Leslie Knowlton

In an attempt to reframe the long-standing debate over the either-or impact of genetics versus environment on emotional makeup, a panel titled "Genes-Environment Interactions: Developmental and Psychotherapeutic Implications" convened at the American Psychoanalytic Association's Winter 2005 Meeting in New York City.

Glen O. Gabbard, M.D., Brown Foundation chair of psychoanalysis and professor of psychiatry at the Baylor College of Medicine in Houston, presented data on the gene-environment interaction in antisocial and borderline personality disorders, showing that DNA is both inherited and environmentally modifiable. Gabbard told 

 that there is today, in the field of psychiatry, a simplistic thinking that wants everything reduced to the genome.

"Most people do not like complexity, so there's a seductiveness about genetic reductionism," he said. "But genes alone do not determine personality, and we have good data now showing that it is a matter of genes interacting with the environment in the expression of those genes, and the environment making actual changes in that expression."

At the meeting, Gabbard described a long-term, follow-up study of 1,037 children in Dunedin, New Zealand--a birth cohort assessed every two years up to age 26 (Caspi et al., 2002). Measures included degree of maltreatment, monoamine oxidase A (MAOA) gene activity and antisocial behavior. Results showed that males with low MAOA activity who were maltreated in childhood had elevated antisocial scores, whereas males with high MAOA activity did not have the elevated scores even when they had experienced maltreatment. Overall, 85% of the males with both the low MAOA activity genotype and severe maltreatment became antisocial.

"The authors concluded that a functional polymorphism in the MAOA gene moderates the impact of childhood maltreatment on development of antisocial behavior. The point here, against reductionism, is that neither the low-activity gene alone nor the environmental maltreatment alone is enough to create antisocial behavior," explained Gabbard.

Those findings were replicated in a study of 514 male twins (ages 8 to 17), which showed that low MAOA activity increased risk for conduct disorder only in the presence of an adverse childhood environment (Foley et al., 2004). "Once again, the combination had to be present," Gabbard said.

In a study of the effects of differential parenting on antisocial behavior in 708 families with at least two same-sexed adolescent siblings, almost 60% of the variance in adolescent antisocial behavior and 37% of the variation in depressive symptoms were accounted for by conflictual and negative parental behavior directed specifically at the adolescent, not at the sibling (Reiss et al., 1995).

"So there's differential parenting and you can't assume that every kid in a family has the same parenting," said Gabbard. "Non-shared environmental influences appear to have the largest impact on normal versus pathological development."

Inherited traits can produce differential parenting responses that could ameliorate or exacerbate those traits.

"One implication that hasn't been studied in a sophisticated prospective design is that psychotherapeutic interventions with caregivers might actually alter genetic expression in genetically vulnerable children," said Gabbard.

Provocative data confirming this idea comes from a 15-year follow-up of a randomized, controlled trial of the impact of home visitation by a nurse on children's antisocial behavior (Olds et al., 1998). The study found that adolescents born to young, low-income women who received nurse visits indeed had significantly lower rates of antisocial behavior than controls. They also had lower rates of substance abuse and fewer lifetime sex partners.

"So this kind of intervention made quite a difference in what we might expect from these kids," Gabbard said. "So what I am saying so far is that genes and environment are inextricably connected in the pathogenesis of antisocial behavior; a strict dichotomy is specious. Psychotherapy of parents and caregivers may influence genetic vulnerability, and a neglected benefit of psychotherapy in the literature is its impact on offspring of the patient."

Shifting to a discussion of borderline personality disorder (BPD), Gabbard said there are much less genetic data regarding this condition. Some data come from neuroimaging studies that showed smaller hippocampus and amygdala volumes in patients with BPD versus controls (Driessen et al., 2000; Schmahl et al., 2003; Tebartz van Elst et al., 2003). "But the exact relationship between early trauma and decreased volumes in the amygdala is unclear, since 60% to 80% of patients with BPD have substantial childhood trauma," explained Gabbard.

A volumetric study of response to facial expressions found that patients with BPD showed significantly greater left amygdala activation to happy, sad and fearful expressions compared with normal controls, and attributed negative qualities to neutral faces (Donegan et al., 2003).

"A hyperactive amygdala may be involved in the predisposition to be hypervigilant and overreactive to relatively benign emotional expressions," said Gabbard. "Misreading neutral faces is clearly related to transference misreadings that occur in psychotherapy and the creation of bad object experiences linked with projective identification."

Another study found that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter gene demonstrated greater amygdala neuronal activity in response to fearful stimuli compared to individuals homozygous for the long allele (Hariri et al., 2002).

"There may be a genetic vulnerability that predisposes one to amygdala hyperreactivity in response to trauma," Gabbard said. "We need more data to know that, but we do know from the Dunedin longitudinal study that the short allele moderated the influence of stressful life events on depression, and stressful life events predicted suicidal ideation or attempt among individuals carrying the short allele but not among those with the long variant [Caspi et al., 2003]."

In a study of how social support might moderate depression after mistreatment, 57 maltreated children were compared to 44 controls (Kaufman et al., 2004). "What was ideal here is that there were no differences in short versus long alleles of the serotonin transporter gene between maltreated [participants] and controls," said Gabbard. Results showed that maltreated children with the short allele and no social support had the highest depression ratings, but positive social supports reduced risk of depression associated with maltreated children and the short allele.

"So the environment can moderate the impact of the genetic constellation," said Gabbard. "This is a very provocative study showing that genetic vulnerability can be modified by intensive social support."

It may be more than the presence of trauma that makes the difference in outcome, according to Gabbard. The child's intrapsychic interpretation of the trauma may be highly relevant. Parents and caretakers can contextualize events so that the child can make sense of them in ways that are beneficial. These ideas also relate to the potential for psychoanalysis and other therapies to change the impact of those experiences, added Gabbard.

"Whether or not environmental factors trigger the expression of the gene may depend on the conscious or unconscious meaning attributed to these experiences," stated Gabbard.

