van gogh wheat field

Depression
Author Paul Kenyon
Google
Overview:
This lecture is 'a wolf in sheep's clothing'. It is important that psychologists understand something about the metabolism of catecholamines. On its own this can be a rather dry topic, therefore the facts are presented in the context of a theory of human depression.

Hopefully you will begin to appreciate why it is important to know the dry facts so that they can be used to formulate an effective treatment for a very serious human illness.

n addition, I will explain to you the rationale for animal models of human behaviour so that you can begin to decide for yourself if it is justifiable to use animals in experiments. This is a complex question, but by the end of your studies you will have been exposed to sufficient information to form an informed opinion - one way or the other.

Learning objectives
After studying the material on this page you should be able to:
  • recognise the signs of clinical depression
  • list two catecholamines
  • identify DA and NA pathways within the brain
  • describe the synthesis of CAs and list the enzymes involved and the reactions they catalyse
  • describe the effects of AMPT, disulphiram, a MAOI, reserpine, amphetamine, COMT and tricyclics on neurotransmission
  • write a rationale for animal models of human behaviour
  • state the CA theory of mood, & list two predictions from it
  • list and explain the action of drugs that could be used to test the CA theory of mood
  • describe the main components of a Skinner box
  • explain how a cumulative recorder shows performance on an operant schedule
  • describe Sidman avoidance behaviour
  • describe the effects of tetrabenazine, a MAOI and a tricyclic antidepressant - alone and in combination - on operant behaviour and evaluate the results in the light of the CA theory of mood

Signs of clinical depression
Warning! The information provided below is to be used for educational purposes only. It should NOT be used as a substitute for seeking professional care for the diagnosis and treatment of any medical/psychiatric disorder. The diagnosis and treatment of depression and other psychiatric disorders requires trained medical professionals.
I have included this information in the lecture because a significant number of depressed people contemplate suicide, some attempt suicide, and some of these attempts succeed. Therefore depression is a serious disorder and should be considered life-threatening. If you think you or a friend is depressed - Seek Help - the majority of depressed people can be helped by modern psychiatric treatments.

How do you know when what you are experiencing is just a bad day or something more serious? We all have our ups and downs depending on how our day or week is going. The transition from bad day to rut to clinical depression can be gradual and leave even the strongest person thinking, "What is wrong with me? I just have to try harder! Why am I so lazy? Why can't I get out of bed?"

If someone experiences most of the following symptoms for more than two weeks, there is a good chance they are suffering from a clinical depression.

Symptoms of depression
  • Concentration is often impaired
  • Inability to experience pleasure
  • Increase in self-critical thoughts
    with a voice in the back of one's mind
    providing a constant barrage of harsh, negative statements
  • Sleep disturbance or unable to fall back to sleep
  • Feeling fatigued after 12 hours of sleep
  • Decrease in appetite or food loses its taste
  • Feelings of guilt, helplessness and/or hopelessness
  • Thoughts of suicide
  • Increased isolation
  • Missing deadlines or a drop in standards
  • Change in personality
  • Increased sexual promiscuity
  • Increased alcohol/drug use

 

Point to ponder
If depression has a biological basis why is diagnosis based on clinical interview rather than a blood or urine test?


Some very famous people have suffered from depression, for example:


Beethoven Ludwig van Beethoven wrote "...my misfortune pains me doubly, in as much as it leads to my being misjudged. For me there can be no relaxation in human society; no refined conversations, no mutual confidences. I must live quite alone and may creep into society only as often as sheer necessity demands; I must live like an outcast. If I appear in company I am overcome by a burning anxiety, a fear that I am running the risk of letting people notice my condition...such experiences almost made me despair, and I was on the point of putting an end to my life - the only thing that held me back was my art. For indeed it seemed to me impossible to leave this world before I had produced all the works that I felt the urge to compose, and thus I have dragged on this miserable existence..."
- from Emily Anderson, The Letters of Beethoven, Vol. 3

 

