Mood disorders are rising exponentially in the younger population, affecting around 20% of young Australians.
We are well-aware of the effects of computer gaming, social media and the "online life" of teenagers, and how these influence mood, but what about dietary effects on depression, anxiety, anger and aggression? Compounding this is the fact that teenagers are notorious for poor sleep hygiene and compliance with medications and medical advice.
In today's podcast, Dr Adrian Lopresti takes us through his research into the positive effects of herbal medicines, and details his future research plans using well-accepted diet and lifestyle interventions to target teenage mood disorders in an integrative and wholistic way.
Covered in this episode
[00:58] Welcoming back Dr Adrian Lopresti
[02:15] Teenage Mental Health
[04:14] Building rapport with teens
[05:22] What do parents need to be looking out for?
[11:50] Factors influencing youth mood and behaviour?
[14:39] Aggression and addressing nutrient status
[18:13] Spotlight on Saffron research in teens mood disorders
[21:56] Mental Health Care Plans: is ten sessions enough to effect change?
[24:28] The research for natural therapies in youth populations
Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. Joining us on the line today from Western Australia is Dr. Adrian Lopresti. He's a clinical psychologist in private practice, and senior researcher at Murdoch University, Western Australia. He has over 20 years of clinical experience, working with children and adults suffering from a range of mental health conditions.
Dr. Lopresti has experience in a range of psychological therapies and has received extensive training in nutritional and lifestyle treatments for mental health disorders. He regularly publishes in peer-reviewed and high-impact journals on the effects of diet, nutraceuticals, sleep and exercise for the treatment and prevention of depression, anxiety, attention deficit hyperactivity disorder, that's ADHD, and bipolar disorder.
He's completed several clinical trials investigating the effects of curcumin, saffron and ashwagandha for the treatment of anxiety and depression in children and adults. And indeed has recently published, this year, 2018, a paper using saffron. Dr. Lopresti is also the founder of Personalised Integrative Therapy and regularly conducts workshops, both nationally and internationally.
Now, when we last had Adrian on FX Medicine, we spoke about his integrative approach to mental health. Today we're going deeper, into teenage depression and mood disorders. Now, I guess this is the question have you got five hours? It's a massive topic, Adrian, so welcome back to FX Medicine. How are you?
Adrian: I'm great. Thanks for having me back.
Andrew: Now, as I said, this is a huge issue. We're seeing more and more of it in our community. Indeed, more and more resources are being thrown at it because it's such a huge issue. How big, or how common is this issue, especially in youth?
Adrian: Yeah, it’s actually, yeah, it's quite a big problem. You know, it's estimated that about 10% to 20% of children and adolescents experience a mental health disorder during their youth. Which is probably even an underestimate. But, and it's particularly concerning because if you suffer from anxiety or depression as a youth, you're at greater risk of also then suffering from similar disorders as an adult, too. And then, obviously, the longer that you suffer from the condition, the harder it is to treat.
Andrew: We're seeing huge issues with self-esteem, bullying, social media, peer group issues, you know, all of these sort of issues regarding, or having an effect on our affect. How important is this in the profiling...is that the right word? The diagnosis in assessment of teenagers?
Adrian: Yeah, I mean if we...early intervention's the key. So if we can identify youth at risk, and obviously, the earlier we identify it, then the greater we have of either preventing it progressing into a full-blown disorder and the greater likelihood we have of having a successful treatment outcome.
So it's really important for us to be able to identify some of the risk factors associated with mental health problems in youth and then treat accordingly.
Andrew: And of course, we as adults rattle off these things about, you know, assessment, and then you have a teenager sitting in front of you that's, you know, looking rather closed and withdrawn and not really wanting your company. How do you get through to teenagers? How do you get them to open up?
Adrian: Yeah, it is difficult for some...for some teenagers, it can be quite difficult. For others, they're quite happy to come in and have a discussion. I mean, I think the issue with teenagers coming in for an assessment is that unlike adults, where generally, as a general rule, they've come in willingly and they're the ones that are making their appointment and so forth. With teenagers it's not necessarily the case.
You know, they're brought in because if mum or dad's concerned about them, and may not necessarily be a compliant recipient to treatment. So it's really important for us to develop rapport with them, and it may just take some time, firstly, to just get to know them first before we start getting into the nitty-gritty of what's going on for them.
