have been evaluated in the treatment of schizophrenia. In one study,27 the group receiving the NK3 antagonist osanetant showed significantly greater improvement over baseline than the group receiving placebo as measured by PANSS total score, Clinical Global Impressions (CGI) severity of illness score, and BPRS psychosis cluster score. Talnetant has not been evaluated in clinical studies with respect to schizophrenia.

Cannabinoid Receptors

In view of the fact that there appears to be significant correlation between prior cannabis use and the development of schizophrenia, the study of the endogenous cannabinoid system has been of interest.48,49 There are two cannabinoid receptors, namely, CB1 and CB2. A selective CB1 antagonist SR 141716, while showing some preclinical antipsychotic efficacy, did not show antipsychotic efficacy versus placebo.27

Neurotensin Receptors

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. There is evidence that since neurotensin agonists may reverse amphetamine-induced effects on hyperactivity, neurotensin may have a potential for use in schizophrenia. Clinical trials on neurotensin agonists need to be evaluated. Since there is neurotensin tone in schizophrenia, a neurotensin antagonist may be useful in schizophrenia. A recent study,27 however, showed that the neurotensin antagonist compared with haloperidol and placebo did not equal the group receiving haloperidol or differ from the group receiving placebo on any outcome measure (PANSS total score, CGI severity of illness score, and BPRS psychosis cluster score).


Generally, with clozapine being the ideal drug, it seems we need to develop drugs that mirror clozapine without its side-effect profile. Clozapine as the “ideal drug” has affinities for numerous receptors, including 5-HT1A, 5-HT2A, 5-HT2C, D1, D2, D3, D4, alpha-1, alpha-2, M1, M2, and H1 receptors. It would seem that this might require the use of polypharmacy and augmentation strategies, but the hope is for the development of non-selective single compounds that can target multiple domains, while decreasing side effects. Pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia. PP


