Endocrine and Metabolic

Problems in Psychiatric Disease

Dr Alison Wren

Consultant and Honorary Senior

Lecturer in Endocrinology and

Diabetes

Topic Areas Cardio-metabolic complications of psychiatric

disease second generation antipsychotics (SGAs) Weight gain Hyperglycaemia/Diabetes Dyslipidaemia

Hyperprolactinaemia in the patient on antipsychotics

Endocrine Toxicity of Lithium Hyperparthyroidism Thyroid effects

Cardiometabolic Risk

25-30 years

reduced life

expectency

Diabetes 2X

4

Total Efficacy: SMD±95% CI.

CI, confidence interval; SMD, standardised mean differences.

Adapted from Leucht S, et al. Lancet. 2013;382(9896):951-962.

Weight Gain: Antipsychotics Versus Placebo (Leucht, 2013)

Haloperidol 0.09 (-0.00 to 0.17)

Lurasidone 0.10 (-0.02 to 0.21)

Aripiprazole 0.17 (0.05 to 0.28)

Amisulpride 0.20 (0.05 to 0.35)

Paliperidone 0.38 (0.27 to 0.48)

Risperidone 0.42 (0.33 to 0.50)

Quetiapine 0.43 (0.34 to 0.53)

Chlorpromazine 0.55 (0.34 to 0.76)

Clozapine 0.65 (0.31 to 0.99)

Olanzapine 0.74 (0.67 to 0.81)

More Weight Gain With Placebo More Weight Gain With Active Drug

-0.50 0.00 1.00 1.50

5

Differing Tolerability Profiles (Leucht, 2013)

SMD=standardised mean differences; OR=odds ratio

Leucht et al. Lancet 2013;382(9896):951–962

Favours

drug

Weight gain (SMD)

HAL

ZIP

LUR

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ASE

PAL

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SER

CHL

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CLO

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OLA

EPS (OR)

CLO

SER

OLA

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ARI

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AMI

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ASE

PAL

RIS

LUR

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ZOT

HAL

Prolactin (SMD)

ARI

QUE

ASE

OLA

CHL

ILO

ZIP

LUR

SER

HAL

RIS

PAL

AMI

CLO

ZOT

QTc (SMD)

LUR

ARI

PAL

HAL

QUE

OLA

RIS

ASE

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AMI

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Sedation (OR)

AMI

PAL

SER

ILO

ARI

LUR

RIS

HAL

ASE

OLA

QUE

ZIP

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Favours

placebo

Drug

better

Placebo

better

Favours

drug

Favours

placebo

Favour

drug

Favours

placebo

Drug

better

Placebo

better

Set to rise to 5 million with diabetes by 2025 if current trend

continues

SGAs Diabetes and DyslipidaemiaDirect Effect

May be Rapid

And Dramatic

May also

cause marked

increase

Triglycerides in

normal wt

Indirect Slow via Visceral Obesity

Prevention and treatment of SGA-

Induced Obesity/Metabolic Syndrome

Choose Metabolically friendly anti-psychotic if possible, particularly in those at highest risk of harm (pre-existing high BMI, IGT/DM or FH of these)

Promote and Encourage healthy lifestyle – simpleprogram.org

Treatment of cardiovascular risk factors

Adjunctive treatments to prevent/reverse assoicated weight gain

Meta-analyses Metformin most studied + most consistent benefit.

Topiramate, sibutramine, aripiprazole and reboxetine also significant (smaller) beneficial on weight.

Mizuno et al, Schizophrenia Bulletin vol. 40 no. 6 pp. 1385–1403, 2014

<< Prev Fig. 2. Next >>PMC full text: Schizophr Bull. 2014 Nov; 40(6): 1385–1403.

Published online 2014 Mar 17. doi: 10.1093/schbul/sbu030

Copyright/License ► Request permission to reuse

Fig. 2.

