psicofarmacología - UV

psychopharmacology

• study of the use, mechanisms and effects of drugs (used in treatment of mental disorder) that act on CNS and consequently alter behavior

• science that studies the effect of drugs on the brain and behavior as well as the biological mechanisms through which they act (Stahl)

• born in the 1950s

psychotropic drug

• all substances used in psychopharmacology

• psychotropic = affects the mind/acts on the mind

• coined by Ralph Gerard

• Delay: chemical substances whose origin may be natural or synthetic + can produce wide range of effects

significant advances of the 19th century psychopharmacology: synthesis of active principles

• synthesis of active principles (active compounds)

• isolation of active chemical ingredients from raw plant materials:

• morphine from opium (Friedrich Sertürner): first drug (extensively) therapeutically used in psychiatry

• later Niemann obtains pure cocaine → prescribed for almost everything (morphine use lessened)

• Bayer synthesized barbituric acid

significant advances of the 19th century psychopharmacology: rise of experimental studies

• use of scientific method

• Moreau de Tours with hashish: experimental model for psychosis

• Kraepelin: founder of pp → systematic experiments on the effects of substances like coffee and alcohol on intellectual processes

significant advances of the 19th century psychopharmacology: publication and dissemination of findings

• practice of publishing and sharing clinical results gained importance → debate

• Freud among first researchers of pure cocaine

• existence of unexpected effects began to be reported

early 20th century treatments (1900-1950)

• goal often sedation (opiates, bromine, barbiturates)

• also emergence of amphetamines and LSD

• sedation insufficient? ‘shock therapies’ employed: insulin shock treatment and electroconvulsive therapy (violent and uncontrollable behaviors for whom ECT failed got a lobotomy)

the Golden Age: the pharmacological revolution (1950)

• truly effective therapeutic tools in the management of psychiatric patients

• discovery of most psychotropic drugs (mostly by chance)

the golden age - lithium

• mood stabilizer

• Cade (1949)

• manic-depressive symptoms were similar to those in some endocrine (especially thyroid) disorders → MD might have biological origin

• test this idea: animal experiments using lithium urate from urine of manic patients → urine caused excitation, but this effect was blocked by lithium salts

the golden age - chlorpromazine

• 1st modern antipsychotic

1. synthesis: Charpentier

2. pharmalogical study: Courvoisier notes its antihistamine (allergies) and sedative effects

3. surgical application: prevent surgical shock

4. psychiatric application: Laborit convinced psychiatrists Delay and Deniker to try it on psychotic patients → calming, motor slowing and affective indifference (‘neuroleptic syndrome’)

• known as Largactil/Thorazine

• enabled many patients to be treated outside of asylums

the golden age - tricyclic antidepressants (TCAs)

• first one being imipramine: antihistamine, forgotten until chlorpromazine (similar molecule)

• Kuhn (1956)

• proved ineffective for psychosis, but highly effective as antidepressant

the golden age - monamine oxidase inhibitors (MAOIs)

• when Iproniazid (tuberculosis treatment) was observed to significantly improve patients’ moods

• treatment of depression

• less popular than TCAs due to risk of hypertensive crisis when combined with certain foods

the dopaminergic hypothesis of schizophrenia (first major biological theories of mental illness)

• researchers observed drugs like phenothiazines and reserpine depleting or blocking neurotransmitter dopamine + producing Parkinsonian symptoms

• it was known that Parkinsons involved a dopamine deficit → led to the hypothesis that schizophrenia may be related to an excess of dopamine-dependent neural activity

the monoaminergic theory of affective disorders (first major biological theories of mental illness)

• scientists understood that TCAs inhibit the reuptake of nordadrenaline, while MAOIs prevent its breakdown

• both resulted in increased availability of monoamine neurotransmitters → based on this: depression was associated with a functional deficiency of catecholamines, particularly noradrenaline

evidence in favor of the monoaminergic theory of affective disorders

• reserpine: depletes monoamines (noradrenaline, dopamine, 5-HT) and can induce clinical depression

• TCA/MAOI’s: agonists that increase monoamine availability improve depressive symptoms