1.    Delay J, Deniker P, Harl JM. Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP). Ann Med Psychol (Paris). 1952; 110(2:1):112-117.
2.    Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988;24(1):62-67.
3.    Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia.Psychoneuroendocrinology. 2003;28:(suppl 1):9-26.
4.    Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
5.    Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217-1219.
6.    Creese I, Burt DR, Snyder SH. Dopamine receptors and average clinical doses. Science. 1976;194(4264):546.
7.    Bakshi VP, Geyer MA. Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology (Berl). 1995;122(2):198-201.
8.    Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302(1):381-389.
9.    Tamminga CA. The science of antipsychotics: mechanistic insights. CNS Spectr. 2003;11(9 suppl 2):5-9.
10.    Agid Y, Buzsáki G, Diamond DM, et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 2007;6(3):189-201.
11.    Swartz MS, Perkins DO, Stroup TS, et al. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428-436.
12.    Keefe RS, Bilder RM, Harvey PD, et al. Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006;31(9):2033-2046.
13. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005;28(3):613-633,
14.    Bender KJ. Investigational agents and methodologies at NCDEU. Psychiatric Times. 2001;18(11):40.
15.    Mauri M, Volonteri LS, Fiorentini A, et al.  Clinical outcome and plasma levels of clozapine and norclozapine in drug-resistant schizophrenic patients. Schizophr Res. 2004;66(2-3):197-198.
16.    Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S Evaluation of N-desmethylclozapine as a potential antipsychotic–preclinical studies. Neuropsychopharmacology. 2007;32(7):1540-1549.
17.    Geffen Y, Nudelman A, Gil-Ad I, et al. BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia. Eur Neuropsychopharmacol. 2008 Aug 29 [Epub ahead of print].
18. Safety and Efficacy of RGH-188 in the Acute Exacerbation of Schizophrenia. Available at: Accessed November 18, 2008.
19.    NeuroSearch. ACR325. Available at: Accessed November 18, 2008.
20. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl). 2004;174(1):3-16.
21.    Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007;12(10):904-922.
22. Reavill C, Taylor SG, Wood MD, et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther. 2000;294(3):1154-1165.
23.    Laszy J, Laszlovszky I, Gyertyán I. Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005;179(3):567-575.
24.    Tarazi FI, Zhang K, Baldessarini RJ. Dopamine D4 receptors: beyond schizophrenia. J Recept Signal Transduct Res. 2004;24(3):131-147.
25.    Kramer MS, Last B, Getson A, Reines SA. The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry. 1997;54(6):567-572. Erratum in: Arch Gen Psychiatry. 1997;54(12):1080.
26. Corrigan MH, Gallen CC, Bonura ML, Merchant KM; Sonepiprazole Study Group. Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry. 2004;55(5):445-451.
27. Meltzer HY, Arvanitis L, Bauer D, Rein W; Meta-Trial Study Group. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry. 2004;161(6):975-984.
28.    de Paulis T. M-100907 (Aventis). Curr Opin Investig Drugs. 2001;2(1):123-132
29. Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113(2):296-320.
30. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3(4):353-359.
31. Zieba R. Obesity: a review of currently used antiobesity drugs and new compounds in clinical development]. Postepy Hig Med Dosw (Online). 2007;61:612-626.
32. Roth BL, Hanizavareh SM, Blum AE. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl). 2004;174(1):17-24.
33. Reavill C, Rogers DC. The therapeutic potential of 5-HT6 receptor antagonists. Curr Opin Investig Drugs. 2001;2(1):104-109.
34.    Fields RB, Van Kammen DP, Peters JL, et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;1(6):417-423.
35.    Friedman JI, Adler DN, Howanitz E, Harvey PD, Brenner G, Temporini H, White L, Parrella M, Davis KL. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry. 2002;51(5):349-357.
36.    Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1-2):28-46.
37.    Ferreri F, Agbokou C, Gauthier S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci. 2006;31(6):369-376.
38.    Sur C, Mallorga PJ, Wittmann M, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003;100(23):13674-13679.
39.    Shekhar A, Potter WZ, Lightfoot J, et al Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039.
40.    Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29(6):1021-1034.
41.    Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984-997.
42.    Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19(2):151-157.
43.    Tsai G, Lane H, Yang P, Chong M, Lange N. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia”. Biol Psychiatry. 2004;55(5):452-456.
44.    Lane H, Huang C, Wu P, et al. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia”. Biol Psychiatry. 2006;60(6):645-649.
45.    Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29.
46.    Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001;21(5):484-487.
47.    Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, Weinberger DR. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002;57(2-3):221-226.
48.    Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull. 2005;31(3):608-612.
49.    Vinod KY, Hungund BL. Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders. Expert Opin Ther Targets. 2006;10(2):203-210.


Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.
Disclosure: Dr. Luo is consultant to S.M.A.R.T. Link Medical, Inc., on the speaker’s bureau of Epocrates, and on the advisory board of Spyglass Consulting.


Today’s computers actually have more power and memory than most users need. Ten years ago, a high-end computer with the fastest processor, most memory, and large capacity hard drive would cost over $3,000, destined primarily for computer gamers and video editing. Today, even the most basic computers (under $1,000) have sufficient computing power for the majority of users, who typically only use office productivity software such as a word processor, spreadsheet, and database programs, as well as a Web browser to access information on the Internet. As health information and medical software increasingly become Web based, such as the National ERx initiative,1 maximizing the Web-browsing experience has become a must for medical professionals.


The medical office needs a variety of tools, which have increasingly become dependent on the Internet for delivery. Today’s practice can no longer maintain high levels of productivity with just practice management software and a word processor for documentation. Electronic communication with patients is increasingly becoming the norm, and eventually Web-based appointment scheduling will be the predominant appointment booking method. Patients will rely more upon e-mail appointment reminders with subsequent integration into their iPhone or Blackberry calendar than the traditional phone call confirmation. Just as the need for intense computing power has diminished over the years, the medical office will depend less upon medical software and information installed on office-based computers and rely heavily on subscriptions to Web-based applications such as electronic health records.

