Mental disorders

Vijay Suppiah

Pharmacotherapeutics Theory II

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2 On the Threshold of Eternity (1882) by Vincent van Gogh

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Mental health is as important as physical health to the overall well-being of individuals, societies and countries. Yet only a small minority of the 450 million people suffering from a mental or behavioural

disorders are receiving treatment

(The World Health Report 2011)

Mental disorder

A mental disorder or mental illness is a

psychological or behavioural pattern that

occurs in an individual and is thought to

cause distress or disability that is not

expected as part of normal development or

culture.

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Australian Bureau of Statistics, 2013

This is how common mental disorders are in Australian adults

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Classification

May 2013 American Psychiatric Association published/refined: Diagnostic and Statistical Manual of Mental Disorders, 5th Ed (DSM V)

DSM V contains descriptions and recommendations for 18 different mental disorders

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Major Depressive Disorder

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Major Depressive Disorder

MDD is a mood state that is characterised by significantly lowered mood and a loss of interest or pleasure in activities that are normally enjoyable.

However, a major depressive episode can be distinguished from `normal' depression by its severity, persistence, duration, and the presence of characteristic symptoms (e.g., sleep disturbances).

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Pathophysiology

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Neurotransmitter availability

Receptor regulation Receptor sensitivity

i. Serotonin, Norepinephrine, Dopamine, Glutamate

Brain-derived neurotrophic factor

ii. Lesions in certain parts of the brain iii. Difference in brain structures iv. Aging

Etiology

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Genetics Environment

Concordance of 40-50% in twins 3 times more likely if you have a

depressed first degree relative than in the general pop

SLC6A4 gene serotonin transporter

HTR3A and HTR3B - serotonin receptors

Chronic pain Medical illness Psychosocial stress

Epidemiology

Lifetime risk for major depressive disorder 10-25% females vs 5-12% males

Ave onset age of first episode: mid-20s onwards

Recurrent and potentially lifelong illness for most patients.

Symptoms develop over days to weeks.

Sudden onset associated with major stress.

Untreated moderate episodes can last up to 9 months.

Recurring condition:

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Complications

Suicide rates

i. 6% of those diagnosed with depression over

their life time

ii. 10-15% of those admitted to hospital for

depression (30 x more than general pop)

iii. 25-50% will attempt suicide

Treatment halves the risk of suicide, esp for men below the age of 30.

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DSM V criteria: Major Depression

Note:

At least 5 of the above, nearly everyday for 2 weeks (1 or 2 is essential)

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The symptoms cause clinically significant distress or impairment in social, occupational or

other areas of functioning.

Do not include symptoms that are clearly due to a general medical condition or physiological

effects of a substance.

Bereavement exclusion in DSM V

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Signs of depression

Emotional Signs

Depressed mood

Anhedonia

Low self-esteem

Anxiety

Pre-occupation with negative thoughts

Physical Signs

Headache

Chronic fatigue

Disturbed sleep

GI complains (nausea, diarrhoea, constipation)

Sexual dysfunction

Menstrual problems

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Other symptoms

Intellectual symptoms

- Decreased ability to conc, slowed thinking, poor memory for

recent events

- May appear confused and indecisive

Psychomotor disturbances

- May appear noticeably slowed or retarded in physical

movements, thought processes and speech (psychomotor retardation)

- May have psychomotor agitation = purposeless, restless

motion eg pacing, outbursts of shouting

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Severity

Mild episodes Few symptoms beyond the minimum required to make the diagnosis

Moderate episodes several symptoms may be present to a marked degree and the individual usually has considerable difficulty continuing with usual activities.

Severe episodes most criteria present. Marked interference with social and/or occupational functioning, producing clear-cut observable disability

Nature of symptoms (eg suicidal thoughts and behaviour) should also be considered in

assessing severity.

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Subtypes

i. Severe with psychotic features

ii. Chronic

iii. With atypical features

iv. With seasonal pattern

v. Postpartum onset

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Treatment

Aim

- To reduce symptoms of acute depression

- Facilitate patients return to a premorbid level of functioning

- Prevent further episodes

Options

- Non-pharmacological: Psychological, ECT, others

- Pharmacological: Antidepressants, complementary therapies(?)