Adrian: So, rapport is important for everybody, but I think it's particularly important with teenagers, in particular.
Andrew: Can I, out of interest, take a little step back here, and sort of think about this from the parent's perspective? And the reason I ask this is it's not uncommon for parents, you know, in their grief, to say “I never saw it coming,” you know, when they've got a teenage suicide. What sort of light bulbs need to go on? What warning lights need to go off, and why? What do we look for?
Adrian: Yeah, so it's something we do need to be aware of. I mean, although suicide is uncommon in teenagers, you know, it's less than 1% of teenagers. The reality is, though, that it is a particularly high-risk time. It's actually the third leading cause of death for 15 to 24-year-olds, so it's something we do need to be very mindful of.
Adrian: And some of the warning signs include, obviously, talking about death, saying things like, oh, yeah, no, I'd be better off dead. Even glorifying death, you know, talk around that would be, certainly, obviously, setting off alarm bells.
But the other hints would even be changes in behaviours, withdrawing from peers, spending more time on their own. You know, they might be light bulb moments that you need to consider and think about what's going on for my child. So, kind of that social separation, if they were quite social before and now they're no longer doing that, that's one that I'd be quite concerned about. If they're engaging in kind of greater at-risk behaviours or riskier behaviours, that can be another sign. I mean, obviously, if they're giving away treasured possessions and they're writing songs, or reading poetry, or writing letters about death, you know, they're all these things that we need to be mindful of.
Andrew: Well, no wonder it's so confusing. All of those things I was going, yep, I did that, yep, I did that, you know? Songs, yep.
So, how do you pick? I mean, this must be so confusing for parents. Is there any way that a parent can direct their child, and say, "Listen, I'm worried about you," you know, "I know that you're probably going to close down, but I'm worried about you for this reason." You know, "Are you thinking of killing yourself?" Have you ever, I guess, taught parents? Or is there any psychologist’s way of approaching this, for the parents to say you need to ask a direct question, or you need to ask an indirect question? How is it supposed to be handled?
Adrian: Well, it really varies. It varies depending upon the type of relationship the parent has with their child. So for some parents, where the relationship is quite open and quite a positive relationship, then, you know, certainly directly asking is not going to be a problem.
For others, where that relationship isn't there, then it may be more difficult getting information. So that's where I would kind of look at, well, you know, are there any other family members, or any other friends that can talk to your youth? So I would try to enlist the support of other significant others who may have a better relationship with the youth.
So, it is very individualised rather than a direct thing, but ultimately, if there's changes in behaviours, that, you know, those behaviours not characteristic for their youth. And also, you know, other particular alarm and stresses going on, has there been changes in their relationships? Has there been a breakdown in friendships, has there been a breakdown in, you know, a girlfriend/boyfriend relationship going on there? Has that changed? I mean, obviously, there’re risk factor is if there's parental divorce or separation going on, that increases the risk. So it needs to be kind of coincided with, you know, are there any other stressors going on that might increase the risk of suicidal ideation.
Andrew: So, how do you get teenagers, once you've sat down with them for an hour or so and you've had a little bit of an introduction, how do you get them to comply, to stick to, a re-visitation, adhering to their...hopefully, it's a mental health care plan? How do you get them to stick to that?
Adrian: Well, I think it's really about having that conversation with them. I think one of the things that I do when I'm seeing teenagers is, you know, I obviously first just try and develop some type of rapport with them. And then just talking a bit about their areas of...you know, what things are they interested in, are there particular areas that they want to change in their life, are there particular areas that they're not quite happy with? And then from there, talk a bit about, you know, how their mood might be impacting on their school performance, for example…
Andrew: Ahh, yep.
Adrian: If that performance is important. And so just something to engage them with. Is it socialisation, are friendships important to them? And what impact of their anxiety or low mood have on relationships?
So I think it's a...you know, even for some, I've got many who are very interested in sport and athletic performance, and so we might kind of use that as a, I suppose, a direction for us to move towards. We're going, okay, you've got your...you're interested in sport, you're interested in academic, then your athletic ability, is your...you know, are your mood problems impacting on your ability to perform in that area?