The studies on the influence of genes and environment on human development are supported by studies of primates and rats. "The support from laboratories, where you can manipulate genes and environments in ways you can't do with human beings because of ethics, definitely shows that the environment alters genetic expression," explained Gabbard.

One example is a series of lab and field studies of monkeys done by Stephen Suomi, Ph.D., chief of the Laboratory of Comparative Ethology, and his team at the National Institute of Child Health and Development (see Suomi, 2003). Suomi presented data on a group of rhesus monkeys that showed the aggressive and highly impulsive characteristics of antisocial personalities. Such monkeys had deficits in serotonin, a highly heritable characteristic also associated with a tendency to drink an excessive amount of alcohol. But a series of studies showed that these highly heritable characteristics can be modified substantially by a nurturing environment.

Specifically, the studies looked at monkeys with short and long alleles of the serotonin transporter 5-HTT promoter gene, the short version being associated with low serotonin and the long version associated with normal serotonin levels. The two types of monkeys were separated into groups raised by peers and other groups raised by mothers. The mother-raised monkeys of both allele types showed normal 5-HIAA levels, while peer-raised monkeys with short alleles showed much lower levels than either group of normal monkeys. The same pattern was seen with aggression, with short-allele mother-raised monkeys showing the same low level of aggression as normal monkeys in either group, and peer-raised short-allele monkeys showing high levels of aggression. The peer-raised monkeys acted far more anxious, clingy and fearful, no matter what their allele type.

"So good mothering is very important and goes a long way toward protecting these [at-risk] monkeys," said Suomi.

Furthermore, there is a non-genetic transmission of mothering, as the attachment style of monkey mothers--whether foster or not--is usually copied by daughters. Rat studies also support evidence for the gene-environment interaction.

Regina Pally, M.D., assistant clinical professor at the University of California at Los Angeles Neuropsychiatric Institute and chair of the panel, reviewed rat projects conducted by Michael Meaney, Ph.D., and colleagues at McGill University (see Zhang et al., 2004.) She explained that in rats, maternal care runs across a spectrum from highly nurturing mothers to poorly nurturing mothers, and that offspring resemble their mothers as to behavior and emotional temperament.

To address the question of nature versus nurture with regard to these observations, Meaney used an experimental design called "cross-fostering," wherein rats who are inbred to share the same genes are developed into two strains, each at opposite ends of the nurturing spectrum. Right after birth, some of the pups of low-nurturing mothers are placed with high-nurturing mothers, and some of the pups of high-nurturing mothers are likewise switched. Therefore, each mother is rearing both biological and foster pups.

"The mothering environment shaped the genes. Every gene has a promoter region which turns it on or off, and the environment influences the promoter," explained Pally.

Results showed that in terms of emotion and behavior, pups resemble the mother that raised them more than their biological mother. The results were interpreted in terms of gene expression.

"It is in this way that over the course of development, the growth of the brain--in terms of neurons, neurotransmitters, and neurotransmitter receptors--will be affected and will be manifest as behaviors and emotions, such as how that individual responds to stress or how nurturing that individual is," concluded Pally.

Caspi A, McClay J, Moffitt TE et al. (2002), Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851-854 [see comment].

Caspi A, Sugden K, Moffitt TE et al. (2003), Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386-389 [see comment].

Donegan NH, Sanislow CA, Blumberg HP et al. (2003), Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation. Biol Psychiatry 54(11):1284-1293.

Driessen M, Herrmann J, Stahl K et al. (2000), Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch Gen Psychiatry 57(12):1115-1122.

Foley DL, Eaves LJ, Wormley B et al. (2004), Childhood adversity, monoamine oxidase A genotype, and risk for conduct disorder. Arch Gen Psychiatry 61(7):738-744.

Hariri AR, Mattay VS, Tessitore A et al. (2002), Serotonin transporter genetic variation and the response of the human amygdala. Science 297(5580):400-403 [see comment].

Kaufman J, Yang BZ, Douglas-Palumberi H et al. (2004), Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A 101(49):17316-17321 [see comment].

Olds D, Henderson CR Jr, Cole R et al. (1998), Long-term effects of nurse home visitation on children's criminal and antisocial behavior: 15-year follow-up of a randomized controlled trial. JAMA 280(14):1238-1244 [see comments].

Reiss D, Hetherington EM, Plomin R et al. (1995), Genetic questions for environmental studies. Differential parenting and psychopathology in adolescence. Arch Gen Psychiatry 52(11):925-936.

Schmahl CG, Vermetten E, Elzinga BM, Bremner DJ (2003), Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder. Psychiatry Res 122(3):193-198.

Suomi SJ (2003), Gene-environment interactions and the neurobiology of social conflict. Ann N Y Acad Sci 1008:132-139.

Tebartz van Elst L, Hesslinger B, Thiel T et al. (2003), Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study. Biol Psychiatry 54(2):163-171.

Zhang TY, Parent C, Weaver I, Meaney MJ (2004), Maternal programming of individual differences in defensive responses in the rat. Ann N Y Acad Sci 1032:85-103.

Articles

In an attempt to reframe the either-or debate over the impact of genetics versus environment on emotional makeup, a panel convened at the American Psychoanalytic Association’s Winter 2005 Meeting in New York City. This article highlights studies presented at the meeting.

Nature Versus Nurture: How Is Child Psychopathology Developed?

At the New York Academy of Medicine's 71st annual Thomas William Salmon Lecture, Nora D. Volkow, M.D., director of the National Institute on Drug Abuse (NIDA) told attendees that she has been obsessed with trying to understand what neurobiological changes explain aberrant behavior in addictive people. "We don't know to what extent changes in people who are addicted are effects of chronic drug exposure, effects of genes that predispose them to become addicted or effects of the environment that facilitate the translation of addiction," she explained. "I'm going to start to try to dissect those elements."