Vincent van Gogh (1853-1890) is generally considered the greatest Dutch painter after Rembrandt; he powerfully influenced the current of Expressionism in modern art. His work, all of it produced during a period of only 10 years, hauntingly conveys through its striking colour, coarse brushwork, and contoured forms the anguish of a mental illness that eventually resulted in suicide.
To me, these self portraits capture the decline of his mental condition.
Autumn, 1886
v-gogh-paris-1886
January, 1889
v-gogh-arles-1889
September, 1889
v-gogh-saint-remy-1889
These portraits of other people may also reflect his mental condition.
Winter, 1886/87
woman-1887
October, 1889
patient-1889
June, 1890
doctor-1890



van gogh painting wheatfield,1889
David Brooks wrote:
"Vincent van Gogh's final works are a paradox and this is probably no better demonstrated than in his work Wheat Field with Crows, shown here. Vincent's mental state during the last six months of his life fluctuated wildly. At times, Vincent was in good health and in seeming perfect control of his faculties; at others he was deep in the throes of complete mental breakdown. Some of his best, and most moving works come from these months. There's a peace and near contentment in many of the paintings of parks and fields he undertook while in Auvers-sur-Oise. Given that, how then can one interpret Wheat Field with Crows? This is one of Van Gogh's final works and is among the most controversial. Many feel that the dramatic and stormy skies, as well as the churning wheat field with the ominous crows rising above it, are a clear reflection of Vincent's own mental state in his last days. Others find some glimmer of hope in the vibrant colours and the path which may finally lead to peace at last. Whatever the case, it's clearly one of Vincent's greatest works and, given the ultimate tragedy of his too-short life, one of the most moving. "


Commentary from David Brooks' Vincent Van Gogh Information Gallery - a rich resource on the artist's life and work.


  • Scots writer and poet Robert Louis Stevenson (1850-1894), best known for works such as 'Treasure Island', 'Kidnapped', and 'The Strange Case of Dr. Jekyll and Mr. Hyde', showed symptoms of manic-depressive illness early in life; once, reminiscing how as a child he would lie for hours in bed in a "miserable exaltation," . On a winter day, he wrote "Let me get down on the hearthrug, full of laudanum grog, or as easy as may be, into the nice wormy grave."
  • Shakespeare's fictional character Hamlet is the manic-depressive that everyone can relate to in some sense. Hamlet shows a full range of emotions, beginning with confusion and depression, to melancholy and eventually murderous rage.
  • The British wartime prime minister, Winston Churchill, suffered from what he called "Black Dog", Churchill's name for depression
  • The recent Russian president, Boris Yeltsin, may have experienced periods of depression.
  • The Supplementary material section at the end of this page contains links to pages which discuss the impact of depression on the lives of these and other famous people.
Point to ponder
What part has madness played in human evolution?

The Catecholamine Theory of Mood

The catecholamine theory of mood was suggested by Schildraut and Kety. They suggest that:

This proved to be a very fruitful theory because it was put forward at a time when there was an explosion in our knowlegde about where neurotransmitters were located in the brain, and the discovery of chemicals that interfered with the manufacture and actions of various neurotransmitters in the brain.

Points to ponder
Is this a correlational or a causal theory?
Does this theory explain the cause of depression?
Could this theory lead to a successful treatment for depression?

Catecholamines: Dopamine & noradrenalin
da-na-moleculesDopamine and noradrenalin are both members of a family of chemical molecules called catecholamines.
Noradrenalin is also known as norepinephrine
The following abbreviations are commonly used:

This diagram shows that the DA and NA molecules are very similar.


Dopamine pathways in rat brain
Dopamine pathways in rat brain DA pathways originate from groups of cells in the rostral areas of the brain. These groups were given the titles A8, A9, and A10 by the Swedish neuoanatomists Falck and Hillarp who developed ways of visualizing catecholamine cells in the brain in the 1960s.

DA neurones are organised into pathways in the brain.

Relatively few brain cell contain DA. There are over 10 billion cells in the human brain, only 1 million contain DA. Nevertheless, they play an important role in our behaviour.

For example, increased DA activity in the mesolimbicocortical has been implicated in schizophrenia. The nigrostriatal system is damaged in Parkinson's disease. Drugs with addictive potential release DA in the nucleus accumbens.


Noradrenalin pathways in rat brain

The nuclei that give rise to noradrenergic pathways lie in the pons and medulla. They travel forwards in a dorsal and ventral noradrenergic bundle which come together to form the medial forebrain bundle as the pathways traverse the hypothalamus.
Noradrenalin pathways in rat brain

This lecture explores the theory that depression is associated with reduced activity in this pathway.