Adrian: So it's really just trying to see what they're interested in, and then try and engage them in that particular area.
Andrew: And of course, the mental health care plan...I say mental health care, but it's mental health plan, correct? Is that the correct terminology? Which in Australia is given as a six-visit thing, and then you can extend it. Is that right? Or five, is it, then?
Adrian: Yeah, so it's six visits, and then you can have another four visits per calendar year.
Andrew: So it can be extended next year. The wily practitioner, I guess, would start to use some at the end of one year, and some of the beginning of another. But anyway... Do you fe-...
Adrian: If it works out that way, of course.
Andrew: Yeah, that's right. Unfortunately, we can't control our minds. But anyway.
I don't know what that's like around the world. If our FX Medicine listeners would like to give us a bell on what's available for them in their country and their situation, we'd love to hear about how health care plans vary around the world.
Adrian: Yeah, there's lots of changes going on for teenagers, from a physiological point of view and that certainly can contribute to mood problems. You know, your changes in hormones, your testosterone levels in boys, and so forth. So I'd say that hormones do certainly play a part in youth mood.
I mean, the other thing, too, is also the environmental factors. Obviously, we've talked about kind of your bullying and your social pressures, but it is also your academic stressors, things like that that are going on. The other thing, too, you’ve got your, even what's going on in the home? What's the home environment like?
Adrian: What's the parent's relationship like? So it may not necessarily have to do specifically with them, but it could be that their parents, that they're going into a home environment that's not very positive, and that, obviously, will affect their mood.
And then you've got things like the desire for independence, and negotiating that independence with parents, and the conflict that often occurs around that. You've got for some, for many teenagers, your poor diet, your disrespect of sleep, I suppose, that often occurs, too. And then your technology and social media use.
So all those different things can affect their mood, and ultimately, it's about trying to identify what specific factors are influencing the person sitting in front of us, which could be very different to someone else coming in.
Andrew: And do you find that teenagers are receptive or non-receptive to assessment tools, like for instance, you know, the HAM-A, the HAM-D, the DASS, you know, rating scales that are freely available?
Adrian: I don't use a lot of questionnaires with youth, to be honest. But generally, I'll use questionnaires if they're struggling with verbalising and talking, so I might use that as a kind of a discussion point. And I'm not so much interested in the final score, I'm interested in the questions, the answers that they give to a particular question. So if they say... And that might then be the discussion point.
So let's say they say they're not...you know, their sleep is poor, they give it a rating of zero, for example, indicating that it's poor. Then I might then use that to talk a bit about their sleep, what's going on with their sleep? And use that as kind of a point of discussion. So, I'm more interested in the, I suppose, the qualitative information that I get from the questionnaires, rather than an ultimate score indicating that it's high or low.
Adrian: A lot of teenagers will, and even children, will display their sadness through aggression. And particularly boys. So it's very difficult to...you know, a lot of the symptoms are not dissimilar to adults.
So I think if there's a lot of aggression, and that's not characteristic, if there's a lot of moodiness that's occurring, then that might be a warning sign of sadness and low mood going on.
Adrian: And that, again, then requires a bit more questioning and assessment around that.
Andrew: And, you know, indeed, there's been some nutrient implications with aggression, whether it be a deficiency or even an overload. Do you assess for these? Do you question, or do you look at maybe demographic factors? Like, for instance, I understand Perth is quite high in copper, and what was...was there another heavy metal that was implicated in aggression somewhere?
Adrian: Yeah, look, I mean, I don't necessarily organise a lot of blood assessments for teens. I think it's really...it can certainly be useful to do. But if they're not even wanting to be there, it can be very difficult for them to then see me, and then I've got to refer them to go to GP to get a blood test done.
Andrew: Yep, got you.
Adrian: So I might then just educate...if I can then engage them, and they are interested in improving their mood, and they go, "Yeah, it is impacting on my life. And it is impacting on a particular area of my life that I think is really important," then we'll talk about what factors can affect mood. And I'll talk a lot about diet and nutrients, and provide some education around how that affects our mood. And then we might just talk a bit about, let's say, for example, zinc, and we'll talk about some of the foods that are high in zinc, and what foods that they're consuming that may be high in zinc, or if they're not consuming that at all, and we'll kind of develop some goals around maybe just modifying that.