There are many reasons for this switch from office-based computing to Web-based delivery. Access is easier for multiple providers at different locations if the electronic health record system is centralized on the Internet. Timely backup and data integrity is improved since the busy practice manager or physician is no longer responsible for daily backup of records, billing, and scheduling. Communication between multiple health plans and healthcare service providers to streamline financial, clinical, and administrative transactions has now gone online. To enhance the experience with these services requires the optimization of the Web browser.


In the medical setting, the security of the browsing experience is of paramount importance beyond the Health Insurance Portability and Accountability Act. Although the Web is a portal to web-based medical software and medical information, it is also the gateway for vulnerability of computers to viruses and hackers. Phishing is the type of attack that uses both social engineering and technical subterfuge to steal personal identity data and financial account credentials.2 These social-engineering schemes use “spoofed” e-mails, which appear to be from a credible Website, to lead victims to counterfeit Websites designed to trick them into divulging financial data or providing account information. Medical offices are vulnerable because they often have demographic information such as social security number, birthday, and address that hackers may use for other purposes. Technical subterfuge schemes implore users to click on a button on a Website, which plants “crimeware” onto computers. This software, usually a Trojan keylogger, basically captures keystrokes and sends them to phishers so that they can steal information directly.

AntiPhishing.org3 provides general advice to consumers to avoid phishing tactics. These include recommendations such as not to use links embedded in e-mails if there is suspicion that the e-mail is not authentic, and checking on the URL to determine if the site is authentic. Even the yellow lock on a URL and its “https://” can be forged by phishers. It is highly recommended that instead of clicking on e-mail links, enter the web site URL directly in the browser to avoid being sent to a phishing site.

There are a variety of tools to avoid phishing sites. Earthlink4 and Netcraft5 provide free toolbars that can be embedded into Internet Explorer or Firefox browsers to alert users if they have entered a site that may be risky. GreenBorder is a Windows-based Web browser that provided secured browsing by using virtualization technology to keep the Web browser from being hijacked and taking over the operating system. Google purchased GreenBorder in 2006, and its developers helped contribute to Google’s own Web browser, Chrome.6

Chrome is an open-source browser compiled by Google from a variety of sources.7 It uses components from Apple’s WebKit, which is incorporated into Apple’s Safari browser, and elements from Mozilla’s Firefox. These components have been tweaked to run complex Web applications better and to run clean as well as fast. Elements from GreenBorder’s technology help Chrome keep each tab in a secure “sandbox” so that they do not crash the browser and improve protection from phishing sites. At present, this product is still in beta and only for the Windows operating system, but Mac OS X and Linux versions are promised.

Microsoft has not been idly watching the secure browsing phenomenon. The new version 8 of Internet Explorer (IE8), now in beta testing, also offers secure Web browsing features.8 IE8 has a SmartScreen Filter that detects phishing sites, and domain highlighting which focuses the user’s attention to the domain name in the URL to spot misleading addresses.


Even 20 seconds waiting for a Website to load can create frustration for the medical office. Google’s Chrome browser and Microsoft’s IE8 are faster than earlier versions of Internet Explorer and Mozilla’s Firefox by incorporating various technologies to enhance the speed of access to information. Chrome has a simple interface and a revamped JavaScript engine to improve speed of Web-based applications. Application shortcuts in Chrome are specialized windows in the Chrome browser just for Web applications. They can be invoked from the desktop once the shortcut is created and they also do not display tabs, menus, and the address bar to maximize the application speed and appearance. IE8 has “Web slices,” which are favorite Websites that are routinely checked by IE8 for updates and then highlighted for the user. IE8 also has Web accelerators, installed mini-applications that help users copy information on one Website to be used on another with one click.