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Principles of treatment

Mild: Psychological therapies are more effective than antidepressants

Moderate: both approaches are equally effective (initial option is still based on patient pref)

Moderate to severe or severe: Antidepressants with concurrent psychological therapy

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Non-pharmacological

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Psychotherapy

Whenever patient is able and willing to participate

Mild to moderate disease psychotherapy is first line

Combination may be advantageous for those who have partial response to either treatment alone or those with

chronic course of illness

Cognitive/behavioural therapy and interpersonal therapy equally effective and have the strongest evidence of

efficacy.

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Cognitive Behavioural Therapy (CBT)

Based on two key principles:

i. cognitions may control feelings and behaviour

ii. behaviours affect thought patterns and emotions.

Aims to identify, challenge and modify maladaptive, automatic or core thoughts, beliefs, perceptions and behaviours.

Occurs over a series of clinical interviews, and cognitive and behavioural tasks.

Acute treatment typically takes between 12 - 20 weekly sessions. Follow-up booster sessions at 3 or 6 months are often useful.

CBT may be effective alone or it may aid pharmacotherapy in acute treatment and reduce relapse risk after drugs are discontinued.*

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Interpersonal PsychoTherapy (IPT)

Developed for the treatment of depression.

Uses the connection between onset of depressive symptoms and current interpersonal

problems as the treatment focus.

Treatment typically occurs over 12 to 16 weekly sessions.

Interpersonal counselling, derived from IPT, is a brief form of therapy (up to six sessions).

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Should be considered in severely depressed patients who have any of the following (first line):

i. Psychotic depression

ii. Poor response to several adequate courses of antidepressant

drug

iii. Severe reduction in food and fluid intake (where rapid response is NEEDED)

iv. Strong suicidal ideation

v. Catatonia

vi. Previous good response to ECT

*It is vital that the patient is accepting of this treatment.

Electroconvulsive therapy (ECT)

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Works quickly.

Administered under GA + muscle relaxant (major risks are with the GA).

Modern treatments involves individually determined stimulus dosing.

EEG to monitor brain (esp seizure).

dose adjustment in accordance with EEG parameters and clinical response (individualised treatment*).

Excellent at getting people better but poor at keeping them well.

A course consists of either unilateral or bilateral ECT administered 2-3 times/week for a total of 6-12

treatments.

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ECT and psychotropic drugs

BZDs should be tapered and ceased

Anti epileptics different approaches (maintaining, reducing or suspending administration)

Antidepressants taper and d/c all antidepressants before ECT*

Lithium does not impair effectiveness of ECT but can cause severe postictal confusion

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Others

To reverse unhealthy or destructive lifestyle habits and consider other activities that may relieve stress and facilitate well-being.

Exercise

Light therapy (Seasonal Affective Disorder)

Relaxation therapy

Massage

Tai Chi/ Yoga

Note: Evidence for effectiveness for the above varies

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Pharmacotherapy

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Antidepressants

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Classification Drugs

Selective serotonin reuptake inhibitors

(SSRI)

Escitalopram, Paroxetine, Fluoxetine,

Fluvoxamine, Citalopram, Sertraline,

Tricyclic antidepressants (TCA) Imipramine, Clomipramine, Amitriptyline,

Doxepin, Dothiepin, Nortriptyline

Non-selective MAO inhibitors Phenelzine, Tranylcypromine

MAO A inhibitor Moclobemide

Serotonin/noradrenaline reuptake

inhibitors (SNRI)

Venlafaxine, Duloxetine, Desvenlafaxine

Others:

Noradrenergic and specific serotonergic

modulator

Mirtazapine, Mianserin

Selective noradrenaline reuptake

inhibitor

Reboxetine

Mood stabiliser Lithium carbonate

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Treatment vs placebo

Note:

- NNT is the average number of patients who need to be treated to prevent one additional bad outcome

(i.e. the number of patients that need to be treated for one to benefit compared with a control in a clinical trial).

- ARR is the decrease in risk of a treatment in relation to a control treatment.

- Table also shows the effectiveness of CBT vs placebo.

- CBT (or IPT) in addition to meds gives better results than either treatment alone.