Delivered last December, Volkow's talk, "Addiction: The Neurobiology of Behavior Gone Awry," focused on imaging studies exploring what role--if any--the brain's dopaminergic system has on addiction (Volkow et al., 2004). In introducing Volkow, John M. Kane, M.D., called her a "national treasure" with more than 300 peer-reviewed publications as well as a key role in setting national drug policy and NIDA's research agenda. She formerly held three concurrent positions at Brookhaven National Laboratory and was the first to use imaging to investigate neurochemical changes occurring in the human brain during drug addiction.

Volkow said her group began studying dopamine two decades ago because it was known that drugs of abuse, whether legal or illegal, increase that neurotransmitter in specific brain areas--increases that appear crucial for reinforcing effects.

"This property has been recognized as indispensable in the characteristic a drug has to have to induce repeated administration, but what's not understood is whether dopamine is involved in the loss of controls toward drug administration that occurs with addiction," she said. "I'm going to concentrate only on dopamine D2 receptors ... because it's one of the [areas] where we've seen consistent abnormalities across drug addictions."

Volkow first described an imaging study of inpatients who abused cocaine and whose brains were scanned about a month after the last use of cocaine and again three months later (Volkow et al., 1990). Results documented that decreases in D2 receptors shown in people addicted to cocaine as compared to controls persisted at least four months after last drug use.

The researchers also planned to test a year after participants were released from the hospital, but 90% had relapsed by then.

Showing a graph of D2 receptor level as a function of age, Volkow said it has been consistently documented that receptor density decreases 4% to 6% per decade. The graph showed these decreases with age in both controls and cocaine abusers. Cocaine users had overall lower levels as a group. However, there was a highly significant overlap between the groups, with some cocaine users looking like controls and some controls looking like cocaine abusers. This overlap has been replicated in different samples of cocaine abusers and with different methodologies.

"Certainly it means that decreases in D2 receptors, while they may be important in addiction, by themselves are not sufficient to account for addiction," Volkow explained, adding that such decreases have also been found in alcoholics, heroin addicts and methamphetamine addicts.

She said one could postulate that dopamine cells signal saliency in the brain to motivate behavior, thereby increasing likelihood of doing pleasurable things and avoiding aversive things. Since the probability of a signal to occur is a function of both how much dopamine is in the synapse and the number of receptors, a consequence of decreased receptors might be reduced sensitivity to events supposed to generate a signal.

Since natural reinforcers increase dopamine much less than a drug of abuse--and for a much shorter period of time--such reinforcers may be insufficient to generate a signal in people with drug addictions who have low receptors, whereas drugs of abuse that increase dopamine five- to 10-fold and for a longer duration will produce a signal, despite the fact that the receptor levels are down.

"The person who is addicted stops learning that natural reinforcers are stimulating and exciting, which is extremely important in order to condition ourselves to do things that motivate and drive our everyday life. In turn, they learn that the drug of abuse and stimuli associated with it are very powerful in activating the system," Volkow said. "This is one of the mechanisms that ... could make you more vulnerable to taking drugs."

Still unknown was whether or not receptor levels were down before the person started taking the drug, noted Volkow, adding that studying that in humans would be cost-prohibitive.

She next showed study data only for non-drug-abusing participants who show significant variability in D2 receptor expression. She estimated that throughout almost 20 years of studies, the range of variability of expression of D2 receptors in controls has been about 50%.

"If we were postulating that decreases in receptors were making individuals more vulnerable, then the question that followed was: 'What is the consequence in the [non-addicted] individual of low levels of dopamine D2 receptors?' ... Specifically, is the difference in expression of dopamine D2 receptors in any way affecting the person's response to drugs of abuse?"

Volkow and colleagues (1999) studied 23 males, first measuring D2 receptors and then injecting the participants with intravenous methylphenidate (Ritalin, Metadate, Concerta)--a drug that cocaine abusers report has similar effects to cocaine.

"We've tested IV methylphenidate in more than 100 cocaine abusers, and all but one have liked the way it made them feel. But when you give it to ... controls, you see a very different pattern. Approximately half with previous drug experience, but with no dependence, report they like the way IV methylphenidate makes them feel, and half report the effect as being very aversive. And this variability in response to stimulus drugs for other behavioral measures has characterized the literature whenever amphetamine or methylphenidate has been utilized."

In the study of males, the main variable under investigation was whether or not the effect of this drug was pleasant or unpleasant (Volkow et al., 1999). "Are the differences in receptors affecting that response of pleasant or unpleasant? The answer is yes," said Volkow, reporting that about half of the participants experienced methylphenidate as pleasant, and that those participants had significantly lower levels of D2 receptors than participants reporting unpleasant effects.

"So what we documented here was that just the levels of dopamine D2 receptors are associated in differences in the [response] to the administration of a large dose of IV methylphenidate ... Intriguingly, if you have high levels of receptors, effects are very unpleasant."

Volkow noted that preclinical electrophysiological studies have found there is a minimal electrical current delivered to the lateral hypothalamus necessary for an animal to perceive its effect as reinforcing. "If [the current is] too low, the animal doesn't bother to press a lever--it's not sufficient to elicit the behavior," Volkow explained. "What is fascinating is that if the current is too strong, the animal stops pressing the lever because it becomes aversive. So there's an optimal window of stimulation."

Therefore, she continued, one could postulate that a similar process occurs in humans given IV methylphenidate, "If you have a lot of receptors, that's going to lead you to an aversive response. On the other hand, if you have low levels of receptors ... that attenuate the signal, bringing it to a window where it is pleasurable."

To test the hypothesis that responses were unpleasant because they were too large, the group next attempted a study which would bring participants back to receive one-tenth of the IV methylphenidate dose to see if that smaller dose would be pleasurable. However, participants refused, reporting that the prior experience had been too aversive.

"Retrospectively, what we should have done was randomly assign patients to different doses ... but things are very easy retrospectively. When you're starting, you always have to start in a certain framework," said Volkow. "So I don't know if that hypothesis is correct, but I suspect it is."