Synthesis of Dopamine & Noradrenalin
Here is a very important diagram.

It is important to learn the steps in this metabolic sequence because many drugs that are used to investigate the role of neurotransmitters in behaviour work by interfering with particular steps in this process.

Notice the subtle molecular changes brought about by the enzymes involved in catecholamine synthesis. The term metabolism is used to describe the chemical processes involved in the manufacture and breakdown of neurotransmitters.


Effects of drugs on catecholamines

You will recall this diagram from the previous lecture on neurotransmission. It shows that neurotransmitters are stored in vesicles which are transported to nerve endings where they are released by an action potential travelling down the axon.


There are a number of ways in which drugs interfere with catecholamine metabolism:


These drugs have been used to study the effects of increasing and decreasing neurotransmitter levels on behaviour

Effects of drugs on catecholamines

 


Point to ponder
How do you think this information might help us alleviate human suffering?

Predictions from the Catecholamine Theory of Mood

The catecholamine theory makes the following predictions:


Drugs used to test the Catecholamine Theory of Mood

You now have a body of knowledge that can be used to test the catecholamine theory of mood.

Drug Effect on the catecholamines DA and NA Predicted effect on depression
Reserpine depletes CAs produce depression
Tetrabenazine (TBZ) depletes CAs for a shorter length of time than reserpine produce depression
Alpha-methyl-para-tyrosine (AMPT) inhibits the enzyme tyrosine hydroxylase - stops CA synthesis produce depression
FLA-63 inhibits the enzyme dopamine-beta-hydroxylase - stops conversion of DA into NA. Theory does not make clear prediction
Disulphiram inhibits the enzyme dopamine-beta-hydroxylase - stops conversion of DA into NA. Theory does not make clear prediction
Pargyline inhibits the enzyme monoamine oxidase (MAOI) alleviate depression
Iproniazid inhibits the enzyme monoamine oxidase (MAOI) alleviate depression
Imipramine inhibits CA reuptake alleviate depression

At first glance you might be tempted to use only those drugs that are associated with clear predictions - for example reserpine and pargyline - to test the theory. But it would be premature to dismiss the dopamine-beta-hydroxylase inhibitors as useful agents. The catecholamine theory does not distinguish between the roles of DA and NA in depression. Using a dopamine-beta-hydroxylase inhibitor may help to make the relative roles of these two neurotransmitters in depression.

Point to ponder
Can you think of a way to use a dopamine-beta-hydroxylase inhibitor to distinguish between the role of DA and NA in depression?

Rationale for animal models of human behaviour

Psychologists use animal models to test biological theories of human behaviour. A model is a simple representation of a complex system. For example, a model aeroplane or train looks similar to the real thing but lacks all the features of the full size object. An animal model of depression is an attempt to capture the essence of the condition, but it does not claim to reproduce the human condition in an animal. Depression is a uniquely human condition. The purpose of an animal model is to discover novel medicines that combat the abnormal behaviour in the animal model which could be then be used to alleviate human suffering.

The development of an animal model often begins with the accidental discovery that a drug produces abnormal behaviour in otherwise normal people. Psychologists interested in the biological bases of abnormal behaviour then follow these five steps to determine whether it would be worthwhile using the drug to construct an animal model of the abnormal human behaviour.

Steps in the construction of an animal model
1 Drug X has a behavioural effect in humans that resembles human pathology e.g. drug X produces depression when given to humans
2 Drug X produces similar behavioural effects in animals, allowing for any species differences in behaviour
3 Drug X produces specific biochemical effects in animals
4 Thus the biochemical effects produced in animals provide data relevant to the behavioural effect of drug X in humans
5 If the behavioural effect of drug X in humans has the same characteristics as pathological behaviour, then the biochemical changes produced by drug X in animals may also provide data relevant for the understanding of the abnormal human behaviour.

One of the first animal models of depression involved the use of drugs that reduced catecholamine levels in the brain. Here are the steps that encouraged neuroscientists to develop an animal model that involved injecting rats with reserpine or tetrabenazine.