But again, it needs to be realistic. I think if we are recommending drastic changes in diet, there's probably 1% of, well, in my experience, you know, 1% to 5% of youth are quite happy to look at dramatic changes in their diet, and the rest of the 95%, there's no way I can engage them with that.
So we'll just look at modifying certain areas, try and incorporate extra fruits and veggies, or they might set some goals to eat a particular food that's high in zinc every couple of days, and we'll work towards that. We might supplement...generally, youth are pretty good at taking supplements, so that's often, then, an easier way them to take it.
Andrew: That's really strange. I would have thought they'd have a compliance issue with supplements. Not so, you reckon?
Adrian: Well, it all depends. I think a lot of...some teens can be very resistant to changing their diet. And so really, then, I'm looking at, well, where can we change? And although supplements are not ideal, and you want to try to derive a lot of the vitamins and minerals from...at least the base from a good diet, some teens are just not willing to make those changes.
Adrian: So we've made it easier for them to take a zinc tablet, or omega-3 fatty acids, or things like that. And it just depends, you know. Some teens are open to changing their diet, but I think there's more resistance for a lot of them.
Andrew: Yeah. Research on nutraceuticals and herbs and nutrients for the treatment of youth mood and behavioural problems is increasing. You've, indeed, been involved for quite some time, and you've got a recently published study on saffron. Can you please take us through this? What was it useful for? What was your cohort? And what did the results tell you?
Adrian: Yeah, well, I looked at the effects of saffron for anxiety and depressive symptoms in teenagers. I wrote a paper several years ago looking at, just reviewing, some of the nutrients for depression, in particular for youth. And I was quite alarmed, actually, at the lack of good quality research looking at nutrients with youth, and there wasn't a lot of good controlled studies. So that kind of then triggered me to really want to do more research looking at the effects of nutraceuticals in youth.
And so I managed to get some funding to look at the effects of saffron, I use a patented saffron extract, with youth. And it was an eight-week study, where they took 14 milligrams of saffron twice a day for eight weeks. And so it's a double-blind, placebo-controlled study. And the kids that I recruited were teenagers not with diagnosed depression or anxiety, I wanted to look at kind of your moody youth, I suppose. Ones who had kind of...were reporting anxiety or depressive symptoms, but not necessarily having a diagnosis.
And what we found was that in terms of looking at the internalising symptoms, so the anxiety and depressive symptoms collectively, there was I think about a 35% reduction in symptoms over the eight week period. Compared to only about 17% in the placebo. So it was really quite positive, the results were statistically significant, and probably clinically meaningful, too.
So just by taking saffron, we're looking at at least, you know, a 20% improvement, compared to a placebo, in their mood, which is really positive.
Andrew: Mmm, really positive. And what was the cohort size?
Adrian: So, it was...we recruited 80, and I think about 65 or so finished the study.
Andrew: Oh, that's decent. That's very decent, particularly for teenagers. Like, that's really decent.
Adrian: Yeah. Yeah. What we also did… we got the teenagers to do some questionnaires over the eight weeks, and then we also got parents to rate their youth, too, in terms of their mood. So we got the two perspectives. And what we found was that the effects were greater in the youth. So they reported generally better improvement, compared to their parents. And I'm not sure why that was the case. What seemed to be the case is maybe the youth self-reports are a more a reliable measure of mood than the parent's reports of their youth, if that makes sense. And so...I don't know, we'll see.
And now, I suppose the other thing, too, is that if parents, if a youth are suffering from anxiety and depression, it could also be that the parents have their own mental health issues, too.
Andrew: Yeah, yeah.
Adrian: So for them to be able to see some of the changes in the youth might be difficult.
Andrew: Yeah. And maybe not cognisant of the actual issues presented with their offspring. Wow. That's both enlightening and sad, at the same time.
Adrian: Yes. Exactly.
Andrew: I think it says something about the stressors in our whole society. And with regard to...I was going to ask you earlier, with regards to the mental health plans, when you've got, you know, a five, maybe an added on four...oh, sorry, six, maybe added on four visits, so a potential maximum of ten in a year, what's the realistic time to see a real result? I mean, we're talking about things like self-perspective, self-esteem, self-awareness. What's the realistic time to expect a result in a teenager vs. what's subsidised?