Returning to the question of vulnerability, Volkow said that if a person with high D2 receptor levels took a drug for the first time and found it aversive, the likelihood of taking that drug again is much lower than if the first exposure was very pleasant. "Indeed this has been very clearly documented in the case of nicotine in the cigarette smoker. Thus, you could postulate that if you have high levels of D2 receptors, you are protected against taking drugs. This is actually the hypothesis I favor."

Volkow said one limitation in many clinical studies is that results show association, not causality. Theoretically, a causal link could be proved if researchers were able to increase receptors in participants and find that a drug once perceived as pleasant is now unpleasant.

"Practically, how do you do it and we have no means," she said. "The only way we can increase receptors is by giving a neuroleptic but for many reasons that defeats the purpose, because you are blocking the receptors."

However, numbers of receptors can be increased in animals, so her group did several such experiments. In the first study, rats taught to self-administer alcohol were injected with an adenovirus containing a D2 receptor gene that led to an upregulation of D2 receptors in the nucleus accumbens (Thanos et al., 2001). The highest density of receptors was reached at four days, when the increase was about 50%. This is equivalent to the range of variability formerly seen in human controls.

"I think this is clearly telling us something about the regulation of the expression of these receptors ... Even though you're injecting a lot of the gene, it was not increased 300% or 400%. It was 50%, and others have also observed this same range."

On day four, alcohol intake was reduced by almost 70%. "[Intake] is not abolished, [rather] it's dramatically decreased ... As receptors go back to baseline, what you see is that the animals go back to drinking [large amounts], and when injected again with adenovirus, again you see a dramatic decrease in drinking."

Controls injected with adenovirus not containing the gene showed no reduction of alcohol intake. "Indeed, increasing receptors appears to protect the animal from the administration of large doses of alcohol," said Volkow, adding that the finding has been replicated in different breeds of rats and also replicated for cocaine. "This is quite fascinating because it completely modified our thinking. ... I began to think we were seeing decreases in receptors in addicted [participants] not because that makes them more vulnerable, but because they don't have the protection of high levels of receptors."

Before her shift in thinking, Volkow wrote a grant proposing that low levels of receptors were creating vulnerability to alcohol abuse and did a pilot study comparing 10 participants with positive family history of alcoholism to 10 participants with a negative family history, hoping to find that those with a positive history would have lower levels of D2 receptors.

"When I looked at the data I said, 'Oh no, it cannot be,'" she recalled. "The level of dopamine D2 receptors in high-risk [participants] was significantly higher than the level of receptors in [those] with no family history."

One explanation for this might be that these individuals with positive history did not inherit the gene for alcoholism. "The other thing that struck me is that none of these [participants] was an alcoholic, despite the fact they had high density of family alcoholism. Having the animal data that increasing receptors protects, the reason these [individuals] were not alcoholics was that increases in receptors were being protective."

In another study, Peter K. Thanos, Ph.D., a researcher in Volkow's group, took rats genetically inbred for propensity to self-administer alcohol and increased their D2 receptor levels (Thanos et al., 2004). Results showed that, at baseline, the preferring rats had lower levels of D2 receptors, but when receptor levels were increased, alcohol intake dramatically decreased.

"This was very significant ... providing evidence that difference in expression of D2 receptors may be one of the variables that modulates either vulnerability or resilience for taking drugs," Volkow said.

She concluded, "Now we have the tools of understanding how the environment affects genes that in turn will affect the neurobiology of the brain in ways that make it either more vulnerable but also more resilient. Ultimately, it's that type of knowledge that will allow us to do intervention, to be able to prevent drug addiction in those who may be vulnerable because of genetics but also in those who may be vulnerable because they come from a very adverse environment."

Thanos PK, Taintor NB, Rivera SN et al. (2004), DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking. Alcohol Clin Exp Res 28(5):720-728.

Thanos PK, Volkow ND, Freimuth P et al. (2001), Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem 78(5):1094-1103.

Volkow ND, Fowler JS, Wang GJ (2004), The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology 47(suppl 1):3-13.

Volkow ND, Fowler JS, Wolf AP et al. (1990), Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 147(6):719-724.

Volkow ND, Wang GJ, Fowler JS et al. (1999), Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 156(9):1440-1443 [see comment].

What actually happens neurochemically in the brain to cause addiction? A well-known researcher discusses her findings on the role that dopamine levels play in addiction and aversion to cocaine.

Why Are Drugs Abused By Humans?

In a groundbreaking effort to attempt quantitative comparison of therapies for depression, Arthur L. Brody, M.D., assistant professor of psychiatry at University of California, Los Angeles' (UCLA) Neuropsychiatric Institute, is using positron emission tomography (PET) scans to observe brain changes in patients receiving talk therapy, as compared to patients receiving psychopharmacological therapy.

Funded by an award from the National Association for Research on Schizophrenia and Depression (NARSAD), Brody, who is also director of UCLA's Interpersonal Psychotherapy Clinic, recently presented his group's work at NARSAD's 11th annual scientific symposium held in New York City. The session was moderated by William E. Bunney Jr., M.D., distinguished professor and Della Martin Chair of Psychiatry at University of California, Irvine, and a member of NARSAD's scientific council.

Brody told the assembly that in functional imaging studies, the brain regions most commonly found to have abnormalities in major depression are the prefrontal cortex, anterior cingulate gyrus, temporal cortex and caudate nucleus (Baxter et al., 1989; Drevets et al., 1997; Mayberg, 1997). Therefore, his group sought to determine metabolic changes in these regions in subjects with major depression from pre- to posttreatment with either paroxetine (Paxil) or interpersonal psychotherapy (IPT). Before discussing that study, however, Brody turned to a published preliminary study in which his group used PET scans to examine changes in 16 depressed subjects treated with paroxetine (Brody et al., 1999).

"What we did there is compare responders to treatment to nonresponders," he said. "And what we found is that responders to treatment had decreases in activity in the ventrolateral prefrontal cortex and the orbital frontal cortex, the part of the cortex right above the eyes. That's a region that has strong input from the serotonin system, so that might explain why that region had a decrease in activity when subjects were treated with a serotonin reuptake inhibitor. Nonresponders did not have these decreases in activity."