Rationale for the tetrabenazine/reserpine animal model of depression
1 About 15% of humans treated with reserpine for hypertension develop depression
2 Reserpine and TBZ produce profound disruptions of conditioned and unconditioned animal behaviour
3 Reserpine and TBZ produce profound depletion of catecholamines
4 Thus the depletion in CAs may be related to human depression - this is the CA theory of Mood
5 The depression produced by reserpine in humans is similar to 'naturally occuring' depression. Thus CA depletion may be responsible for 'naturally occuring' depression.


Point to ponder
  • Why do you think only 15% of humans treated with reserpine for hypertension develop depression?
  • Do you think it is justifiable to use animals to develop models of abnormal human behaviour?
  • Do you think it is justifiable to use animal models to develop medicines to alleviate human suffering?

 

The next part of the lecture explores the tetrabenazine/reserpine animal model of depression. Here are some stills from an animation showing the effects of reserpine on transmitters.

 

Skinner box
At this stage in the lecture you are armed with a theory of depression, and knowledge of the drugs which can be used to test predictions made by the theory. We now need to consider how we can measure the effects of drugs on an animal's behaviour. An area of psychology called psychopharmacology is concerned with the effects of drugs on behaviour. Exploring the effects of drugs on operant schedules of reinforcement has a long tradition in psychopharmacology. But first we must explore the technology used by psychopharmacologists.

Skinner boxThis picture gives an idea of the facilities available in an operant chamber, or Skinner box.

The box is equipped with a lever; responses on the lever are recorded on a cumulative recorder (see below). Reinforcements in the form of food, water or electric shock can be delivered according to the contingencies of reinforcement setup by the experimenter.

Electric shock can be delivered to the animals feet through the floor of the box which consists of a grid of parallel rods. Food or water can be delivered through a food trough to one side of the lever.

The box is equipped with lights and a speaker for the delivery of stimuli which can come to control the rat's behaviour.


Cumulative recorder: Diagramatic representation

How a cumulative recorder works. The paper unrolls (yellow roller) under the two pens at a constant speed (normally 5mm/min, but speeded up in this demonstration).

Each bar-press moves the response marking pen a small increment to the left along a brown steel bar . Note that when the pen reaches the left hand edge of the paper, it is automatically reset to the baseline on the right hand side. An automatic reset is indicated by a vertical line running from left to right of the paper. Automatic resets can be programmed to occur at fixed time intervals e.g. every 15 minutes. Reinforcements are indicated by a short blue diagonal slash on the cumulative record.
Cumulative recorder: Diagramatic representation

The relative angles of successive slopes gives a visual indication of the regularity in response rate. Steep slopes reflect high response rates and vice versa.


Sidman avoidance schedule
Avoidance schedules are very useful to psychopharmacologists because the rat's motivation does not change during a test session. A rat may grow less hungry during a long test session because it is receiving food pellets for pressing the lever. In contrast, the motivation to avoid shock does not wane with the passage of time.

A rat working on a Sidman avoidance schule has no external signal to mark the onset of shock. A shock is delivered to the rat that lasts 1-2 seconds at regularly spaced intervals (the shock-shock interval; normally 5 seconds). The presentation of shock can be delayed by a fixed time interval ( the response-shock interval, normally 20 seconds) if the rat presses a lever.

The library has us all on a Sidman avoidance schedule. You can borrow a book for 14 days. If you take it back before the loan period is up, you can sign it out for another 14 days. If you don't take it back within 14 days you start to get fined. Every day you keep the book beyond the loan period the fine rises. Thus the library is operating a 14 day response-shock (borrow-return) interval, and a 1 day shock-shock (fine-fine) interval. A smart person who was a slow reader would return the book to the library every 13-14 days and keep renewing the loan period.

Well trained rats can show very accurate time discriminations - responding every 19 seconds and rarely getting shocked; we don't really know how they do this, but they certainly don't wear Rolex!

The library has a book by Murray Sidman "Tactics of Scientific Research" in which he describes this behaviour in some detail, and more importantly lays out the behaviourists' approach to the study of behaviour which you will find is very different to the line taken in your course on Experimental Design & Statistics!


Tetrabenazine: An animal model of depression?
Tetrabenazine (TBZ) depletes catecholamines (NA & DA) and was used to test the Catecholamine Theory of Mood.

