Tripartite 12

Tripartite Model of Depression:Tripartite Model of Depression: Psychopharmacological Psychopharmacological

Applications Applications

Dr Khalid MansourDr Khalid MansourLocum Consultant PsychiatristLocum Consultant Psychiatrist

St Andrew’s HospitalSt Andrew’s Hospital

The Other Face of Depression, Reduced Positive Affect: The Role of Catecholamines

in Causation and Cure (2006)

David NuttDavid Nutt University of Bristol Psychopharmacology Unit, Bristol, UK.University of Bristol Psychopharmacology Unit, Bristol, UK.Koen DemyttenaereKoen Demyttenaere UZ Gasthuisberg, Adult and Geriatric UZ Gasthuisberg, Adult and Geriatric

Psychiatry, Belgium.Psychiatry, Belgium.Zoltan JankaZoltan Janka Department of Psychiatry, University of Szeged, Department of Psychiatry, University of Szeged,

Hungary.Hungary.Trond AarreTrond Aarre Nordfjord Psychiatric Centre, Sjukehusvegen.Nordfjord Psychiatric Centre, Sjukehusvegen.Michel BourinMichel Bourin Faculté de Médecine Pharmacologie Clinique, France.Faculté de Médecine Pharmacologie Clinique, France.Pier Luigi CanonicoPier Luigi Canonico Department Facoltà di Farmacia, Università Department Facoltà di Farmacia, Università

del Piemonte Orientale, Italy.del Piemonte Orientale, Italy.Jose LuisJose Luis Carrasco Carrasco Department of Clinical Psychiatry, U. Complutense Department of Clinical Psychiatry, U. Complutense

de Madrid, Hospital Universitario Clinico San Carlos de Madrid, Spain.de Madrid, Hospital Universitario Clinico San Carlos de Madrid, Spain.Steven StahlSteven Stahl Neuroscience Educational Institute, California, USA.Neuroscience Educational Institute, California, USA.

Introduction 1

Tripartite modal was developed mainly in the Tripartite modal was developed mainly in the context of research in clinical psychology to context of research in clinical psychology to create better self assessment questionnaires for create better self assessment questionnaires for both anxiety and depression. In such both anxiety and depression. In such questionnaires differentiating anxiety from questionnaires differentiating anxiety from depression can be difficult.depression can be difficult.

One of the basic concepts of such research One of the basic concepts of such research models has been that our every day affect is models has been that our every day affect is really the outcome of mixing two different really the outcome of mixing two different affects: Positive Affects (PA) and Negative affects: Positive Affects (PA) and Negative Affects (NA).Affects (NA).

Introduction 2

PA: positive mood states, e.g. PA: positive mood states, e.g. happiness (joy), happiness (joy), interest, energy, enthusiasm, alertness and interest, energy, enthusiasm, alertness and self-confidenceself-confidence. .

NA: distress mood states, e.g. NA: distress mood states, e.g. fear, anxiety, fear, anxiety, sadness, irritability, loneliness, guilt, disgust sadness, irritability, loneliness, guilt, disgust and hostilityand hostility. .

Introduction 3 Psychiatric studies seems as if it had ignored Psychiatric studies seems as if it had ignored

such psychological research for a long time such psychological research for a long time (most research done by psychologists). (most research done by psychologists).

However, recent developments in However, recent developments in psychopharmacology have increased interest in psychopharmacology have increased interest in PA and NA as a way to refine treatment of PA and NA as a way to refine treatment of depression. depression.

This new approach has been increasingly This new approach has been increasingly popular among psychiatrists in the USA and UK.popular among psychiatrists in the USA and UK.

General Background: 1Two Factors Structure of Affect

Theories like the Tripartite Model of Theories like the Tripartite Model of Anxiety and Depression are part of a Anxiety and Depression are part of a long tradition of psychometric studying of long tradition of psychometric studying of emotionsemotions (e.g., Izard, 1972; Tomkins, 1962, 1963, (e.g., Izard, 1972; Tomkins, 1962, 1963,

Davidson, 1992, 1998; Gray, 1994).Davidson, 1992, 1998; Gray, 1994). One common feature of these models is One common feature of these models is

the emphasis on the “Two-Factor the emphasis on the “Two-Factor Structure of Affect”Structure of Affect” (Shankman & Klein, 2003).(Shankman & Klein, 2003).

General Background: 2Two Factors Structure of Affect

Two-Factor theories: emotions fall along Two-Factor theories: emotions fall along two dimensions: Positive Affect (PA) and two dimensions: Positive Affect (PA) and Negative Affect (NA)Negative Affect (NA) (Zevon&Tellegen, 1982)(Zevon&Tellegen, 1982) ..