Effects of metformin, nizatidine, and aripiprazole on body weight, mean difference (kg). (a) Metformin vs

From: Mizuno et al, Schizophrenia Bulletin vol. 40 no. 6 pp. 1385–1403, 2014

Prevention and treatment of SGA-Induced

Obesity – Metformin practicalities

Off-licence but precedent – PCOS

500mg-2550mg daily 2-3 doses, either after wt gain or

prophylactically, mostly schizophrenia, some in bipolar, typically

small and short duration studies <6 months, most 12 weeks

First episode, early treament may be most effective

Average weight difference 3-5kg compared to placebo

Praharaj et al : British Journal of Clinical Pharmacology, Volume 71, Issue 3, pages 377–382, March 2011

Generali et al Hosp Pharm 2013;48(9):734–735,777

Meta-analysis 1547 patients from 21 RCTs (778 Met, 769 Placebo)

Zheng et al J Clin Pharm Oct 2015

Benefits Weight, BMI, fasting glucose, fasting insulin, trigs, total cholesterol. Higher N&V.

Newer better tolerated anti-diabetic

agents given once daily (or less)

SGLT-2 Inhibitors

No glucosein filtrate

Collecting

duct

Glucose

S1 segment of proximal tubule

• ~90% glucose reabsorbed

• Facilitated by SGLT2

Distal S3 segment of proximal tubule

• ~10% glucose reabsorbed

• Facilitated by SGLT1

16Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038.

Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277.

Glomerulus filters

Proximal tubule

reabsorbs

SGLT: sodium-coupled glucose transporter

SGLT-2 Inhibitors: First in class Dapagliflozin (Forxiga)

launched in UK Nov 2012

GLP 1 Agonists

Exenatide

Liraglutide

>1% HbA1c reduction4-5kg weight lossSustained > 80weeksPossibly better with weekly preparationEasy to teach (even doctors can do it!)

Date of Preparation December 2011 Job bag number UK/Deg/0611/0031b

Agenda

Half-life of insulin degludec is twice as long as of insulin glargine

Insulin degludec Insulin glargine

0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg

Half-life (hours) 25.9 27.0 23.9 11.8 14.0 11.9

Mean half-life 25.4 12.5

Insulin degludec 0.8 U/kg

Insulin glargine 0.8 U/kg

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

type 1 diabetes

Road Map Cardio-metabolic complications of psychiatric

disease second generation antipsychotics (SGAs) Weight gain Hyperglycaemia/Diabetes Dyslipidaemia

Hyperprolactinaemia in the patient on antipsychotics

Endocrine Toxicity of Lithium Hyperparthyroidism Thyroid effects

Prolactin Regulation

Dopamine (D2)

Antagonists

- antipsychotics

- antiemetics (eg

metoclopramide)

25

Differing Tolerability Profiles (Leucht, 2013)

SMD=standardised mean differences; OR=odds ratio

Leucht et al. Lancet 2013;382(9896):951–962

Favours

drug

Weight gain (SMD)

HAL

ZIP

LUR

ARI

AMI

ASE

PAL

RIS

QUE

SER

CHL

ILO

CLO

ZOT

OLA

EPS (OR)

CLO

SER

OLA

QUE

ARI

ILO

AMI

ZIP

ASE

PAL

RIS

LUR

CHL

ZOT

HAL

Prolactin (SMD)

ARI

QUE

ASE

OLA

CHL

ILO

ZIP

LUR

SER

HAL

RIS

PAL

AMI

CLO

ZOT

QTc (SMD)

LUR

ARI

PAL

HAL

QUE

OLA

RIS

ASE

ILO

ZIP

AMI

SER

CLO

CHL

ZOT

Sedation (OR)

AMI

PAL

SER

ILO

ARI

LUR

RIS

HAL

ASE

OLA

QUE

ZIP

CHL

ZOT

CLO

Favours

placebo

Drug

better

Placebo

better

Favours

drug

Favours

placebo

Favour

drug

Favours

placebo

Drug

better

Placebo

better

Antipsychotics and Prolactin

Asymptomatic hyperprolactinaemia

Symptomatic hyperprolactinaemia

Prolactinoma (exacerbated/?caused/treatment complicated by dopamine antagonist)

Symptoms of

Hyperprolactinaemia/Prolactinoma

Hyperprolactinamia

Oligo/Amenorrhoea

Galactorrhoea

Subfertility

Sexual dysfunction – reduced libido

Women present earlier !