Adrian: Look, the research does show that most change occurs in the first few sessions.
Andrew: Ahh, okay.
Adrian: And that's the case with adults, and I don't expect it to be that much different with youth. So I kind of stopped complaining about the ten sessions a long time ago. The reality is that's what I've got, and that's what I've got to work with, so there's no use complaining about it.
So within that, I go, I know I've got ten sessions. Obviously, people can come in more, but now they're going to be totally out of pocket for my sessions when they come and see me. But if I know that I've got sessions, I go, well, what can I do, you know, in those ten sessions? And there's lots that I can do, but I don't have to do it myself.
So I know that social connections is really important for them, so what about if, as part of my work, I try to connect them with a youth group? I try to do some work by developing or getting them engaged in some type of hobbies or interests or sporting activities? That's where the change is going to occur, not in my office.
Adrian: So part of my work is also about trying to change their environment. I'm also teaching them, if I think their sleep perhaps, sleep hygiene is poor, you know, it doesn't take long...you know, within a week you can change some of your sleep hygiene. The key is the motivation to change. But if we know that if we can sleep an extra hour or two a night, the impact on our mood is huge.
So ten sessions is what I've got, and ten sessions is what I'll work with. I might not be able to change the core belief systems, and....but I'll have had that ten sessions to be able to do that. And then maybe we can do a piece of work now, and a piece of work next year, or the year after, when they're ready.
Andrew: Going back to that saffron study, forgive me, I totally forgot to ask you before. How quickly did subjects respond to the intervention?
Adrian: Yeah, we did...every two weeks we got them to complete the questionnaires.
Adrian: So, everybody starts getting better in the first two weeks, whether you're on placebo or not on placebo...or on saffron. So, there's changes that are occurring within the first two weeks. And I think the changes within the first two weeks were statistically significant for both placebo and saffron.
Adrian: So even if you put somebody on placebo, they'll feel better. As a general rule, they'll feel a little bit better after two weeks. Now, obviously, they continue to get better. And what it seemed to do, it was about four weeks, they'd almost reached their peak and if they weren't better after four weeks, they probably weren't going to get any more better, if that makes any sense grammatically.
Adrian: But, so about four weeks, they hit their peak, and maybe they got a little bit better in the second four weeks. But you know, the improvements occurred quite rapidly.
Andrew: And can you just discuss a little bit about safety aspects of saffron, say, with perhaps, long term treatment, for those people that might need it?
Adrian: Well, with this study, the saffron was very well tolerated. In actual fact, there was a tendency for less reported headaches in people on saffron, compared to those on placebo. So, very well tolerated.
The issue with a lot of saffron studies is that the longest studies are generally...there's one study done with Alzheimer's patients, which went for a year, but that was the only one that's been done for a longer period. So the studies are generally about eight weeks long and well-tolerated.
So you know, it's safety over a longer period we're not quite sure about. I suspect it would be very, very safe. But we just don't know, so... And the other thing that I don't know is, you know, we've given a dose of the 15 milligrams twice a day, what I would normally...well, I suppose what would be useful to do is if they weren't better after four weeks, if we had titrated it up, if we had increased the dose to 30 milligrams twice a day, could those non-responders start responding?
Andrew: Ohh, now that's interesting.
Adrian: Yeah, and that's another study.
Adrian: We're always giving 15 milligrams twice a day for all the studies, but we don't know whether that's the optimal dose.
Andrew: I mean, that's interesting. And I take your point, like, we're dealing with saffron. And I think this is the thing where, you know, yeah, I get, you know, for the sceptics of natural medicine. I get that we'd love larger sample sizes. I get it. Yep, sure. We need more research, give us some money. Give you some money, give Dr Adrian Lopresti some money.
Adrian: Exactly. Yeah. I'm happy to have it.
Adrian: My bank account's ready.
Andrew: But I think the thing that people should be cognisant of is, especially in sensitive or vulnerable populations, safety is a massive aspect to consider. Particularly with psychoactive substances, you know, so this is something that really should seriously be looked at, it really, really should.