Adapted from the RANZCP guidelines

First line drugs

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Source: Australian TG

The choice of drug is determined by the following:

i. adverse effect profile of the antidepressant

ii. patient response or lack of response to previous treatments

iii. adverse effects of previous treatments

iv. family history of response to treatments

v. risks of drug interaction with other concomitantly administered drugs

vi. Antidepressant safety in overdose

vii. Concurrent medical/psychiatric conditions

viii. simplicity of administration (minimal titration, OD dosing)

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Side effects and relative frequency

Note:

1. Start off with the lowest possible dose and titrate up may reduce the impact.

2. Additive and synergistic effects may occur when two or more drugs with similar

adverse effects are used concurrently. 35

How do the others fare?

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SSRIs and suicide

37 Fergusson 2005 BMJ

Activating or not?

38 Stahl 2002 J Clin Psychiatry

Interactions

SSRI + MAOI

Serotonin toxicity can occur, particularly with high doses or if other serotonergic drugs are co-administered. These combinations can produce serotonin toxicity which has been associated with fatalities.

SSRI + NSAID/Aspirin

Risk of upper gastrointestinal tract bleeding in patients taking SSRIs is significantly increased. Patients vulnerable to GI bleeding (eg those with a history of peptic ulcer disease, oesophageal varices or who are undergoing surgery) should be observed carefully and considered for an alternative class of antidepressant, or given a protective drug.

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SSRIs and hepatic enzymes

SSRIs are metabolised in the liver by cytochrome P450

isoenzymes. They can inhibit the metabolism of many other

drugs, causing increased plasma drug concentrations and

possible toxicity.

For example,

i. plasma TCA conc cardiovascular toxicity;

ii. plasma bupropion/clozapine conc seizures;

Note:

i. Individual SSRIs are metabolised by different isoenzymes, hence their

potential for interactions varies.

ii. Citalopram, escitalopram and sertraline have the least potential to interact

in this way.

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SSRI + Warfarin

Due to action on serotonin release from platelets, and may

increase the risk of bleeding. Can bring about increase in

INR. Monitor the INR and decrease warfarin dose as req.

SIADH

Syndrome of inappropriate antidiuretic hormone (SIADH)

may occur and is more common in older people. As

hyponatraemia can be asymptomatic, consider checking

base-line serum Na conc in older people. This should then

be repeated within a month, or earlier if the patient has

symptoms.

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SNRIs

Schueler 2011 Acta Psychiatr Scand 42

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Venlafaxine and hypertension

Can cause clinically sign increases in bld pressure

< 200 mg/day low incidence

> 225 mg/day 5% incidence of clinically sign sustained hypertension

300 375 mg/day mean increase of diastolic bld pressure was 7mm Hg

Not seen in newer SNRI duloxetine

Mirtazapine

Block pre-synaptic 2 adrenoreceptors (directly increasing adrenergic and indirectly enhancing serotonergic transmission) and block post-

synaptic 5-HT2 and 5-HT3 receptors (minimise serotonergic SE)

15 to 30 mg orally ON, initially, increasing to 60 mg at night.

Note:

1. Mirtazapine has fewer cardiovascular and anticholinergic adverse effects than the

TCAs and has a wider margin of safety in overdose.

2. Mirtazapine can induce neutropenia and deaths have occurred from agranulocytosis.

A full blood count is required before initiation of treatment and this should be repeated

at 4 to 6 weeks or if there are any clinical features suggestive of neutropenia (eg

infection, sore throat).

3. Fasting lipid levels should be measured before commencing and during treatment

with mirtazapine as these levels may become elevated.

4. Mirtazapine is metabolised by CYP3A4, thus drugs that inhibit or induce this enzyme

may alter plasma mirtazapine concentration.

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How do you pick one over the other?

These older SSRIs have plenty of interaction with other drugs,

they dont get used as much as the newer SSRIs which dont Interact as much.

Associated with hypertension including de novo in

normotensive people.

Both have stereoactive enantiomers which are also available

as drugs.

Has been shown in a meta analysis that it works rapidly

than SSRIs for acute depression within the first 2 weeks.

But its HIGHLY sedating.

Anticholinergic side effects are a real problem in elderly

patients.

Both has active metabolites with long half lives.

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Fluoxetine Fluvoxamine Paroxetine

Venlafaxine

Venlafaxine Citalopram

Mirtazapine

Paroxetine

Fluoxetine Sertraline

S-enantiomer of citalopram

S enantiomer has improved potency and

faster onset of action than

citalopram

Compares better than others: SSRIs, SNRIs

A few dollars more expensive than

citalopram

Leonard and Taylor 2010 J Psychopharmacol

Odds ratio at week 8

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How do you pick one first line drug over the other?