Mass effects

Headache

Visual field defect

What are the worries about

hyperprolactinaemia?

Are you sitting on one of these?

Not if it’s a

macroprolactinoma

PRL in 10s of

thousands (80,000)

Could be non-

functioning

(Headache,

fields, other

pituitary

dysfunction)

BASELINE PROLACTIN REALLY HELPFUL!

What are the worries about

hyperprolactinaemia?

Symptoms: Galactorrhoea, amenorrhoea, loss of libido, impotence,

subfertility

Harmful Effects of Prolonged Hyperprolactinaemia

Demineralisation of bone secondary to hypogonadism

Breast cancer risk? – probably not Meta-analysis suggests possible increase in 6000 women with schizophrenia (6/13

studies slight increase risk, but subsequent systemic reviews failed to detect increased risk

Bushe et al: Schizophr Res. 2009 Oct;114(1-3):6-16. Hert et al Psychiatr Danub. 2016 Sep;28(3):243-254

Dutch pharmacological database study suggests no excess in 1342 patients receiving DA agonist for hyperprolactinaemia

Dekkers et al: Pituitary 2009

No excess in short term use of risperidone vs other antipsychotics Reulfors et al, Schizophr Res. 2017 Apr;182:98-103

Other factors eg nulliparity, obesity, diabetes mellitus, and unhealthy lifestyle behaviours (alcohol dependence, smoking, low physical activity) probably more important than hyperprolactinaemia

What should be done about

hyperprolactinaemia

Could it be a significant pituitary adenoma?History for symptoms headache/ blurred visionClinically assess visual fields Is pre-treatment prolactin available/normalCheck baseline pituitary function:

9am cortisol, TFT, GH/IGF1, oestradiol/testosterone, LH/FSH

Is it an artefact?Check MACROPROLACTIN

Review antipsychotic medication –Aripirazole?:Substitute (risk relapse of psychotic symptoms 30-40%)

Add/Dose sparing aripiprazole, especially if symptomatic?

Role for metformin? – likely PCOS subset?Bo et al. Psychiatry Res. 2016 Mar 30;237:257-63

What can be done for bone protection?

Persistant hyperprolactinaemia and unable to change antipsychotic agent

No structural pituitary disease

Evidence of hypogonadism (amenorrhoea, loss of libido, low oestradiol/testosterone)

Consider oestrogen/testosterone supplementation

Calcium and vitamin D

Bisphosphonates if older with osteoporosis (annual IV preparation improves compliance) – DEXA especially if prolonged amenorrhoea

Endo Referral and who to MRI

Endo referral if:>5000 (or less but increasing/fails to improve with altered

therapy)Abnormality of other basal pituitary function, or visual fields or

marked headache? For fertility

Incidence of coincidental pituitary microadenoma (non-functioning) in MRI head done for other indication approx 5%

Can antipsychotics cause prolactinoma?Atypical antipsychotics and pituitary tumours: a pharmacovigilance studyA Szarfman et al, Pharmacotherapy, 26 (6), 2006

No. reports Adjusted

Drug pituitary tumours Risk Ratio

Risperidone 54 18.7 (14.9- 23.3)

Haloperidol 9 5.6 (2.9-13)

Ziprasidone 6 3.0 (1.5- 5.6)

Olanzapine 11 2.3 (1.4- 3.7)

Clozapine 4 0.9 (0.4- 1.7)

Quetiapine 1 0.6 (0.1- 1.7)

Aripiprazole 0 -

Ascertainment Bias?

Antipsychotics and pituitary tumours –

ascertainment bias or biological effect?