Moving on to the current study, Brody described IPT (Klerman et al., 1984; Weissman and Markowitz, 1994), explaining that the therapy's goal is improvement of depressive symptoms through strengthening the patient's interpersonal relationships.

 "The focus is on current stressors in a person's life and practical ways to improve relationships to alleviate those stressors and strengthen existing relationships," he said. "It's a very direct therapy where we use behavior change techniques and actually suggest alternatives for patients to do in their current relationships. The therapist in this therapy is a patient advocate, not neutral...and active, not passive. It's a very interactive type of psychotherapy."

The 24 study subjects with major depression were allowed to choose either IPT or medication therapy. This resulted in 14 subjects in the psychotherapy group and 10 subjects in the paroxetine group. Also included were 16 normal controls who received no psychotherapy or medication. All subjects were scanned two times, about 12 weeks apart. Pre- and postmeasures of affect were evaluated by the Hamilton Rating Scale for Depression  (HAM-D).

"This was a slightly sicker group overall than in our previous study of depression, in that the people in the IPT group had an average of 3.5 previous treatments for depression, and the paroxetine group had 2.1 previous episodes," Brody noted. "The IPT group also started out with a slightly higher [HAM-D score] than the paroxetine group."

Results for the paroxetine-treated subjects showed a 62% drop in their affective ratings scales scores, whereas for the psychotherapy subjects, there was only about a 40% drop in scores. Brody said that, similar to the previous study, PET scans of the paroxetine patients showed a decrease in activity in the more ventral portion of the frontal lobe.

"Finding this decrease in both of our studies of patients treated with Paxil makes this a much stronger finding," he said. "These were two different groups of subjects and done on two different scanners with slightly different methods, and we found the same thing. Other groups have had similar findings as well [Mayberg et al., 1999]."

In the IPT group, PET scans showed a highly significant increase in activity in the inferior frontal gyrus and anterior insula for all subjects. Normal controls had no significant change on their PET scans other than normal changes seen with repeated scans.

"This is an area that's been associated with language," Brody said of the inferior frontal gyrus and anterior insula region. "It's also been associated with movement and emotion. So one of our hypotheses is that maybe after the talk therapy they received, they were thinking about talking more, or more talkative in general."

Asked about long-term implications of medication versus psychotherapy, Brody said that his group has not done those kinds of analyses, but several other large studies have.

"What actually tends to happen is that people who get treated with IPT...tend to maintain better social functioning later on," he explained. "But in terms of who does better in the long run, medication and psychotherapy both have strengths and weaknesses. Neither therapy has definitively been proven superior to the other, but some studies have shown superior efficacy for medication as perhaps being a little more effective than psychotherapy (in more severely depressed individuals). But the people who get the psychotherapy tend to have better social functioning one, two or three years out of the psychotherapy."

A good next step, added Brody, would be to examine the combination of psychotherapy and medication.

"Medication tends to work a little bit quicker than the psychotherapy, so it would be interesting to see what happens in people's brains as you go along, if treated with the combination."

Regarding the fact that both interventions yielded mood changes but each showed different effects on the brain, Brody said he plans to explore that further.

"Our first hypothesis is that it has to do with different symptoms changing," he said. "The two treatments are actually different in how effective they are for specific symptoms of depression, so, for example, neurovegetative symptoms like sleep trouble and appetite trouble tend to do better with medication, whereas, as I mentioned before, social interactions and anhedonia tend to improve more with psychotherapy. So the first thing we're going to look at is the symptoms that the patients had, and which symptoms changed and didn't change with treatment."

Another issue Brody hopes to address in future work is controlling for possible pretreatment differences in groups.

"In a future study, we would randomize which group the people go in to," he said. "In this preliminary study, we weren't able to do that. We just let people choose whatever treatment they wanted."

Another interesting strategy would be to give controls treatment, but there are ethical questions surrounding the dispensation of active medication to normal subjects, Brody noted.

Asked about the possibility that more weeks of IPT might have shown stronger results, Brody explained that the 12-week time frame was selected because of the Paxil group.

"It would be unfair to subjects with major depression to treat them with Paxil for more than 12 weeks if they weren't responding," he said. "So in order to get a comparable time frame between the two groups, we chose 12 weeks of psychotherapy. But you're right, we used a high dose of Paxil and a relatively low dose of psychotherapy, so that might explain some of the differences."

Commenting on Brody's work, Bunney said there are two issues.

"The first issue is looking at PET changes associated with drugs, and the other is looking at PET changes associated with psychotherapy," he said. "There may be 300 studies looking at changes with drugs, but looking at changes with psychotherapy is absolutely pioneering," Bunney added, "this is...very nice [work]."

, Brody said his group had uncovered more findings.

"In our statistical parametric mapping analysis, we found some similarities in that both groups had decreases in the ventral lateral prefrontal cortex," he explained. "The finding wasn't as significant in the IPT group as it was in the Paxil group, but that was a big similarity we found."

Another similarity the researchers found was that both groups had decreases in activity in the right caudate. Brody said that both the similarities and the differences found between the groups may be related to specific symptoms each therapy addresses.

"Both groups had their depression get better overall," he said. "The Paxil group had a bigger improvement than the IPT group, but they both got better. My hypothesis would be that the areas of similarity may reflect common symptoms being treated by both therapies, while the areas of difference may reflect different symptoms addressed by each therapy. We haven't proven that hypothesis, but we're looking into proving it now."

What's interesting, Brody added, is that, despite their proven effectiveness, neither IPT nor cognitive-behavioral therapy is widely used.

"There just aren't that many people trained in these kinds of psychotherapies," he said, "and we would certainly like to see more who are."

Baxter LR Jr, Schwartz JM, Phelps ME et al. (1989), Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46(3):243-250.


Brody AL, Saxena S, Silverman DH et al. (1999), Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res 91(3):127-139.


