SECTION 2A Flashcards
Schizophrenia & Depression
Outline the positive symptoms of Schizophrenia
Perceptual Hallucinations (esp. auditory)
Delusions
Thought Broadcasting
Disorganised Speech
Outline the negative symptoms of Schizophrenia
Lack of Motivatiion Blunting of emotional responses Poverty of Speech (alogia) Social withdrawal Catatonia
Describe some of the theories explaining the causes of Schizophrenia
Viral infection during Development
Genetic Inheritance
Developmental brain abnormality
Describe the possible neuronal mechanisms that lead to Schizophrenia.
1) Excessive 5-HT transmission - 5-HT2a/2c activation by LSD leads to hallucination
2) Excessive Dopamine transmission - Amphetamine blocks DA uptake and induces psychosis resembling Schizophrenia
3) Excessive Glutamate Transmission - Phenycyclide blocks NMDARs and mimics positive and negative symptoms of Schizophrenia.
What is meant by Extra-Pyramidal Side Effects?
Neuroleptics that target Dopaminergic systems aim to antagonise DA action in the mesolimbic and Mesocortical pathways (pyramidal effects) but they inevitably effect other DA systems such as nigrostriatal and tuberoinfundibular pathways (extra-pyramidal) can result in a pseudo Parkinson’s
Name a typical neuroleptic
Chloropromazine
Flupenthixol
Haloperidol
What are the advantages the typical neuroleptics?
They relieve the positive symptoms of Schizophrenia
They are sedatives as well (can be disadvantageous)
What are the main disadvantages of the typical neuroleptics
Ineffective against the negative symptoms of Schizophrenia
EPS effects- dystonia (abnormal muscle tone), akathisia (restlessness)
Tardive Dyskinesia (repeated stereotyped movements enduring after cessation of drug)
Hyperprolactinaemia which can lead to reduced gonadal function.
What are the molecular targets of the typical neuroleptics?
Antagonism of D2 receptors
Antagonism of H1 (histamine) receptors –> sedation
Antagonism of mAChRs –> relief of pseudo PD effects
Antagonism of alpha 1 and 2 adrenoceptors –> hypotension
Name two of the atypical neuroleptics
Clozapine
Risperidone
What are the advantages of Clozapine, an atypical neuroleptic?
It relieves both positive and negative symptoms of Schizophrenia.
It’s capable of relieving psychosis resistant to typical neuroleptics
It has a lower incidence of EPS
What are the disadvantages of Clozapine, an atypical neuroleptic?
Dribbling Agranulocytosis (loss of granulocytes, a type of white blood cell) Weight gain (systemic and visceral fat) --> diabetes/CVD Elongation of QT interval
What are the molecular targets of Clozapine, an atypical neuroleptic?
Antagonist Affinity for D4 (D2 family)
Antagonism of 5-HT2a/2c receptors (possibly causes the weight gain)
Weak Partial agonist at 5-HT1a receptors (increase DA release in Mesocortical pathway relieving negative symptoms)
Antagonism of Muscarinic ACh receptor alpha 2 adrenoceptor
List three main symptoms of Depression
Anhedonia (inability to feel pleasure)
Weight gain/loss
Insomnia
Describe the treatment of Electroconvulsive Therapy
ECT is procedure done under general anaesthesia where small electric currents are passed through the brain inducing a brief seizure. ECT is thought to sensitize the brain to 5-HT and Na. It is only given unilaterally to minimize amnesic effects
What is the Monoamine Hypothesis of Depression?
The hypothesis states that depression is caused by a functional deficit of NA, 5-HT and possibly DA in the brain
What pharmacological evidence supports the Monoamine hypothesis of Depression?
Reserpine (used to treat Schizophrenia) depletes Monoamine storage in vesicles by irreversibly binding to VMAT2. It was found to induce depression in 15% of people.
Iproniazid (used to treat tuberculosis) caused euphoria in patients as it is a non-selective inhibitor of MAO
Name a first generation Monoamine Oxidase inhibitor and its mechanism of action
Iproniazid: it is an irreversible non-selective inhibitor of MAOs
What is the Cheese Reaction?
Tyramine is present in cheese. When patients taking non-selective MAO inhibitors have tyramine in their diet, it is able to enter the CNS as MAOs in the periphery which normally block its entry are inhibited. In the CNS, the tyramine acts a false transmitter and disrupts the VMAT2 causing a build up of monoamine.
Name a second generation Monoamine Oxidase inhibitor
Clorgyline. It is a reversible MAOA selective inhibitor.
What are the benefits of second generation Monoamine Oxidase inhibitors?
They are reversible so the effects of a tyramine diet are less severe
They are MAOA selective so are likely to have less widespread effects than the non-selective 1st generation inhibitors.
What are the adverse effects of both types of Monoamine Oxidase inhibitor?
Hepatotoxicity
CNS overstimulation –> insomnia, convulsions
Postural Hypotension
Sympathetic NS overstimulation –> dry mouth, sweating
Name a tricyclic antidepressant and outline its usefulness in treatment of Depression
Imipramine
5-HT reuptake inhibition
NA reuptake inhibition
Relatively weak DA reuptake inhibition
What are the side-effects Imipramine? What molecular targets are responsible for them?
Antagonism at alpha 1 receptor –> tachycardia
Antagonism at mACh receptors –> tachycardia
Antagonism at H1 receptors –> sedation
What class of drug is Venlafaxine?
Serotonin Noradrenaline Reuptake Inhibitor (SNRI)
What advantage do SNRIs have over the tricyclic antidepressants?
SNRIs don’t have additional effects on mAChRs, adrenoceptors or histaminergic receptors.
