Investigating ‘emotion’ in humans and animals to develop new treatments for mood disorders

1. Investigating ‘emotion’ in humans and animals to develop new treatments for mood disorders Dr Emma Robinson Senior Research Fellow and RCUK Academic Fellow

2. What are mood disorders? These are psychiatric disorders involving a change in mood that is NOT appropriate to the situation i.e. pathological Examples of psychiatric disorders where mood changes are a common feature: • Depression • Anxiety disorders • Bipolar disorder • Substance abuse • Schizophrenia Sometimes referred to as ‘affective disorder’ or to have an ‘affective component’

3. What is depression • Depression is the most common mood disorder • Currently affect 1 in 5 people and female > male • 2nd highest cause of death amongst persons aged 20-35 • Overall mortality ~15% • WHO predict the rise in depression will mean it is the leading cause of disability adjusted life years • Major impact on quality of life and productivity (particularly in knowledge-based society) • High rates of alcohol and substance misuse, impact on relationships and productivity. • Depression can be mild, moderate or severe (major depressive disorder)

4. Treatment is with antidepressant drugs (available since 1950s) • Approximately 30% of patients fail to respond • Depression often goes undiagnosed and untreated. (only 1/3 are being treated • Depression is episodic with untreated episodes lasting 6 – 24 months followed by recovery (6months+ of remission) or remission (all symptoms gone). • Peak onset of age 20 – 40. 2x more likely in women. (increased risk (6 months) following child birth) • Married males low than unmarried, married women higher than unmarried. • Much higher rate of depression in developed versus non-developed countries.

5. What are the symptoms of depression? “Some people say that depression feels like a black curtain of despair coming down over their lives. Many people feel like they have no energy and can't concentrate. Others feel irritable all the time for no apparent reason. The symptoms vary from person to person, but if you feel "down" for more than two weeks, and these feelings are interfering with your daily life, you may be clinically depressed.” Ref: www.depression.com Symptoms • rumination of negative thought • constant feelings of sadness, irritability, or tension • decreased interest or pleasure in usual activities or hobbies • loss of energy, feeling tired despite lack of activity • a change in appetite, with significant weight loss or weight gain • a change in sleeping patterns, such as difficulty sleeping, early morning awakening, or sleeping too much • restlessness or feeling slowed down • decreased ability to make decisions or concentrate • feelings of worthlessness, hopelessness, or guilt • thoughts of suicide or death

6. What is the cause of depression? Little definitive evidence for the cause or treatment of depression has been achieved but: • Disease of brain chemistry • Neurotransmitter systems in certain brain areas or circuits are not functioning optimally resulting in the development of depressive symptoms • Psychological and medical treatments can benefit patients • Drug treatments have delayed onset of action and must be used for a prolonged period after initial recovery

7. What is the cause of depression? • Family history. Genetics play an important part in depression. It can run in families for generations. • Trauma and stress. Things like financial problems, the breakup of a relationship, or the death of a loved one can bring on depression. You can become depressed after changes in your life, like starting a new job, graduating from school, or getting married. • Negative emotional bias. People who have low self-esteem and a negative outlook are at higher risk of becoming depressed. These traits may actually be caused by low-level depression (called dysthymia). • Physical conditions. Serious medical conditions like heart disease, cancer, and HIV can contribute to depression, partly because of the physical weakness and stress they bring on. Depression can make medical conditions worse, since it weakens the immune system and can make pain harder to bear. In some cases, depression can be caused by medications used to treat medical conditions.Other psychological disorders. Anxiety disorders, eating disorders, schizophrenia, and (especially) substance abuse often appear along with depression.

8. Biology of depression Problems occur at the level of nerve to nerve communication Changes in the neurotransmitter serotonin is strongly linked with depression Brain areas involved in emotion are affected

9. Overview of neurotransmission *Antidepressant drugs target the synapse

10. Treatments for depression (and anxiety) Aim: to reverse the impairment in nerve to communication How: use a drug* to increase the level of neurotransmitter available in the brain BUT These treatments are effective in only 60-70% of patients Don’t really know why this works Action is delayed by 4-6 wks Antidepressant drug examples: Amitrityline (1950s) Fluoxetine (1990s) Moclobemide (1990s) Mirtazapine (1990s) *the term ‘drug’ describes any chemical that can alter biology and includes medicines, research drugs, natural products etc

11. Research into depression Scientific need • Major socio-economic problem due to lack of understanding of cause and treatment approaches e.g. Why do some people respond and others do not? • What is the cause of depression? e.g. Which parts of the brain are involved? Which chemical system in the brain are key? • Why do some people get depression but others do not e.g. Role of genes and family history Role for environmental factors such as stress • Can treatment be improved? e.g. Reduce time for medicine to work Increase the % of patients in which the treatment works • Government and EU priority area

12. What can we study? • Normal people • How does a normal brain control emotion? • Can a normal person be made depressed by changing their brain chemistry? • Patients • How do their brains and brain chemistry differ from normal people? • What changes in response to treatment? • What exactly is depression? • Animal studies • How does depression arise? • Are there new targets within the brain where a drug might help to treat depression? • Is this target safe?