Cipriani 2009 Lancet 47

Top two: Escitalopram Sertraline Bottom two: Fluvoxamine Duloxetine

Recommendations

Use any first-line antidepressant at standard dose.

Assess response to antidepressant after 2 to 4 weeks of treatment:

i. Continue at this dose if the patient responds well.

iia. If there is only a partial response after 3 to 4 weeks, increase the

dose. (The relatively flat doseresponse curve of SSRIs limits the advantages of increasing the dose. Due to individual patient variability, some patients will

respond to increased doses of SSRIs.)

iib. If there is no additional response after 2 to 4 weeks of treatment at

the higher dose or further dose increase is not possible, switch to a

different drug.

iii. If there is no response after 3 to 4 weeks, check for adherence.

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Vital questions to ask

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Within or across class switch?

Patients switching to non-SSRI drugs (venlafaxine mainly) slightly more likely to experience remission.

No difference in response rates between the two groups.

Intolerability to non-SSRI 17.7% while intolerability to SSRI was only 11.5%

Pooled RR=1.29 95% CI=1.07-1.56

SSRI to either paroxetine or venlafaxine SSRI to citalopram or venlafaxine XR SSRIs to sertraline or mirtazapine Citalopram to sertraline or venlafaxine Citalopram to sertraline or bupropion

Papakostas 2008 Biol Psychiatry 50

Equivalent doses

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Source: Ogle and Akkerman. 2013

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Second line treatment options

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Reboxetine

Selective noradrenaline reuptake inhibitor

The dose range of reboxetine is narrow compared to most other antidepressants.

4 to 8 mg divided into 2 doses; increase if required after 3 weeks to 10 mg daily in divided doses. Maximum 12 mg daily.

Note:

1. Urinary hesitancy is more common in males. Care should be taken in older men as

urinary retention may be precipitated or exacerbated.

2. Reduced plasma potassium concentration has been observed in older patients

following prolonged administration and hyponatraemia has also been reported.

3. Reboxetine is metabolised by CYP3A4, thus drugs that inhibit or induce this enzyme

may alter plasma reboxetine concentration.

Changing one drug for another

An appropriate interval when changing from one antidepressant to another is recommended to

avoid interactions.

Mindful of:

i. patients particular situation

(other medication, drug history, physical health, the considerable

interindividual variation in elimination half-lives)

ii. dose of old and new drugs (includes PK of parent drug, presence of an active metabolite)

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Changing one drug for another

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Drug Recommendation Rationale Category A changeover

fluoxetine, phenelzine, tranylcypromine

gradual withdrawal generally unnecessary; withdrawal symptoms very unlikely wait for >1014 days before starting next antidepressant consider hospitalisation during washout/changeover if severely depressed

drug (or metabolites) with long half-life or persistent effects

Category B changeover

TCAs, SSRIs (except fluoxetine), mianserin, mirtazapine

withdraw gradually to prevent withdrawal symptoms (particularly if higher dose or long-term use); usually reduce dose by 25% per day wait for 24 days before starting next antidepressant consider hospitalisation during washout/changeover if severely depressed

drug (or metabolites) with intermediate half-life of 2448 hours

Category C changeover

duloxetine, moclobemide, reboxetine, venlafaxine, desvenlafaxine

venlafaxine, desvenlafaxine: withdraw gradually to prevent withdrawal symptoms moclobemide: withdrawal symptoms not reported wait for 12 days before starting next antidepressant

drug (or metabolites) with short half-life of

Failure to respond to initial therapy

Should be used ONLY after unsuccessful trials of at least 2 first-line treatment (drug or psychotherapy)

If initial treatment was with an SSRI, there is little evidence on whether changing to another type of treatment is superior to another SSRI.

However these drugs should be considered first line for those who have responded well to these previously.

i. TCA

ii. Mianserin

iii. Irreversible non-selective MAOI

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i. TCA - Nortriptyline

50 mg orally ON, increasing every 2 to 3 days (depending on adverse effects) to 100 mg at night by the 7th day. If there is no response after 3 to 4 weeks, the dose may be increased at 3- to 4-week intervals by increments of 25 to 50 mg per day (while monitoring the patient for adverse effects) to 200 mg ON.