• 5-HIAA levels: low levels of this serotonin metabolite are specificially linked to violent suicides and impulsive violence

evidence contradicting the monoaminergic theory of affective disorders

• MHPG levels: many patients show normal levels of this norepinephrine metabolite

• therapeutic latency: clinical improvement takes over 25 days, despite immediate chemical changes

• cocaine: increases monoamines but lacks antidepressant efficacy

talidomide

• introduced as sedative and antiemetic (vomiting)

• widely prescribed

• later discovered that it causes severe congenital malformations and limb development (phocomelia)

the development pipeline of a psychotropic drug

1. drug discovery (molecular design)

2. preclinical phase (in vitro and animal)

3. clinical studies (human phases I-IV)

two critical administrative milestones every new compound must achieve

• investigational new drug development (IND) application: permission to start clinical trials in humans after preclinical studies have been completed successfully

• new drug application (NDA): comprehensive submission of all (pre)clinical data for final approval

ways to discover new drugs or compounds

• natural products

• computer-designed chemical synthesis (in silico)

• synthesizing analogues (improved derivatives of existing, successful drugs)

• target newly identified biological mechanisms (e.g. receptors)

• chance (serendipity)

preclinical studies

• the period from the moment a promising molecule is discovered until it is first tested in humans

key steps

1. physicochemical analysis: biochemical characteristics are meticulously described (e.g. solubility and stability)

2. in vitro studies: evaluation of compound on isolated cells and tissues → molecule’s biological activity and potential toxicity at the cellular level

3. animal studies: assess safety and potential efficacy in a whole biological system (at least two different mammalian species, both male and female)

main goals of animal studies

toxicity profiling

• acute toxicity (LD50 and ED50)

• sub-acute (medium-term) and chronic (long-term) toxicity

• other dangers like teratogenic (fetal malformations), mutagenic or carcinogenic effects

pharmacological and behavioral screening

• potential psychoactive effects

• self-admission, site preference, elevated cross maze, prepulse inhibition tests

ED50 and LD50

• ED50: the dose that produces the desired effect in 50% of the subjects (effective dose)

• LD50: the dose that is lethal to 50% of subjects (lethal dose)

• the greater the distance, the safer the drug

clinical stages: phase 1 (evaluating safety and efficacy in humans)

• main goal: assess short-term safety and toxicity

• small group of healthy participants (N=30-100)

• pharmacokinetics (what the body does to the drug)

• pharmacodynamics (what the drug does to the body)

• establish maximum safe dose

• limitation: efficacy is unknown at this stage

clinical stages: phase 2 (evaluating safety and efficacy in humans)

• main goal: therapeutic efficacy

• big sample size with people who are sick (N=100-400)

• does the drug produce the desired therapeutic effect

• strict inclusion (e.g. age, sex) and exclusion criteria

• use of strict inclusion criteria: homogenous sample → easier to detect differences between treatment, but might not be applicable to the general population

• safety, adverse effects, optimal dosage

clinical stages: phase 3 (evaluating safety and efficacy in humans)

• verify long-term safety and efficacy

• large scale (N=1000-3000)

• comparison of new drug against a placebo and/or standard reference drug

• determining drug’s usefulness in daily clinical practice (doses per day, patient preference) and comparing cost against existing treatments

• establish comprehensive benefit-risk ratio: important for NDA

clinical stages: phase 4 (evaluating safety and efficacy in humans)

• pharmacovigilance (epidemiological studies in very large populations over an indefinite period)

• after drug is approved and marketed

• monitor real-world performance by detecting rare of late-onset side effects, identifying new drug interactions and discovering new therapeutic applications

stratification

• bv. sociale stratificatie - indelen van de bevolking in hiërarchische klassen op basis van inkomen, opleiding, etc.