Drevets WC, Price JL, Simpson JR Jr et al. (1997), Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386(6627):824-827 [see comments].


Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES (1984), Interpersonal Psychotherapy of Depression. New York: Basic Books.


Mayberg HS (1997), Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 9(3):471-481.


Mayberg HS, Liotti M, Brannan SK et al. (1999), Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156(5):675-682.


Weissman MM, Markowitz JC (1994), Interpersonal Psychotherapy. Current status. Arch Gen Psychiatry 51(8):599-606 [see comments].

Can brain scans show a difference between drug therapy and psychotherapy? A researcher at University of California at Los Angeles uses positron emission tomography to observe the difference in brain changes between these two types of treatment for major depression.

PET Scans Compare Effects of Drug Treatment and Talk Therapy

For more than eight years, Richard P. Brown, M.D., associate professor of clinical psychiatry at Columbia University College of Physicians and Surgeons, has used the natural dietary supplement S-adenosylmethionine (SAM-e) to treat more than an estimated 400 patients suffering from depression, many of whom were treatment-resistant. This month, Brown is scheduled to discuss SAM-e at the American Psychiatric Association's annual meeting in New Orleans.

Stop Depression Now: SAM-e, the Breakthrough Supplement that Works as Well as Prescription Drugs in Half the Time...With No Side Effects.

 His primary collaborator on the book project was Teodoro Bottiglieri, Ph.D, director of neuropharmacology and senior research scientist at Baylor University's Institute for Metabolic Disease. Bottiglieri, also an associate professor of biomedical studies at Baylor, has been conducting research on SAM-e for 15 years.

Brown reviewed research on SAM-e and discussed his clinical experience with it.

Although SAM-e has only been on the U.S. market since 1999, it has been studied for decades internationally and is approved as a prescription drug in Spain, Italy, Russia and Germany. More than 1 million Europeans have used it, primarily for depression and arthritis.

"I first heard about SAM-e 20 years ago when I was doing my residency in psychiatry at New York Hospital, Cornell Medical Center," Brown recalled. "At a meeting of the American College of Neuropsychopharmacology, a colleague had learned about an exciting new antidepressant being studied in Europe that was nontoxic, without side effects, and worked better and faster than traditional medications."

Fifteen years later, after Brown had developed a subspecialty practice treating patients resistant to conventional drug therapy by integrating alternative approaches such as nutrients and herbs with prescription medications, a patient brought him information about SAM-e from the Internet. That launched his investigation and clinical use of SAM-e.

SAM-e was discovered in Italy about four decades ago (Cantoni, 1952), according to Brown. Since then, SAM-e "has been evaluated for various disorders in more than 75 clinical trials involving over 23,000 people," Brown said. However, the first clinical study of SAM-e's use for depression was not completed until the 1970s (Agnoli et al., 1976).

"Because there was no usable oral preparation [then], early studies used intravenous [IV] and intramuscular [IM] formulations," Brown said. "Over time, improvements have provided an oral form that is much more resistant to oxidation and gastric enzyme degradation."

Brown explained that SAM-e is produced in the body from methionine, a sulfur-containing amino acid, and the energy-producing compound adenosine triphosphate. SAM-e is a physiologically essential compound, he said, adding that some chemists believe it ranks with adenosine triphosphase (ATP) as a pivotal molecule in living cells. Distributed throughout the body, SAM-e is most concentrated in the brain and liver and is crucial to three central pathways of metabolism that stimulate more than 35 different reactions.

"The three major pathways are transmethylation, transulfuration and transaminopropylation," he said. "Animal studies show that the transmethylation pathway boosts levels of the neurotransmitters serotonin, dopamine and norepinephrine. This process probably contributes to the antidepressant action" (Andreoli et al., 1978; Curcio et al., 1978; Czyrak et al., 1992; Fava et al., 1990; Losada and Rubio, 1989; Otero-Losada and Rubio, 1989).

Brown said that donation of carbon groups by SAM-e protects catecholamine neurons and that SAM-e improves nerve cell membrane uptake of phospholipids, enabling the coupling of protein receptors to second messengers within a more fluid lipid bilayer and enhancing transmission of impulses by neurons.

"SAM-e is vital to the production of our most important antioxidant, glutathione, as well as the secondary antioxidants, cysteine and taurine," he noted. "The American diet yields insufficient quantities of SAM-e either for wellness or treatment of illness. Moreover, the form of SAM-e found in food is not stable. It oxidizes too rapidly to absorb well. Our bodies can only generate a small amount of SAM-e...Therefore, SAM-e levels are most easily increased through dietary supplementation."

According to Brown, lower than normal levels of SAM-e are found in cerebral spinal fluid in some patients with depression, Alzheimer's disease, dementia, Parkinson's disease treated with levodopa (Atamet, Sinemet), disorders of folate metabolism and other illnesses (Bottiglieri et al., 1990; Bottiglieri et al., 1994).

He cited a study indicating that folate, B

are necessary for efficient use of SAM-e (Crellin et al., 1993) and reported that SAM-e has been effective for treating major depressive disorder in 13 trials comparing it to placebo and 19 trials comparing it to tricyclic antidepressants, with more than 1,400 patients studied.

"From 1973 to 1988, 14 double-blind, European studies [Janicak et al., 1988] showed that intravenous and intramuscular preparations of SAM-e were more effective than placebo and comparable to imipramine [Tofranil], amitriptyline [Elavil, Endep] and clomipramine [Anafranil] for treatment of major depression," he said.

In 1988, American psychopharmacologists Bell and colleagues conducted a double-blind, randomized, two-week trial comparing IV SAM-e to oral imipramine. By the end of the second week, 66% of the S-adenosylmethionine patients "had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients," the study authors reported.

Since 1988, double- and single-blind studies using higher doses of SAM-e have shown it to be effective in treating major depression (Bressa, 1994; Delle Chiaie and Boissard, 1997; Delle Chiaie et al., 2000), depression secondary to medical illness (Criconia et al., 1994), postpartum depression (Cerutti et al., 1993), postmenopausal depression (Salmaggi et al., 1993) and treatment-resistant depression (Rosenbaum et al., 1990), Brown reported.