- All other TCAs

50 to 75 mg orally ON, increasing every 2 to 3 days (depending on adverse effects) to 150 mg at night by the 7th day. If there is no response after 3 to 4 weeks, the dose may be increased at 3- to 4-week intervals by increments of 25 to 50 mg per day (while monitoring the patient for adverse effects) to 200 to 250 mg ON.

Note:

1. all TCAs, lower doses are likely to be required if the patient has reduced ability to metabolise medication (such as impaired hepatic functioning or increased vulnerability to adverse effects).

2. Look out for CVS and anticholinergic side effects (cf pharmacology lectures).

3. TCAs should not be combined with other antidepressants. Significant unpredictable drug interactions may occur, particularly with the SSRIs, and interactions with MAOIs may be fatal

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ii. Mianserin

30 to 60 mg orally ON, initially, increasing to 60 to 120 mg at night by the 7th

day.

Note:

1. Mianserin has fewer cardiovascular and anticholinergic adverse effects than the TCAs and

has a wider margin of safety in overdose.

2. Mianserin can induce neutropenia and deaths have occurred from agranulocytosis. A full

blood count is required before initiation of treatment and this should be repeated at 4 to 6

weeks or if there are any clinical features suggestive of neutropenia (eg infection, sore

throat).

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iii. Irreversible nonselective MAOI

- Phenelzine

15 mg orally BD, initially, increasing every 3 to 4 days (depending on adverse effects) to 45 to 60 mg daily in 2 or 3 divided doses by the 7th day. If there is no response after 2 to 3 weeks, the dose may be increased at 2- to 3-week intervals by increments of 15 mg per day, to a maximum of 45 mg twice daily (approximately 1 mg/kg/day).

- Tranylcypromine

10 mg orally BD, initially, increasing every 3 to 4 days (depending on adverse effects) to 15 to 20 mg twice daily by the 7th day. If there is no response after 2 to 3 weeks, the dose may be increased at 2- to 3-week intervals by increments of 10 mg per day, to a maximum of 30 mg twice daily. Note:

1. The last dose should be given no later than early afternoon, to minimise the risk of insomnia.

2. The combination of irreversible non-selective or reversible selective MAOIs and SSRIs or SNRIs is absolutely contraindicated because of the high risk of inducing potentially fatal serotonin toxicity.

3. MAOIs interact with many drugs. Always check for interactions before prescribing.

4. These drugs may cause significant hypertension when combined with certain foods.

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Treatment-resistant depression

Depending on the severity of the depression consider one of the following options:

i. Another class of antidepressant drug

ii. Augmentation with lithium

iii. Augmentation with tri-iodothyronine (T3)

iv. Augmentation with second-generation antipsychotics

v. ECT

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Lithium and T3

62 Source: Connolly and Thase 2011

Second-Generation Antipsychotics

Rationale: i. Olanzapine, quetiapine, aripiprazole and risperidone bind to serotonin

2A receptors.

ii. Aripiprazole is a serotonin 1A partial agonist

iii. Ziprasidone and quetiapine inhibit noradrenaline reuptake (similar to TCAs)

Quetiapine and aripiprazole are effective as adjunct therapies

Olanzapine and risperidone have similar benefits but over a brief period of time.

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Relapse prevention

64 Source: Geddes et al., 2003 Lancet

How long should treatment last?

To reduce the risk of relapse, continue for 6-12 months after remission of symptoms.

People at high risk of recurrence should continue for 2-3 years, or more.

Risk factors include: i. Residual depressive symptoms ii. History of 3 or more prior episodes, or 2 or more in

the last 5 years iii. History of severe depression (with psychotic

symptoms or serious suicide attempt)

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Discontinuing treatment

Antidepressants should be tapered slowly, rather than stopped abruptly, to reduce the risk of discontinuation syndrome (insomnia, nausea, postural imbalance, sensory disturbances, hyperarousal and flu-like symptoms).

More likely to occur with a higher dose, a longer duration of treatment and a shorter half-life drug*

General rule,

If antidepressant therapy is being ceased completely, tapering may need to be undertaken more slowly to prevent relapse.