• er is al een karaktereigenschap die heel belangrijk is: o.b.v dit worden de deelnemers ingedeeld, om vervolgens willekeurig te worden ingedeeld aan condities

• zo zijn de uiteindelijke groepen ‘gelijk’

placebo and nocebo effect

• placebo: positive expectation influences interaction between patient and drug

• nocebo: negative expectation influences interaction between patient and drug

• active control: compare new molecule against the best available standard treatment (in case of life-threatening disease) instead of a placebo (crossover → with washout period)

parallel and crossover design

• parallel: treatment group A and control group B at the same time

• crossover: group A gets treatment A, washout period, then gets treatment B → reduces variability and increases statistical efficiency

pharmacokinetics

• studies what the body does to drugs and the time course of drugs in the body, via phases Liberation, Absoprtion, Distribution, Metabolism (biotransformation), Elimination (LADME)

• important in study of drug actions: drug needs to enter the body, reach the brain and be available to interact with biological systems to have a psychoactive effect

• clinical goals: achieve the plasma concentration needed to produce a therapeutic effect without causing toxic effects (therapeutic window)

therapeutic index and therapeutic window

• the range of plasma drug concentration between the minimum effective concentration (MEC - smallest amount in their blood that actually starts to reduce inflammation) and the minimum toxic concentration (MTC - the smallest amount that causes distress or side effects)

or

• between ED50 and LD50

liberation (phases of pharmacokinetics)

• drug is released from its pharmaceutical form or vehicle (= excipient: an inactive substance that helps with manufacturing, stability, delivery and absorption of the medication)

• disintegration: breakdown of solid forms into smaller particles

• dissolution: passage from solid particles into a solution

• diffusion: the dissolved drug moves through fluid and crosses biological membranes into the blood

bioequivalent drugs

• two drugs are bioequivalent if the rate and amount absorbed are the same

• difference in expenses

absorption (phases of pharmacokinetics)

• process by which a drug from its site of administration into the bloodstream (cutaneous, subcutaneous, oral)

• ability of the drug to diffuse across membranes

factors involved

routes of administration

• enteral: natural body openings

• parenteral: through a non-natural opening

• topical: skin or mucous membranes

• fastest to slowest: intravenous (higher risk of severe reactions and embolism), inhalation (large pulmonary surface area; risk of irritation), sublingual, intramuscular (allows slow release), oral (subject to intestinal transit time and pH)

physicochemical properties of the drug (solubility: higher usually easier, salts, free base)

patient characteristics

only intravenous 100% bioavailability

bioavailability (absorption phase of pharmacokinetics)

the fraction of the drug that reaches the bloodstream and the speed at which this process occurs (how effective drug dose will be)

distribution (phases of pharmacokinetics)

• distributed to target organ (mainly the brain) and to peripheral tissues (e.g. fat, muscle, skin, bone)

• the movement of the drug into different body compartments (incl. intra- and extracellular and interstitial spaces)

• influenced by: molecular size and weight, electrical charge, pH, solubility, binding to plasma proteins

• important: liposolubility plays a key role (esp. for drugs acting on the brain), because they can freely cross the blood-brain barrier (substances with low molecular weight or special affinity also can)

• if the drug binds to proteins it will become inactive (only free drug acts on the target) → when the free drug disappears, the drug bound to proteins dissociates and gets released (stable equilibrium)

• volume of distribution (Vd): drug dose (D)/maximum plasma concentration (Cmax); how a drug spreads throughout the body → low means the drug distributes extensively throughout the body = better

• steady state: the amount of drug entering the body equals the amount being eliminated

half-life

• the time required for plasma concentration to drop by 50%

• time to steady-state is 4-5 half-lifes

• helps us predict how long a drug stays active, how often doses should be taken and how long effects or side effects may last

• drug is still being taken, body is still clearing it

• elimination half-life: the time required for the plasma concentration of a drug to decrease by 50%; important to determine the time needed to reach a steady-state concentration per patient

metabolism (phases of pharmacokinetics)

• process of modifying of terminating a drug’s biological activity

• goal: convert drugs intro more water-soluble compounds, which facilitates the elimination of the drug

• this biotransformation happens mainly in the liver, driven by a group of enzymes (cytochrome P-450 system) → end products are called metabolites (effects are still there, even though the original drug molecule is soluted)

transformation through

• degradation: oxidation, reduction or hydrolysis (produce more polar and hydrophilic compounds, which facilitates elimination through the kidneys and lungs)