The picture below illustrates the effects of tetrabenazine on the avoidance behaviour of a rat trained to avoid electric shock on a Sidman avoidance schedule. Compare control (A-1,A-2) performance (steady response rate) with the effects of 2.0 mg/kg TBZ (B1-B3).
Response rate declines dramatically about 25 min after injection of the drug.
the effects of 2.0 mg/kg TBZ

The next set of cumulative records shows the protective effects of iproniazid - a monoamine oxidase inhibitor (MAOI) - against tetrabenazine.  Note how response rate is actually increased following pretreatment with iproniazid and tetrabenazine. This effect is outlined in red on the diagram.

pretreatment with iproniazid before tetrabenazine

These results were reported by G.A. Heise and E. Boff (1960) J.pharmacol. exper. Therap., 129, 155-161, and are described by David Warburton in his book Brain Behaviour and Drugs, Wiley, 1975 which is available in the library. David supervised my PhD research which involved the use of TBZ, and David himself was a PhD student with George Heise in Indiana. I am grateful to both these great teachers for introducing me to the biological bases of behaviour.

We can now use some of our knowledge about CA synthesis and the drugs that affect it, to test the hypothesis that CAs are responsible for the short period of behavioural excitation following TBZ injection in rats pretreated with a MAOI.


The next slide shows the effect of injection the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) on responding in MAOI+TBZ treated animals. Note how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the AMPT injection. This result tells us that one of the CAs - dopamine or noradrenalin - is involved in this effect. But which catecholamine: DA or NA?
the effect of alpha-methyl-para-tyrosine (AMPT) on responding in MAOI+TBZ treated animals


The next slide shows the effect of injection the dopamine-beta- hydroxylase inhibitor, disulphiram on responding in MAOI+TBZ treated animals. Note once again how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the disulphiram injection. This result suggests that NA is responsible for the behavioural excitation following MAOI treatment.
the effect of disulphiram on responding in MAOI+TBZ treated animals


Tetrabenazine and imipramine

At this point in the story you might think we have succeeded in producing a pretty good animal model of human depression that could be used to test novel drugs for antidepressant potential. The logic would be that if a new drug reversed the disruption of conditioned avoidance behaviour produced by 2.0 mg/kg TBZ then it would be a potential candidate for clinical trials in humans. But there is a sting in the tail of this story.

The first thing we need to do is ask whether other antidepressant drugs reverse TBZ-induced behavioural disruption in our rat model. We already know that tricyclic drugs such as imipramine are effective antidepressants. Unfortunately imipramine does not antagonise the effects of 2.0 mg/kg TBZ.

But imipramine does interact with TBZ in an interesting way. A very low dose of TBZ (0.2 mg/kg) on its own does not interfere with conditioned avoidance behaviour. When this low dose of TBZ is given in comination with imipramine, a period of behavioural excitation is seen - but not until 2.25 hours after the TBZ injection.
This effect is illustrated in the next diagram. The late period of excitation is outlined in red.
Tetrabenazine and imipramine

Point to ponder: From what you know about the mode of action of tricyclics and MAOIs, can you think of an explanation of these drugs' interactions with TBZ?

 

Summary of TBZ antagonism studies
Here is a summary of the current state of our slightly battered animal model of human depression.

  Antagonism of tetrabenazine at
Antidepressant group 0.2 mg/kg 2.0 mg/kg
Tricyclics Yes No
MAOIs No Yes

That's as far as we can take the story in this module of the 'ups and downs' encountered trying to construct simple models of complex human emotional states. One obvious problem with this model is the issue of theraputic-lag. It been known for some time that the antidepressant effects of drugs like imipramine take some time to develop - typically 21 days or more. This is clearly at variance with the rapid changes of behaviour seen in the animal model we examined. But don't get too depressed.

Bear in mind that I am not aiming to give you 'cut and dried' answers to the biology of depression. Instead, I am trying to introduce you to a way of exploring possibilities in a scientific manner. At the end of the day there are no clear-cut answers. We have some good clues to what is going on, but the truth - whatever that is - eludes us. This is what makes it an exciting research area!

The research I have described was carried out some time ago and there have been significant changes in our theoretical understanding of depression at a biological level which we explore at a later stage in your course.