Approach-withdrawal ModelApproach-withdrawal Model (Davidson, 1992, (Davidson, 1992, 1998).1998).Behavioural Activation SystemBehavioural Activation System (Carver & White, (Carver & White,

1994).1994).Behavioural Facilitation SystemBehavioural Facilitation System (Depue &Iacono, (Depue &Iacono,

1989).1989).

General Background: 3Three-Factor Structure of Affect

The three-factor theories (e.g. The three-factor theories (e.g. tripartite model): tend to add to the tripartite model): tend to add to the PA-NA structure an extra structure PA-NA structure an extra structure to explain other mood abnormalities to explain other mood abnormalities especially anxiety disorder, phobia, especially anxiety disorder, phobia, OCD, etcOCD, etc (Shankman & Klein, 2003). (Shankman & Klein, 2003).

General Background: 4Other Three-Factor Theories

Valence-Arousal Model:Valence-Arousal Model: PA, NA and PA, NA and Arousal/Anxious Apprehension (AA)Arousal/Anxious Apprehension (AA) (Heller et al, (Heller et al, 1995,1997; Heller & Nitchke, 1998).1995,1997; Heller & Nitchke, 1998).

Gray’s Three System ModelGray’s Three System Model (Gray, 1994)(Gray, 1994): :

Behavioural Approach System, Behavioural Behavioural Approach System, Behavioural Inhibition System and Fight/Flight System.Inhibition System and Fight/Flight System.

Watson & Clark Tripartite Model: 1Negative Affect (NA)

NA:NA: general factor of emotional distress: e.g. general factor of emotional distress: e.g. fear, anxiety, sadness, irritability, loneliness, fear, anxiety, sadness, irritability, loneliness, guilt, disgust and hostilityguilt, disgust and hostility (Watson & Clark, (Watson & Clark, 1984;Watson &Tellegen, 1985).1984;Watson &Tellegen, 1985).

A common feature of A common feature of both anxiety and both anxiety and depressiondepression..

Traditional self-report measures of Traditional self-report measures of depression and anxiety are tapping NAdepression and anxiety are tapping NA (Laurent (Laurent

& Ettelson, 2001).& Ettelson, 2001). Separating depression from anxiety depends Separating depression from anxiety depends

on PAon PA (Laurent & Ettelson, 2001).(Laurent & Ettelson, 2001).

Watson & Clark Tripartite Model: 2 Positive Affect (PA)

PA:PA: “ “pleasurable engagement with the pleasurable engagement with the environment” environment” (Watson, 1988; Watson & Tellegen, 1985)(Watson, 1988; Watson & Tellegen, 1985) including happiness, interest, energy, including happiness, interest, energy, enthusiasm, alertness and self-confidence:enthusiasm, alertness and self-confidence:Depression is characterized by Depression is characterized by low PAlow PA; ;

i.e. i.e. AnhedoniaAnhedonia. . In anxiety, levels of PA are not In anxiety, levels of PA are not

significantly different than those significantly different than those expected in the general population.expected in the general population.

Watson & Clark Tripartite Model: 3 Physiological Hyperarousal (PH)

Clark and Watson (1991) added a factor Clark and Watson (1991) added a factor they believed to be specific to anxiety: they believed to be specific to anxiety: “Physiological Hyperarousal” (PH).“Physiological Hyperarousal” (PH).

So, Clark and Watson concluded that data So, Clark and Watson concluded that data about anxiety and depression, were best about anxiety and depression, were best captured by a captured by a TripartiteTripartite structure. structure. NA: common to both anxiety and depression. NA: common to both anxiety and depression. PA: characteristic for depression. PA: characteristic for depression. PH: characteristic for anxietyPH: characteristic for anxiety

Watson & Clark Tripartite Model: 4 Assessment Tools

Several assessment tools have been Several assessment tools have been developed based on the tripartite model developed based on the tripartite model e.g.e.g.Positive and Negative Affect Schedule Positive and Negative Affect Schedule

(PANAS)(PANAS) (Watson, Clark, and Tellegen, 1988)(Watson, Clark, and Tellegen, 1988)

Mood and Anxiety Symptom Mood and Anxiety Symptom Questionnaire (MASQ)Questionnaire (MASQ) ((Watson et al, 1995)Watson et al, 1995)..

Depression Anxiety stress Scale (DASS)Depression Anxiety stress Scale (DASS) (Lovibond & Lovibond, 1995).(Lovibond & Lovibond, 1995).

Watson & Clark Tripartite Model: 5

Relationship Between PA & NA

Some authors believe that PA and NA are Some authors believe that PA and NA are bipolar or represent opposite ends of a bipolar or represent opposite ends of a continuumcontinuum (e.g., Feldman Barrett & Russell, 1998, 1999; Russell, (e.g., Feldman Barrett & Russell, 1998, 1999; Russell,

1980; Russell & Feldman Barrett, 1999).1980; Russell & Feldman Barrett, 1999).