"Rapid response to SAM-e was shown in a double-blind trial of 30 depressed inpatients who received either 1600 mg/day of oral SAM-e or imipramine (averaging 140 mg/day) for six weeks," Brown added. "The SAM-e group was significantly better by day 10. Both groups were comparably improved by week 6" (De Vanna and Rigamonti, 1992).

Furthermore, Brown reported that in a small, double-blind, four-week inpatient study of oral SAM-e (1600 mg/day) versus 250 mg/day of desipramine (Norpramin), improvement in depression in those who responded to either SAM-e or desipramine correlated with their SAM-e blood levels (Bell et al., 1994).

"These findings highlight the need for larger and longer-term studies to elucidate the role of SAM-e in recovery from depression and the use of SAM-e in combination with prescription antidepressants," he said. He added that the longest controlled-trial studies of SAM-e efficacy for depression were 42 days (Delle Chiaie et al., 2000; De Vanna and Rigamonti, 1992; Fava et al., 1992).

Brown noted that American companies only sell SAM-e in 50 mg, 100 mg and 200 mg tablets. He recommended a daily dose of 400 mg for mild depression.

"Keep in mind that absorption is better on an empty stomach," he said. "Starting patients with 200 mg 30 minutes before breakfast and 30 minutes before lunch minimizes the overstimulation and insomnia which some patients report in the first few weeks. This can be switched to 400 mg before breakfast after a few weeks." Patients typically notice improvement in energy within two weeks.

Some investigators reported an overstimulation and/or insomnia rate of about 5%, which is the same as placebo (Berger and Nowak, 1987), according to Brown.

Brown continued, "As with most medications, clinical sense indicates starting with lower doses in geriatric, medically ill and anxious patients. SAM-e, like all antidepressants, should be used with some caution in patients with a history of cardiac arrhythmia."

He stressed that there have been surprisingly little data on the use of SAM-e in pregnancy and that the patient should "make a decision about SAM-e and pregnancy and lactation after discussing the pros and cons [with her doctor]."

SAM-e has been used to treat cholestasis of pregnancy in numerous studies with no adverse effects on mothers or children, Brown said. However, there are no definitive prospective long-term studies to exclude the possibility of teratogenic or neurodevelopmental effects (Brown et al., 2000). He added that since high levels of SAM-e are normal for infants, it is unlikely they would be harmed by the amount of SAM-e received through breast-feeding.

In several depression studies, SAM-e induced mania in a significant proportion of patients who had a prior history of bipolar disorder (De Vanna and Rigamonti, 1992; Kagan et al., 1990).

"As with any antidepressant medication, SAM-e can trigger hypomania or mania in patients with bipolar disorder," Brown warned, adding he would not recommend a patient with bipolar disorder take SAM-e unless that patient is under close medical supervision.

"If a patient has a personal or family history of bipolar disorder, lower starting doses of 100 mg once or twice a day, careful monitoring and concurrent use of mood stabilizers are indicated," Brown advised, adding "the dose can be raised by 200 mg to 400 mg every three to seven days."

Treatment for severe depression, Brown said, generally requires higher doses. "Some studies have started unipolar patients on 800 mg or 1600 mg per day," he said. Side effects occurring at the higher doses include mild jitteriness, loose bowels and headaches.

(To date, SAM-e has not been systematically studied in well-defined samples of psychotic or bipolar depressed patients-Ed.)

Brown noted that SAM-e is generally available in two forms: a butanedisulfonate form and a tosylate form.

"In my practice, the butanedisulfonate seems superior, particularly the enteric-coated form," he said, adding that good brands currently available in this country include Nature Made and GNC. "If a patient hasn't responded to an appropriate dose of SAM-e, the physician must be sure that the patient is using a potent brand."

"Only about 3% to 5% of patients discontinue SAM-e because of side effects, primarily gastrointestinal," Brown said. That is a relatively low rate compared to placebo discontinuation rates. In study after study, the investigators said there was no difference from placebo in the side effect rate."

The biggest study of SAM-e, Brown said, was a two-year postmarketing study of 20,641 patients conducted in Germany after SAM-e was approved for treatment of osteoarthritis (Berger and Nowak, 1987). "The investigators found that 80% of patients said they basically felt great on it and had no side effects, [while the other] 20% complained of mild side effects in the first month on high doses like 1200 mg/day to 1600 mg/day," Brown said.

At starting doses of 400 mg/day to 600 mg/day for mild depression, Brown said, there are no significant side effects. At higher doses, there are some "mild, temporary side effects."

Reports of drug interactions have been nearly nonexistent, according to Brown. He mentioned a case report of an elderly woman who was given clomipramine together with SAM-e. The patient exhibited symptoms of what the clinicians diagnosed as serotonin syndrome (Iruela et al., 1993). The investigators attributed it to a "toxic interaction produced by S-adenosylmethionine and clomipramine association."

Brown had some misgivings about the case report, however, explaining, "If you look at the world's literature of serotonin syndrome, the preponderance of cases are from clomipramine."

There have been no reports of SAM-e effects on cytochrome P450 metabolism or on the binding of prescription drugs to serum proteins (Brown et al., 2000).

Research studies (Bell et al., 1994; Criconia et al., 1994; De Vanna and Rigamonti, 1992; Kagan et al., 1990) and his own clinical experience, Brown said, demonstrate that some patients have a dramatic response to SAM-e even after failing on prescription antidepressants. Brown described one of his patients who had been tried on all available antidepressants, including tricyclics (TCAs), serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, combinations of antidepressants and agents used to augment antidepressants, with little or no response.

"One week after beginning SAM-e, he showed significant improvement, which partially faded after several good months," said Brown. "We eventually added an SSRI to the SAM-e, even though previous trials of SSRIs had been ineffective. On this combination, the patient recovered...and has sustained remission on a reduced dose. When either SAM-e or the SSRI is decreased, depressive symptoms return."