You can read more about contemporary research at Depression Central which describes itself as follows: "This site is Internet's central clearing house for information on all types of depressive disorders and on the most effective treatments for individuals suffering from Major Depression, Manic-Depression (Bipolar Disorder), Cyclothymia, Dysthymia and other mood disorders. "


Names of common drugs used to treat disorders of mood


Prozac

Pharmaceutical companies were quite successful in synthesizing drugs which ameliorated depression by changing the actions of various neurotransmitter systems in the brain. These early drugs, while very effective, not only blocked the uptake of serotonin into neurons, but also prevented the uptake of other neurotransmitters. Researchers felt that a drug which only affected the serotonergic system might be better at treating depression than these so called "dirty drugs" that caused massive changes in brain chemistry. They set out to synthesize a drug which would specifically block the uptake of serotonin without blocking the uptake of other neurotransmitters in the brain. Prozac is that drug, a selective serotonin reuptake inhibitor (SSRI).

(I will tell you more about serotonin and its synthesis in a later lecture.)

Prozac and other SSRI's act by blocking the reuptake of serotonin at the presynaptic neuron. The resulting buildup of serotonin in the synapse causes the postsynaptic neuron to continue sending its message.

It is thought that this excess of serotonin in the synapse and the concomitant increase in signal strength, intensity, and frequency of serotonin induced action potentials causes the elevation in mood clinicians see after patients begin taking Prozac. While this is not surprising, considering the role serotonin plays in the brain, there are a few problems with this theory. In vitro studies of Prozac indicate that it stops uptake of serotonin into neurons almost immediately but patients who take Prozac do not notice the salutary effects for an average of four weeks. This presents a problem because the in vivo results seem to indicate that there is something else (other than blocking the reuptake of serotonin) going on. In addition, the serotonergic system is under tight biological regulation, therefore, an increase in the synaptic levels of serotonin should cause a decrease in the amount of serotonin synthesized in the brain. These issues and concerns are currently being researched at this time, but, in the meantime, we really do not know why blocking the reuptake of serotonin results in a decrease in depressive symptoms a few weeks later.

Here is a link to a very comprehensive article on the latest developments in serotonin research: Serotonin: The Neurotransmitter for the '90s by Ronald F. Borne, Department of Medicinal Chemistry, University of Mississippi

Point to ponder
What are the implications of the success of Prozac, for the CA theory of mood?

Supplementary material

Symptoms and treatment of depression

BPDWorld have a very useful page which describes the symptoms and treatment of depression


The search for drugs to treat human illness

Here is an article explaining the steps involved in Drug Development
From the Introduction:
"Hundreds of new drugs have been developed and commercialized for prescription use within the past 50 years. Many diseases that were fatal in the absence of drug treatment now respond favorably to pharmacologic intervention. Other diseases that caused serious dysfunction can now be improved by drug therapy."


Dealing with depression

Dr. Ivan's DEPRESSION CENTRAL: This site is Internet's central clearing house for information on all types of depressive disorders and on the most effective treatments for individuals suffering from Major Depression, Manic-Depression (Bipolar Disorder), Cyclothymia, Dysthymia and other mood disorders.
Here is a very useful set of FAQs (Frequently Asked Questions) about depression. They should load quickly.
FAQ1 of 5
FAQ2 of 5
FAQ3 of 5
FAQ4 of 5
FAQ5 of 5

This site covers Seasonal Affective Disorder (SAD)


The impact of depression on human lives

Information on the life of Ludwig van Beethoven, Winston Churchill.

David Brooks' Vincent Van Gogh Information Gallery - a rich resource on the artist's life and work.

An analysis of Stephenson's mental state written by Kay Redfield Jamison, Ph.D. Professor of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine.

In this article on Boris Yeltsin, Martin Ebon, veteran observer and writer about Russia, discusses Yeltsin's health problems, including his intermittent depressions, his drinking bouts and his periodic disappearances.

Here is a list of famous people who have suffered from depression.

The individuals in this list have publicly stated that they have experienced depression in various forms


Psychopharmacology

Carlton, A Primer of Behavioral Pharmacology, Freeman, New York, 1983.

Heise,G.A. and E. Boff (1960) J.pharmacol. exper. Therap., 129, 155-161,

Murray Sidman, Tactics of Scientific Research,

Warburton, Brain Behaviour and Drugs, Wiley, 1975

 

Copyright Dr. C.A.P. Kenyon 1994-2006