13. Depleting brain transmitters in normal subjects Tryptophan hydroxylase L-tryptophan 5-HTP Competitionby large neutralamino acids 5-HT Protein Blood brainbarrier L-tryptophan Dietary tryptophan

14. A transient reduction in brain serotonin induces a relapse in negative mood Good Normalrange Mood Depressed -24h Time (hours) 0 5 Low tryptophandiet Tryptophandepletion Normal diet

15. What methods are used to measure emotional processing and mood in humans? • Questionnaires • Visual analogue scales • Processing of emotional faces • Facial morphs • Attentional bias • Emotional stroop test • Emotional words • Recall • Homophone test • Emotional go/no-go

16. Facial morphs

17. Studies using emotional words are used to reveal impairments in emotional processing in depression Left: Emotional words used to assess categorisation Right: Emotional Stroop measure latency to complete a word and uses colour as a distracter and a mixture of happy, sad or neutral words. Left: Neuropsychological tests are combined with brain imaging studies to reveal which area of the brain is involved in emotional behaviour.

18. Brain imaging studies reveal a biological basis to depression

19. Using deep brain stimulation in treatment resistant depression

20. Using animals to study depression Why? Many questions that arise from human studies and/or other areas of research cannot be answered using human subjects but require an intact behaving animal For example • Understand the basic biology of emotional behaviour • Understand how neurones communicate • Understand how current drugs work and design better ones • Test how effective a new drug might be before testing in patients • Assess safety

21. Animal emotion: a philosophical conundrum “Recent work in the area of ethics and animals suggests that it is philosophically legitimate to ascribe emotions to nonhuman animals. Furthermore, it is sometimes argued that emotionality is a morally relevant psychological state shared by humans and nonhumans. What is missing from the philosophical literature that makes reference to emotions in nonhuman animals is an attempt to clarify and defend some particular account of the nature of emotion, and the role that emotions play in a characterization of human nature. I argue in this paper that some analyses of emotion are more credible than others. Because this is so, the thesis that humans and nonhumans share emotions may well be a more difficult case to make than has been recognized thus far.” (Beth Dixon) “While the study of emotion is a respectable field, those who work in it are usually academic psychologists who confine their studies to human emotions. The standard reference work, The Oxford Companion to Animal Behaviour, advises animal behaviorists that "One is well advised to study the behaviour, rather than attempting to get at any underlying emotion". (Jeffrey Moussaieff Masson)

22. Animals and emotion Primates show a broad range of emotions but do other animals?

23. Can other species e.g. rodents provide a model for human emotion? • Most laboratory research uses rodents What can a rat (or mouse) tell us about emotional behaviour and depression? • Motivational changes  • Reward sensitivity  • Emotion-related behaviour ?

24. Nature266, 730 - 732 (21 April 1977); doi:10.1038/266730a0Depression: a new animal model sensitive to antidepressant treatmentsR. D. PORSOLT*, M. LE PICHON & M. JALFRE*

25. Animal models of emotion-related behaviour (testing cognitive affective bias) • Pigs, rats and birds have been shown to respond to ambiguous information in a positive or negative bias depending on their intrinsic emotional state • Rats show a disappointment effect when they expect a certain value of outcome but do not receive it • Rats will show a memory bias for an event which occurred during positive emotional stimulation

26. Emotional tone discrimination task: a test of cognitive affective bias for rats and humans Figure 1: Representation of the human and rodent emotional tone discrimination task. Training using ‘pure’ +ve and-ve tones. Intermediate probe tones are used to test emotional bias. Figure 2: Theoretical effect of +ve and –ve affective bias on response bias in the emotional tone discrimination task

27. References • Lopez and Murray, (1998) The global burden of disease, 1990-2020. Nature medicine, 4, 1241-1243. • Doris et al., (1999) Depressive illness. Lancet, 354, 1369-1375. • Slattery et al., (2004) Invited review: the evolution of antidepressant mechanisms. Fundamental Clinical Pharmacology, 18, 1-21