Most believe that PA and NA represent Most believe that PA and NA represent independent constructsindependent constructs (e.g., Watson & Clark, 1997; (e.g., Watson & Clark, 1997; Watson & Tellegen, 1985; Watson, Wiese, Vaidya, & Tellegen, 1999). Watson & Tellegen, 1985; Watson, Wiese, Vaidya, & Tellegen, 1999).

The second view is the view adopted in The second view is the view adopted in psychopharmacology researches.psychopharmacology researches.

Psychopharmacological Research and the Tripartite Model: 1

Since 1960s with TCA > norepinephrine Since 1960s with TCA > norepinephrine (NE) and dopamine (DA) play integral part (NE) and dopamine (DA) play integral part in pathophysiology of depressionin pathophysiology of depression (Willner, 1995; (Willner, 1995;

Delgado, 2000, 2004; Nutt et al, 2006; Stahl, 2009). Delgado, 2000, 2004; Nutt et al, 2006; Stahl, 2009). Many of Many of the TCA were causing exactly such effect.the TCA were causing exactly such effect.

Since the late 1980s, SSRIs started to be Since the late 1980s, SSRIs started to be the first-line therapy for treatment of the first-line therapy for treatment of depression especially in the primary care depression especially in the primary care due to improved safety profile and ease of due to improved safety profile and ease of administrationadministration (Nutt et al, 2006)(Nutt et al, 2006). .

Psychopharmacological Research Psychopharmacological Research and the Tripartite Model: 2and the Tripartite Model: 2

However, 28-55% of patients fail to respond However, 28-55% of patients fail to respond to SSRI therapyto SSRI therapy (Nierenberg (Nierenberg et al.et al., 1999, Nierenberg and , 1999, Nierenberg and

DeCocco, 2001; Peterson DeCocco, 2001; Peterson et al.et al., 2005; Trivedi , 2005; Trivedi et alet al., 2006)., 2006)..

30%-50% of the responding patients continue 30%-50% of the responding patients continue > residual symptoms> residual symptoms (Fawcett, 1994; Bothwell & Scott, (Fawcett, 1994; Bothwell & Scott,

1997; Nierenberg et al, 1999)1997; Nierenberg et al, 1999) e.g. sleep disturbances, e.g. sleep disturbances, diminished pleasure, loss of interest, fatigue diminished pleasure, loss of interest, fatigue or loss of energy and decreased motivationor loss of energy and decreased motivation (i.e. low PA) (Kopta (Kopta et alet al., 1994; Barkham ., 1994; Barkham et alet al., 1996; ., 1996; Opdyke Opdyke et alet al., 1996–1997; Nierenberg ., 1996–1997; Nierenberg et alet al., 1999; Shelton and ., 1999; Shelton and Tomarken, 2001).Tomarken, 2001).


In the mean time, preliminary evidence > In the mean time, preliminary evidence > antidepressants that enhance antidepressants that enhance noradrenaline and dopamine (e.g. SNRIs) noradrenaline and dopamine (e.g. SNRIs) may > therapeutic advantage over SSRI in may > therapeutic advantage over SSRI in treatment of low PA e.g. loss of interest, treatment of low PA e.g. loss of interest, loss of energy and loss of motivation”,loss of energy and loss of motivation”,

(Bremner (Bremner et alet al., 1984; Rampello ., 1984; Rampello et alet al., 1991; Dalery ., 1991; Dalery et al.et al., 1997; , 1997; Jouvent Jouvent et al.et al., 1998; Jamerson , 1998; Jamerson et al.et al., 2003; Papakostas, 2006; , 2003; Papakostas, 2006;

Jefferson Jefferson et alet al., in press).., in press).


Professor Nutt and Professor Stahl started Professor Nutt and Professor Stahl started to suggest the usage of PA and NA to suggest the usage of PA and NA concepts for prescribing antidepressantsconcepts for prescribing antidepressants (Nutt et al, 2006 & Stahl 2009):(Nutt et al, 2006 & Stahl 2009):

Depressed patients with dominant “low Depressed patients with dominant “low PA” > to be treated with drugs which PA” > to be treated with drugs which enhance DA and NA e.g. SNRIenhance DA and NA e.g. SNRI

Depressed patients with dominant “high Depressed patients with dominant “high NA” > to be treated with drugs which NA” > to be treated with drugs which enhance 5HT e.g. SSRI.enhance 5HT e.g. SSRI.