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Some issues to consider

Serotonin syndrome

Withdrawal effects

Toxicity

Suggested management of side effects

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Serotonin Syndrome

Occurs when:

i. A high dose of a single drug

ii. More than 1 serotonergic agents are used together

Synaptic serotonin conc increases, hyperstimulating the serotonin receptors, causing:

i. Neuromuscular effects: hyper-reflexia, clonus, tremor, incoordination

ii. Autonomic effects: hyperthermia, shivering, sweating, fever, tachycardia

iii. Mental status effects: agitation, anxiety, confusion, restlessness

Stop the implicated drug(s) immediately as it may be serious.

Cyproheptadine (4-8 mg orally, up to 8 mg TID) 68

Action Clinical subgroups Specific drugs

Serotonin reuptake inhibitors 1. Antidepressants

a. SSRIs Fluoxetine, Fluvoxamine,

Citalopram, Sertraline,

Escitalopram

b. Others Venlafaxine, Clomipramine,

Imipramine

2. Opioid analgesics Pethidine, Tramadol,

Dextromethorphan

3. Herbal St Johns wort

Monoamine oxidase

inhibitors

1. Irreversible Phenelzine, Tranylcypromine

2. Irreversible MAOI Moclobemide

3. Others Linezolid

Serotonin releasing agents 1. Appetite suppressant Fenfluramine

2. Stimulants Amphetamines, MDMA

Others 1. Mood stabiliser Lithium

2. Amino acid Tryptophan

Table: List of pharmacological agents that can cause serotonin syndrome when used in combinations

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Withdrawal effects

End of Rx course taper slowly and monitor for withdrawal

Changing drugs stopping or rapid tapering to minimise disruption to Rx. Patients should be educated about

possible effects to watch out for.

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Toxicity in overdose

Most toxic

TCAs and MAOIs (avoid in high risk patients for overdose/suicide)

Mid-range

Venlafaxine

Least toxic

SSRIs, reboxetine, mirtazapine, mianserin,

moclobemide

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Suggested management of side effects

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Specific conditions

Cardiac disease

Antidepressants TCA Should never be first choice as

they are anti-arrhythmics and may induce arrhythmias

MAOIs May induce orthostatic hypotension

Interaction with Cardiac drugs SSRI and nefazodone May induce adverse effects via

interaction through cytochrome P450 enzymes

TCAs, MAOIs and trazodone Interact with diuretics to induce orthostatic hypotension

Fluoxetine and fluvoxamine High interaction potential with warfarin

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HIV/AIDS

Antidepressants and protease inhibitors and non-

nucleoside reverse transcriptase inhibitors are metabolised

by similar cytochrome P450 enzymes = increases drug

levels and hence doses need adjusting

Migraine

Fluoxetine and sumatriptan may interact and should be

combined with caution.

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Interventions with unproven efficacy

St Johns wort

- Not superior to placebo in mild to moderate studies.

- Rate of SE is low but significant drug interactions are

consistent with both SSRI- and MAOI-like activity.

Omega-3 fatty acids

- While Omega-3 fatty acid levels are low in depression, no

evidence that they improve depression

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7 things about Depression

1. Depression is NOT a personality flaw. Depression has been associated with chemical imbalance in the CNS,

which can be easily corrected with therapy (non-P or P)

2. ALL antidepressants are equally effective. About 65% of patients will have beneficial response.

3. Most patients will experience some side

effect(s) initially. Healthcare professions and carers must be on the lookout for side

effects and react appropriately

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4. Antidepressants should be taken at the same

time daily.

5. Response to antidepressants is delayed. Several weeks to feel better and up to 4-6 weeks before maximal

benefits are evident.

6. Antidepressants must be taken for a period of

time. Studies have shown that patients who stop medication during the first 6

months are more likely to relapse.

7. Antidepressants are NOT addictive substances. Elevate moods of depressed individuals BUT they do NOT act as

stimulants and not associated with cravings.

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Reference:

World Health Report 2001, World Health Organization - mental health: new understanding, new hope

http://www.who.int/whr/2001/en/index.html

Australian Therapeutic Guidelines Australian and New Zealand clinical practice guidelines for the

treatment of depression. 2004

Cipriani et al., 2009 Lancet 746-758 Connolly and Thase, 2011 Drugs 43-64 Geddes et al., 2003 Lancet 653-661 Hatcher S. 2012 BMJ 344:d8300 Kennedy SH. 2013 Prim Care Companion CNS Disord Kupfer et al, 2012 Lancet 1045-1055 Ogle and Akkerman. 2013 J Pharm Prac Papakostas et al., 2007 Biol Psychiatry 699-704

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