Adrian: Yeah, I think you're exactly right. I think that for a lot of teenagers, or for youth and children, I mean, we're looking at...you know, the research is on your psychological therapies, or your pharmacological treatments. And the research isn't that good on the pharmacological treatment for depression and anxiety in youths.
Andrew: No, that's right, it's not. Yeah, and particularly long term. Yeah.
Adrian: Yeah, absolutely. So, the next option is a look at some of your natural therapies for youth, and looking at things like saffron, and... And this is the first study ever being done on saffron for youth, and I'd say that'd be the case for a lot of natural therapies.
Adrian: You know, there's a little bit there with omega-3s for depression, but a lot of the common herbs and, you know, ashwagandha, for example, there's no research in youth. Curcumin, there's no research in youth. St. John's Wort, there was a couple of really poorly designed studies with youth. So even St. John's Wort hasn't been investigated with youth.
Adrian: So it's just an area that's just not touched.
Andrew: When you see other research, and you look at it, you know, with these negative effects and so they go, "No effect, no effect, no effect," do you find that they're either ignorant or mischievous? Do you find that, like, how could you just give a herbal supplement without addressing your diet? You can't have a fast food diet with high trans fats, high sugar, high carb along with a nutraceutical or a herbal intervention. Do you find that a lot of these studies are poorly done because they don't take heed of how important diet is?
Adrian: It’s… you're right, it's crazy. I mean, the studies that I'm doing, we're looking at one...we're giving a saffron supplement. You know, and they could be eating junk food all day, their sleep is poor, they're using drugs, and I'm giving them a saffron tablet. I mean, let's be serious here. And I would do my clients a disservice if they come into my office and they describe suffering from depression or anxiety, and I go, "Here, take this tablet, and go away."
Adrian: You know? And unfortunately, that's the way studies are done. And then if you did include multiple treatments or multiple components in your study, it's criticised because they go, "Well, we don't know which one worked." It's like, well, who cares?
Andrew: So the problem is the science. The problem is what we used as a control.
Adrian: Yeah, exactly. Exactly. And it's really that integrative approach, which I'm a huge advocate of, is looking at the multiple components and putting it all together, and small changes in several areas. Each on their own may not be that powerful, but collectively, extremely powerful.
And that's where the research needs to be headed towards, incorporating an integrative approach. We don't care which bit of it worked, or which was more powerful. In the end, the whole program works collectively.
Adrian: And, you know, I'm hoping to conduct a study looking at that integrative approach, which is something I've developed as a program, called Personalised Integrative Therapy, which incorporates all the different modalities or areas that can affect mood. And let's put it all together as a program and see if that is going to result in significant improvements, compared to, say, cognitive behaviour therapy.
Andrew: Well, I for one, and I'm sure all of our listeners can't wait for the results of that to come out. Please give more money to cover... Adrian, like, you do really good work. And not just for research purposes, but for your patients. And this is who, all of us, like, this is the whole point of what we do. It's for the patients. Well done to you, I've got to say. I take my hat off to you.
Adrian: Thank you.
Andrew: You've done well, son, keep going. You do awesome stuff, really. It's brilliant work.
Adrian: Yeah, thanks. I mean, it's something I'm passionate about. And, you know, I learned a lot from, you know... I'm not even a very original person, I just take a look at what's been already done and I try to put it together, and take the best bits of everybody else's good work and put it together. And I learned a lot from other practitioners, and I learned a lot from my clients, you know. The amount of teaching that I've had from them has been immense, so I have significant gratitude towards them, and other practitioners.
Andrew: Well, we have our gratitude to you, and we are certainly learning from your investigations. So, thank you so much for joining us on FX Medicine today.
Adrian: Thank you. Thank you for having me.
Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.
|Dr Adrian Lopresti|
|Personalised Integrative Therapy|
|Murdoch University: Dr Lopresti's Research|
Lopresti AL, Drummond PD, Inarejos-García AM, et al. affron®, a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: A randomised, double-blind, placebo-controlled study. J Affect Disord. 2018 May;232:349-357.
Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014 Nov;29(6):517-27.
Tsolaki M, Karathanasi E, Lazarou I, et al. Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. J Alzheimers Dis. 2016 Jul 27;54(1):129-33.