Fans of Firefox who desire speed but do not want to give up their favorite browser still have options. For the Microsoft Windows operating system, K-Meleon9 is an extremely fast, lightweight Web browser based on the Gecko layout engine used in Firefox. For Mac OS X, Camino10 is a specifically compiled web browser based on the same Gecko engine. These browsers, in essence, are similar to Firefox but have fewer features and add-ons. Additionally, their tighter integration with the specific operating system makes a significant improvement in speed.


One of the issues with current Web browsers is many users have important bookmarks on home computers and work computers, and it is a challenge to synchronize the two. An easy solution for Firefox Web browser users is Foxmarks.11 This product is a free add-on extension to the Firefox browser that enables users to synchronize specific bookmarked sites between different computers as well as access and edit these bookmarks online from a third computer. Bookmarks can be shared between members as well as accessed on a mobile device such as an iPhone. Bookmarks are saved on the server, which functions as a backup. For Internet Explorer, there are many services that work as Foxmarks, but BookmarkSync12 is recommended because it can sync between IE and Firefox.

For the adventurous, to share bookmarks is a novel way to discover new Websites that have relevant information. Stumbleupon13 is a Website where members rate other Websites with a thumb up or down and then share this opinion with friends. Stumbleupon will then recommend Websites based on search topics chosen by users. Delicious.com14 is another popular bookmark-sharing Website. Here, users bookmark Websites and tag them on search terms of their own choosing. Users can then create their own network of colleagues with whom to share favorite Websites or they can search for Websites tagged by other members based on keywords.

Web Applications

As mentioned in a previous “Tech Advisor,”15 there are numerous Web-based office productivity software programs such as Google Docs16 and Thinkfree.17 These Web applications free users from dependence on specific productivity software on a computer as well as from carrying files on a USB flash drive. One advantage of using Google Docs is that a Microsoft PowerPoint presentation slideshow can be run directly from the Web browser. Glide OS18 takes this premise one step further toward desktop replacement. Glide OS offers Microsoft Office-compatible programs for word processing, spreadsheets, and presentations, but also offers photo and video management, e-mail, calendar, contact manager, and bookmark management. Eye OS19 is another desktop “operating system” where all software functions on a computer are delivered via the Web browser. Eye OS offers its software via the GNU Affero Public License version 3, which means that one can have one’s own private eye OS server for family, company, or network completely free. The source code is available and with eye OS development tools. The software can be customized with new applications that fit specific needs.


At first thought, the Web browser appears to be a limited tool for medical information and office management. However, with proper customization, it can be the portal to all functions of the medical office such as communication with health insurance companies using NaviNet,20 an electronic medical record system such as ValentMed,21 e-prescribing with NationalERx,1 medication information with Epocrates Online,22 and numerous medical content sites such as PsychiatryOnline.23 Once WiMax, the full wireless Internet for mobile access, arrives, basic Internet tablet devices and inexpensive ultramobile PCs may be sufficient for the daily medical practice. PP


1.    National ERx. National ePrescribing Patient Safety Initiative. Available at: Accessed October 8, 2008.
2.    APWG. What is Phishing and Pharming? Available at: Accessed October 8, 2008.
3.    APWG. Consumer Advice: How to Avoid Phishing Scams. Available at: Accessed October 8, 2008.
4.    Earthlink Toolbar. Available at: Accessed October 8, 2008.
5.    Netcraft Toolbar. Available at: Accessed October 8, 2008.
6.    Methvin D. Google chrome answers the greenborder mystery. Information Week. September 1, 2008. Available at: Accessed October 8, 2008.
7.    Google Chrome. A fresh take on the browser. Available at: Accessed October 8, 2008.
8.    Internet Explorer 8: More secure, private, and reliable. Available at: Accessed October 8, 2008.
9.    K-Meleon. Available at: Accessed October 8, 2008.
10.    Camino. Available at: Accessed October 8, 2008.
11.    Foxmarks. Available at: Accessed October 8, 2008.
12.    BookmarkSync. Available at: Accessed October 8, 2008.
13.    StumbleUpon. Available at: Accessed October 8, 2008.
14.    Delicious. Available at: Accessed October 8, 2008.
15.    Luo JS. Free Software Tools for the Medical Practice. Primary Psychiatry. 2007;14(6):23-28.
16.    Google Docs. Available at: Accessed October 8, 2008.
17.    ThinkFree. Available at: Accessed October 8, 2008.
18.    Glide OS. Available at: Accessed October 8, 2008.
19.    Eye OS. Available at: Accessed October 8, 2008.
20.    NaviNet. Available at: Accessed October 8, 2008.
21.    ValantMed. Available at: Accessed October 8, 2008.
22.    Epocrates Online. Available at: Accessed October 8, 2008.
23.    Psychiatry Online. Available at: Accessed October 8, 2008.


Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosure: Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Please direct all correspondence to: Eric D. Peselow, MD, Research Professor, School of Medicine, Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016-8304; Tel: 917-376-6755; Fax: 718-763-1677; E-mail:


Over the past 50 years, psychotropic agents have revolutionized the field of psychiatry. With the discovery of lithium,1 typical antipsychotics,2 tricyclic antidepressants,3 and benzodiazepine anxiolytics,4 psychiatry has advanced from a psychoanalytic to a biologic field. The discovery of newer agents for mood stabilization (carbamazepine, divalproex sodium), atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and buspirone has led to incremental improvement in treating these disorders. However, despite these remarkable advances, a large number of patients still do not respond to treatment. This issue discusses agents currently being tested for major psychiatric syndromes.

Eric D. Peselow, MD, and colleagues evaluate historic treatments that are no longer used, holistic medical techniques involving an orthomolecular strategy, and “natural” herbal products which are used despite lack of evidence-based trials. In addition, the authors assess the current state of these agents to identify whether these agents will prove to be safe and effective in various disorders or whether they will pass into history.

Yujuan Choy, MD, and  Franklin R. Schneier, MD, present findings of recent controlled trials that examine the evidence of efficacy of various classes of drugs (SSRIs, typical and atypical antipsychotics, anticonvulsants, and novel drug treatments of anxiety disorders) which effect the gamma-aminobutyric acid-ergic, serotonergic, and glutamatergic systems.

Ira D. Glick, MD, and Eric D. Peselow, MD, describe the current antipsychotics in the pipeline that are being clinically tested. They describe preclinical and clinical studies on a variety of agents that affect multiple receptors, including serotonin (5-HT)1A, 5-HT2A, 5-HT2C, dopamine (D)1, D2, D3, D2/D4, alpha-adrenergic receptors (alpha-1 and alpha-2) muscarinic (M)1 and M2 and histamine-1 receptors that are thought to be related to etiology. The authors point out that pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia.

Patrick Ying, MD, evaluates new medications in mood disorders. Some of these medications continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine. Others employ novel mechanisms of action and hold the potential to improve the treatment of patients, such as by modifying the hypothalamic-pituitary-adrenal axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy.

Laurence M. Westreich, MD, and Deborah Finklestein, MD, evaluate the pipeline of investigational medications and vaccines used in the treatment of various illicit drugs. In addition to  these vaccines and the Food and Drug Administration-approved medications, other addiction remedies need to be understood by the general physician. The authors note that clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package.

Understanding these newer agents and treatment strategies may provide enhanced efficacy for patients with various psychiatric disorders. PP


1.    Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-352.
2.    Bower WH. Chlorpromazine in psychiatric illness. N Engl J Med. 1954;251(17):689-692.
3.    Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958;115(5):459-464.
4.    Kerry RJ, Jenner FA. A double blind crossover comparison of diazepam (Valium, Ro5-2807) with chlordiazepoxide (Librium) in the treatment of neurotic anxiety. Psychopharmacologia. 1962;3:302-306.