• conjugation: drug binds to another molecule

• active metabolites

elimination (phases of pharmacokinetics)

• processes with the purpose of removing the drug from the body

• routes: urinary, biliary (bile/feces), sweat, saliva, breast milk, desquamated epithelium (shedding of skin cells)

• clearance: relationship between drug concentration and rate of elimination (how quickly drug is removed from body)

• plasma clearance: volume of blood cleared of the drug per unit of time (renal: cleared by kidneys; hepatic: liver’s ability to metabolize and remove the drug)

pharmacodynamics

• studies the biochemical, physiological and behavioral effects of a drug

• intensity and duration of the drugs actions; how drug achieves its intended therapeutic outcome

• drugs act on specific receptor sites within the body

• receptor: specialized protein structures designed for internal messengers

• drugs mimic or block these internal keys to potentiate or inhibit effects (e.g. morphine reduces pain by unlocking the same receptors designed for natural endorphins)

• affinity (stickiness): how easily the drugs binds to the receptor, higher = better for therapeutic sites (lower dose), lower = better for toxic sites

• efficacy (the power): how intensely does the drug activate the receptor (an antagonist has affinity but zero efficacy)

• drugs do not invent new functions, they hijack existing ones

types of tolerance

• metabolic: the liver breaks down the drug faster

• cellular: neurons become less sensitive to the drug

• behavioral: the environment reduces the drugs effect when it is taken in the same place (certain dose might be okay in familiar context, but deadly in new context)

side effects and secondary effects

• occur when using usual therapeutic doses

• side: direct consequences of the main action

• secondary: indirect consequences unrelated to the main mechanism

• adverse effects: side + secondary + toxic (result of excess dose or exposure time)

neurotransmission

• the process by which a presynaptic neuron translates an electrical impulse (action potential) into a chemical message (neurotransmitter) to bridge the synaptic cleft which leads to either electrical or biochemical changes in the postsynaptic neuron

• ultimate goal: modify gene expression via the CREB (cAMP response element-binding protein) transcription factor

• temporal gap between usage of drug and modified gene expression: receptor binding takes ms, but still clinical improvement may take weeks as it depends on the slow, cascading protein synthesis

classical neurotransmission

• direct release into the synaptic cleft

• acts on immediate postsynaptic receptors

• standard neuromuscular junction signaling

asynaptic transmission

• diffusion through the extracellular space to distant sites

• acts on any compatible receptor within the diffusion radius

• dopamine in the prefrontal cortex (due to a scarcity of dopamine reuptake pumps there)

synaptic sequence

1. synthesis: neurotransmitters are produced from precursors like Tyrosine, via specific enzymes

2. storage: chemicals are packaged into synaptic vesicles by vesicular transporters

3. release: an action potential triggers voltage dependent Na+ channels to propagate the signal, followed by the opening of voltage dependent Ca++ channels → the influx of Ca++ facilitates vesicle fusion (Black Widow spider venom acts as a release facilitator, while Botulinum toxin acts as an inhibitor by interfering with these fusion proteins)

4. receptor interaction: neurotransmitter binds to receptors

5. inactivation: signal is terminated via reuptake pumps or enzymatic degradation

metabotropic intracellular signaling (transduction systems)

• G-protein associated

• binding neurotransmitter activeert G-proteïne → activeert enzymen om second messengers te produceren → leidt tot het openen/sluiten van ionkanalen of andere intracellulaire veranderingen

• neurotransmitter, G-protein, Adenylyl Cyclase stimulation, cAMP (most common second messenger), protein kinases (third messenger), phosphoproteins (fourth messenger)

• critical secondary metabotropic system is the phosphatidylinositol signaling pathway

• 7-transmembrane (cross membrane seven times)

• slow (seconds to minutes)

• target of 30% of drugs

ionotropic intracellular signaling (transduction systems)

• ligand-gated ion channels consisting of subunits surrounding a central pore

• utilizes the influx of calcium as a second messenger → activates protein phosphatase (third messenger), which modifies phosphoproteins by removing phosphate groups

