Drugs → brain structures

APMST

Bipolar disorder

NICE

Diagnosis

Full history of the patient (family, any episode, symptoms between the episodes)

Symptoms profile, triggers to previous episodes, social and personal functioning, comorbidities, physical health, current psychosocial stressors

Interview a family member

NICE

BE CAREFUL

If (Psychotic symptoms, ↑ suicidal ideation, ↑ drug misuse) → late BD and not SKZ (minorities)

If alcohol | drug → wait 7 days before diagnosis Late onset (>40yrs) → hypothyroidism, stroke,

neurological disorders (dementia)

NICE

Before a rapid cycling BD is diagnosed consider:

Erratic compliance hypothyroidism, AD, suboptimal medication

regimes Lithium withdrawal

NICE

Consider a diagnosis of BD before Axis II if there are mood swings

During treatment consider compliance before considering a personality disorder

NICE

Treatment (1/3)

Inform the patient Contraception and risk of pregnancy See patients once / (1|2) week (for 3 months)

NICE

Treatment (2/3)

Acute mania (and mixed→ AP, valproate, lithium, BDZ

AP (olanz, risp, quet)→ severe manic symptoms | marked behavioral disturbances

Valproate or lithium → previous response, good compliance, augmentation of AP

Lithium → not severe symptoms NOT RECOMMENDED: CBZ, Gabapent, Lamo

NICE

Treatment (3/3)

Acute depression

Add AP (quetiapine) to AD (SSRI better than TCI) No AD → rapid-cycling, recent hypomanic, recent

functional impairing and rapid mood fluctuations Stop AD → after 8 weeks of symptoms relief (parox,

venlafax → higher risk of discontinuation syndrome) Avoid → Lamo a single treatment for BDI

Mania, which treatment ?

3 weeks

Mania, which treatment ?

Mania, which treatment ?

Change in mania rating scores

Mania, which treatment ?

Risk difference for treatment responders

Mania, which treatment ?

Risk difference for drop outs

Conclusion 1

Use second generation AP (risp, olanz, quet) for the treatment of acute mania (3 weeks)

Mood stabilizers are second choice

Acute depression, which treatment ?

Acute depression, which treatment ?

Acute depression, which treatment ?

Symptom remission

Conclusion 2

Use second generation AP (olanz, quet) for the treatment of acute depression during BD

Mood stabilizers are less efficacious

No strong evidence for using SSRI

Maintenance, which treatment ?the same regimen that successfully treated the

acute bipolar mood episode

attempt monotherapy. However, many bipolar patients require medication combinations

First line: lithium, lamotrigine, risperidone (im)

Second line: aripiprazole, valproate, quet, olanz

Suicide risk → lithium

Maintenance → lithium

Lithium 41% vs 61% placebo

Conclusion 3

For maintenance use the same drug started during acute phase

If not possible use lithium, risperidone im, lamotrigine, valp

Start with monotherapy, but multitreatment is more effective

neuroimaging

lithium

neuroimaging

1.9 years base-1st fu4 years base-2nd fu

Valproate and AP

Overall, no significant brain volume modification in bipolar patients taking valproate or AP

Valproate

ant

AP mechanism

Serotonin-glutamate

Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers

Serotonin-Dopamine-Scaffolding

The scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state

Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile

Conclusion 4

The molecular events that drive the efficacy of mood stabilizers are related to GSK-3, IPP and

prosurvival genetic expression

The dopaminergic-serotoninergic-glutamatergic balance is central to the activity of AP in the prefrontal cortex. Scaffolding proteins are

thought to be relevant

imaging

Conclusion 5

Lymbic structures and the PFC are key relay points for the efficacy of pharmacological

treatments in BP

Schizophrenia

skz

Treatment

First episode → oral AP, address to specialized unit, write a care plan in collaboration with the patient and send it to the GMP, include a crisis plan

Provide information and discuss the benefits and disadvantages

Chose the AP with the patient, taking into consideration extrapyramidal side effects and metabolic side effects

Assess the cardiovascular risk (ECG)

skz

Start with the lower dose of AP Justify and record reasons for dosages outside the

range given by guidelines Monitor efficacy, side effects, adherence, physical health Record the rationale for continuing, changing or stopping

medication and the effects of such changes Trials for one medication should last 4-6 weeks Do not “neuroleptisize” your patient Rapid tranquillization

skz

Which drug ?

Conclusion 6

Second generation AP are more effective for the treatment of Skz

Use Olanzapine and Risperidone when possible

The side efffect profile must nevertheless guide the clinical choices

imaging

Conventional antipsychotic agents led to an increase of basalganglia volume while ongoing multifocal gray matter loss

Modern atypical agents rather tend to turn increased basal ganglia volumeback to normal while increasing the volume of thalamus and of

gray matter in different key regions

II AP → ↑ glutamatergic turnover and inhibit NMDA receptors

17 (8m/9f) acute psychotic recurrent-episode (chronic) patients treated with

haloperidol or risperidone

30 medication-naive first-episode patients and 36 matchedhealthy controls participatedAtypical antipsychotic treatment

Effect of practice on brain activation in the left dorsolateral prefrontal cortex (DLPFC)

8 skz and 8 controls

Treated with risperidone for 6 weeks

Conclusion 7

II AP increase the DLPC activity This event correlates with outcome

Variations in the NAc may be involved during withdrawal