Brown said he has treated more than 30 patients with treatment-resistant depression who responded well to SAM-e augmentation of all categories of antidepressants without adverse reactions, and noted a review of four studies suggesting that SAM-e boosted and hastened response to tricyclic antidepressants, mianserin and fenoterol, a Ã-agonist (Friedel et al., 1989). He also cited a randomized double-blind study (Berlanga et al., 1992) of 40 outpatients with moderate to severe major depression that confirmed his own clinical experience of using SAM-e to augment imipramine.

Brown said he has also found SAM-e effective for fibromyalgia (Jacobsen et al., 1991; Tavoni et al, 1987, and Tavoni et al., 1998, as cited in Brown et al., 2000), depression in Parkinson's disease, the aging brain, liver diseases (Friedel et al., 1989) and arthritis (Bradley et al., 1994, as cited in Brown et al., 2000; Konig, 1987). It also seems to reverse some effects of alcoholic hepatitis and cirrhosis (Mato et al., 1999) and is used to dissolve gallstones. There is only one small open case series of SAM-e for attention-deficit/hyperactivity disorder (Shekim et al., 1990), but Brown mentioned that he has seen some anecdotal cases of his own (Brown et al., 2000).

"Preliminary studies support the use of SAM-e for depression complicating alcohol and opiate withdrawal" (Agricola et al., 1994), he said. "In several cases, we have used SAM-e to successfully treat post-methamphetamine depression and drug craving."

Brown said accumulated evidence indicates that SAM-e in higher doses is perhaps as effective for major depression as TCAs.

"SAM-e starts to work in approximately half the time needed for tricyclics. Studies show very few side effects, and SAM-e does not cause the sexual dysfunction or weight gain associated with other medications," he said.

Brown expressed concern about the need for most depressed patients to take antidepressants for long periods of time.

"Conventional medicine hasn't yet tackled the issue of long-term effects of prescription drugs," he said. "We hope they are insignificant, but there are no studies to assure us that these drugs are safe in the long-term. Part of our confidence derives from the clinical experience of prescribing tricyclics for over 35 years. Our experience with fluoxetine [Prozac] is only 12 years and with other SSRIs is even less."

Brown said that considering SAM-e's efficacy in treating depression, its mild side-effect profile, and its ability to boost antioxidants and protect DNA through methylation, this nutrient has advantages over prescription antidepressants.

 possible first-line treatment for affective disorders," Brown said.

There have been about eight controlled studies comparing SAM-e in the oral version in decent doses from 1989 through 1997, Brown said, adding that a recently published review article describes the details of those studies (Brown et al., 2000).

"What everybody wants right now is a study comparing SAM-e to an SSRI," he said. "There are five studies showing that SAM-e boosts regular antidepressants [e.g., TCAs] in both their efficacy and speed of onset of therapeutic efficacy (Berlanga et al., 1992; Friedel et al., 1989; Torta et al., 1988). And we need more controlled studies showing that SAM-e can be a booster for other antidepressants...Those studies will probably get going in the United States within the next year or two."

He added that there is a planned study comparing the combination of SAM-e and an SSRI to an SRI alone, but it has not yet been funded.

"In the future, perhaps SAM-e will become available...as a prescription drug approved by the [U.S. Food and Drug Administration]," Brown said. "In the meantime, physicians should be knowledgeable about SAM-e in order to advise patients on its appropriate use as a complementary treatment or as an alternative to traditional pharmacotherapy."

 Agnoli A, Andreoli V, Casacchia M, Cerbo R (1976), Effect of S-adenosyl-L-methionine (SAMe) upon depressive symptoms. J Psychiatr Res 13(1):43-54.


 Agricola R, Dalla Verde G, Urani R et al. (1994), S-adenosyl-L-methionine in the treatment of major depression complicating chronic alcoholism. Current Therapeutic Research 55(1):83-92.


 Andreoli VM, Maffei F, Tonon GC (1978), S-adenosyl-L-methionine (SAMe) blood levels in schizophrenia and depression. In: Transmethylations and the Central Nervous System, Andreoli WM, Agnoli A, Fazio C, eds. New York: Springer Verlag, pp147-150 [Italian].


 Bell KM, Plon L, Bunney WE, Potkin SG (1988), S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry 145(9):1110-1114.


 Bell KM, Potkin SG, Carreon D, Plon L (1994), S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl 154:15-18.


 Berger R, Nowak H (1987), A new medical approach to the treatment of osteoarthritis.


Report of an open phase IV study with adementionine (Gumbaral). Am J Med 83(5A):84-88. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H (1992), Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res 44(3):257-262.


 Bottiglieri T, Godfrey P, Flynn T et al. (1990), Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53(12):1096-1098.


 Bottiglieri T, Hyland K, Reynolds EH (1994), The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 48(2):137-152.


 Bressa GM (1994), S-adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl 154:7-14.


 Brown RP, Gerbarg PL, Bottiglieri T (2000), S-adenosylmethionine in the clinical practice of psychiatry, neurology, and internal medicine. Clinical Practice of Alternative Medicine 1(4):230-241.


 Brown R, Colman C, Bottiglieri T (1999), Stop Depression Now: SAM-e, the Breakthrough Supplement that Works as Well as Prescription Drugs in Half the Time…with No Side Effects. New York: Putnam Publishing Group.


 Cantoni GL (1952), The nature of the active methyl donor formed enzymatically from L-methionine and adenosinetriphosphate. J Am Chem Soc 74:2942-2943.


 Cerutti R, Sichel MP, Perin M et al. (1993), Psychological distress during puerperium: a novel therapeutic approach using S-adenosylmethionine. Current Therapeutic Research 53(6):707-716.


Dietary supplementation of SAM-e--naturally produced and physiologically necessary compound for living cells--is being investigated for its use as a viable treatment for depression. 

Leslie Knowlton

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