Neurobiological Model of Depression (Nutt et al, 2006)

Neurobiological Model of Depression (Nutt et al, 2006): Criticism 1

Many psychological studies dispute the Many psychological studies dispute the sufficiency and/or validity of the Tripartite sufficiency and/or validity of the Tripartite model and found it not able to explain model and found it not able to explain many aspects of depression and anxietymany aspects of depression and anxiety (Lonigan et al, 1994; Clark et al, 1994; Burn & Edison, 1998; (Lonigan et al, 1994; Clark et al, 1994; Burn & Edison, 1998;

Buckby et al, 2008).Buckby et al, 2008).

Including: guilt, sadness, irritability, fear, Including: guilt, sadness, irritability, fear, anxiety, etc,anxiety, etc, in one category, NA, does not in one category, NA, does not make much sense from clinical point of make much sense from clinical point of view.view.


Many patients are still having limited Many patients are still having limited response to both SSRI and SNRI.response to both SSRI and SNRI.

SNRI advantage over SSRI is modest SNRI advantage over SSRI is modest (NNT = 24)(NNT = 24) ((Papakostas et al, 2006)Papakostas et al, 2006)

Including Nor-adrenaline in both PA and Including Nor-adrenaline in both PA and NA in Nutt’s model, does not make sense, NA in Nutt’s model, does not make sense, chemically, as Nor-adrenaline system has chemically, as Nor-adrenaline system has many differences from 5HT and Dopaminemany differences from 5HT and Dopamine..


Nutt’s model needs further development.Nutt’s model needs further development.Nutt’s model does not involve Nutt’s model does not involve

environmental factors in either environmental factors in either causing or treating depression. causing or treating depression.

This model does not explain other This model does not explain other major chemical transmitters in the major chemical transmitters in the brain e.g. glutamte, glycine or brain e.g. glutamte, glycine or acetylcholine. acetylcholine.

Neurobiological Model of Depression (Nutt et al, 2006): Prescribing

It has many clinical applications e.g.It has many clinical applications e.g. Patients with ↓ PA; better avoid anti-dopaminergic Patients with ↓ PA; better avoid anti-dopaminergic

drugs as augmentation therapy for treatment of drugs as augmentation therapy for treatment of depression.depression.

Fluoxetine can be considered superior SSRI as it also Fluoxetine can be considered superior SSRI as it also enhances Dopamine and Nor-adrenaline. Sertraline enhances Dopamine and Nor-adrenaline. Sertraline and Paroxetine also enhance dopamine to less and Paroxetine also enhance dopamine to less extent.extent.

This model might rekindle usage of drugs like This model might rekindle usage of drugs like Bupropion, MAOI or even Amphetamines in low-PA-Bupropion, MAOI or even Amphetamines in low-PA-depression.depression.

Neurobiological Model of Depression (Nutt et al, 2006): non-chemical therapies

Concepts of PA or NA can also be used in Concepts of PA or NA can also be used in behavioural therapy and psychotherapy behavioural therapy and psychotherapy perhaps in both neurosis and well as perhaps in both neurosis and well as psychosis:psychosis:Low PA (-ve): ? Mainly motivational and self Low PA (-ve): ? Mainly motivational and self

esteem activities e.g. DBT, drug rehab, etc. esteem activities e.g. DBT, drug rehab, etc. High NA (ve+): ? Mainly correctional and re-High NA (ve+): ? Mainly correctional and re-

training activities e.g. CBT for phobia or OCD.training activities e.g. CBT for phobia or OCD.

Neurobiological Model of Depression (Nutt et al, 2006): Future Research

Add one extra dimension for better Add one extra dimension for better assessment and treatment of assessment and treatment of depression for the first time in about depression for the first time in about 60 years.60 years.

It brings psychiatrists one step further It brings psychiatrists one step further to more efficient neurobiological to more efficient neurobiological models, though not sufficient yet models, though not sufficient yet (Bullmore et al, 2009; Craddock et al, 2008; St John-Smith et al, (Bullmore et al, 2009; Craddock et al, 2008; St John-Smith et al, 2009)2009)

Neurobiological Model of Depression (Nutt et al, 2006): “10 dimensions Depression” Other components of depression could be considered in Other components of depression could be considered in

future classifications of depression e.g.:future classifications of depression e.g.: Poor interestPoor interest Grief (life losses)Grief (life losses) Low Motivation Low Motivation Negative / Dysfunctional CognitionNegative / Dysfunctional Cognition Doubts / anxietyDoubts / anxiety Homeostasis (discomfort / pain) Homeostasis (discomfort / pain) Low Energy (e.g. asthenia, chronic fatigue syndrome)Low Energy (e.g. asthenia, chronic fatigue syndrome) Stress (environmental & biological)Stress (environmental & biological)

Thank you

Comments

Health & Medicine

Tripartite 12