Mice studies

Long term treatment with risperidone in wild type mice, associated pituitary adenomas and adenocarcinomas

D2 knock-out mice- lactotroph hyperplasia and pituitary tumours

Road Map Cardio-metabolic complications of psychiatric

disease second generation antipsychotics (SGAs) Weight gain Hyperglycaemia/Diabetes Dyslipidaemia

Hyperprolactinaemia in the patient on antipsychotics

Endocrine Toxicity of Lithium Hyperparthyroidism Thyroid effects

Lithium Toxicity – Thyroid Effects

Thyrotoxicosis and thyroid cancer are not seen in excess of background population

T3, T4

Hypothyroidism: Blocks release: prevalence

highest in middle -aged women (>20% in one series).

Annual incidence: Women 2-3% Men 0.5-1%

(Whickham Study: OVERT: women 0.41 , men 0.06%,

Subclinical similar incidence)

Usually other predisposition: iodine deficiency/autoimmunity

Goitre: Annual incidence

4% vs 1% geographically

matched controls (may

regress despite continued

treatment)

Lithium Toxicity

Hyperparathyroidism – high Ca, high PTH

About 150 cases in literature – small series/case reports – common in clinical practice

Prevalence 4-6% (background prevalence in postmenopausal women> 3.4%)

Commoner in women (4:1) –hyperparathryoidism overall also commoner post-menopausal women (3:1)

Multiple gland disease (hyperplasia or multiple adenomas) commoner

May be rapid (1day) or delayed

May not be reversible on stopping Lithium

Lithium Toxicity -

Hyperparathyroidism mechanism

Similar picture to familial hypocalciuric hypercalcaemia = FHH (inactivating mutations CASR)

Similarly often hypocalciuria (effect on CASR in thick ascending loop kidney)

PTH

Approach to hypercalcaemia in patient

on lithium – Is it hyperparathyroidism?

Refer to Endocrinology with Baseline Biochemistry

U+E, Alb, Ca, PO4, PTH, vitamin D

Exclusion other common causes• Renal Failure (tertiary hyperparathyroidism)

• Other drugs (thiazides, milk/alkali, vitamin D)

• Myeloma (serum electrophoresis, urinary BJPs)

• Humoral hypercalcaemia of malignancy (wt loss etc, PTHrp)

• Sarcoid (ethnicity, CXR, serum ACE)

Management Options

Monitor – mild, asymptomatic

Discontinue Lithium?

Medical (cinacalcet –calcimimetic )

Surgical

Vitamin D deficiency - risks

Can I get you

anything son,

cup of tea?,

Vitamin D?

Deficient <40nmol/L, Insufficient 40-70nmol/L, Replete 70-150nmol/L

Vitamin D Preparations

Colecalciferol 20,000 IU capsules Plenachol (no gelatin, kosher and halal capsule and veg

source)

Aviticol and fultium D3 (kosher and halal cert beef gelatin caps, Vit D3 from sheep lanolin)

Colecalciferol 40,000 capsules (plenachol)

Daily higher strength 3000 IU tablets

Colecalciferol liquid 3000 IU/ml

Colecalciferol 800IU (eg Fultium/Desunin)

Calcium and colecalciferol 400IU (eg Calcichew D3 forte, Adcal D3)

Calcium and Ergocalciferol

OTC preparations

Injectable ergo or colecalciferol IM 300,000 IU

Summary Cardio-metabolic complications of second generation

antipsychotics (SGAs)

Use olanzapine with caution in those at highest riskConsider metabolically favourable agent to avoidMonitor for complications and switch or treatLifestyle/metformin addition to prevent/treatTreat CVS risk factors

Hyperprolactinaemia in the patient on antipsychoticsCheck a pre-treatment prolactinMost Drug effect – consider switch/addition/dose sparing aripirazoleThink about bone protection – including vitamin DEndo referral if very high or increasing level, other pituitary function abnormality, sypmtoms or suspicion of mass effect

Endocrine Toxicity of LithiumHyperparthyroidism – slightly above background incidence –

endo referral for allThyroid effects – slight increase hypothyroidism especially older women – easy to treat with thyroxine, don’t need to stop lithium