• crucial for fast and short stream of ions in and out of cells

• 4/5-transmembrane receptors

• target of 20% of the drugs

production of receptors

made by DNA, this production can be modulated by

• physiological adaptations, such as learning or repeated stimulation

• drugs

cotransmission

the simultaneous synthesis and release of multiple neurotransmitters

master key analogy

• neurotransmitters are master keys, capable of opening many locks inside the brain

• psychotropic drugs are imperfect duplicates, may fit the desired lock, but due to structural differences they alsof fit into unintended locks → side effects

most important amino acids, their key functions and which receptor architecture they use

• Glutamate: mostly excitation, uses ionotropic (only NMDA, AMPA and KAinate) and metabotropic

• GABA: mainly inhibition, uses GABA A (ionotropic) and GABA B (metabotropic)

receptor architecture acetylcholine (ACh)

• nicotinic (ionotropic)

• muscarinic (metabotropic)

Stahl’s agonist spectrum

1. full agonist: mimics neurotransmitter (NT) for maximum biological response

2. partial agonist: acts as an agonist when NT levels are low and an antagonist when levels are high (Rheostat effect)

3. antagonist: occupies receptor but produces 0 intrinsic activity (blocking)

4. inverse agonist: produces reverse effect of the agonist (shutdown of receptor)

direct vs indirect agonists

direct: binds at the neurotransmitter’s primary site

indirect: binds at alternative sites to facilitate channel opening (e.g. alcohol and diazepam at GABA A receptor) → needs the neurotransmitter to function

• allosteric modulators bind to sites different from the main neurotransmitter site → can be positive (amplify signal; benzodiazepine at GABA A) or negative (decrease or block the signal; ketamine at NMDA)

which other factor (besides receptors) regulates the economy and duration of the synaptic signal

three major protein classes

• voltage-controlled ion channels

• transporters (reuptake pumps)

• degradative enzymes

voltage-controlled ion channels (proteins)

• critical for action potentials

• regulated by membrane polarity

• target for 10% of drugs

transporters (reuptake pumps; proteins)

• recapturing neurotransmitters

• 12-transmembrane

• monoamine transporters: DAT (dopamine), NAT (noradrenaline) and SERT (serotonine)

• SSRI’s and cocaine block these pumps

• tiagabine inhibits GAT1 transporter (GABA)

degradative enzymes (proteins)

• necessary for fluid communication

• destroy neurotransmitters once their message has been delivered

• MAOI’s: inhibit monoamine oxidase to treat depression

• physostigmine: acetylcholinesterase inhibitor to facilitate cholinergic transmission in Alzheimers

basic breakdown of steps of how mental illness develops

1. alteration of enzymes and receptors

2. disorganization of chemical neurotransmission

3. behavioral and motor abnormalities

main biological ways to study disorders of the CNS

1. neuroscience or -biology: studies normal, unaltered brain; uses drugs on animals

2. biological psychiatry: abnormalities of brain neurobiology associated with the causes or consequences of mental illnesses; post-mortem brain tissue and biochemical measures; identification of enzyme or receptor deficiencies that cause or result from psychiatric disorders

3. psychopharmacology: effect of psychotropic drug on behavior + drug discovery; patients and clinical trials; develop effective treatments and new drugs for known disorders + generate hypotheses from casual clinic observations

biological approaches emphasizing dynamic in genomic expression

• pharmacogenetics: combines clinical response data with patients DNA

• pharmacoepigenetics: how environment regulates gene expression (external factors → RNA conversion → protein expression)

the two-hit hypothesis (how do mental illnesses modify synaptic neurotranmission?)

for a psychiatric illness to appear, you need

• genetic vulnerability

• environmental factor

plasticity (how do mental illnesses modify synaptic neurotranmission?)

• brain’s ability to change: synapses and connections are established, maintained or eliminated dynamically

• during fetal development or early childhood: neurodevelopmental disorders → neurons do not develop correctly, move to the wrong place or fail to connect properly

• therapeutic strategies: some research studies growth factors, no drugs yet that can fully control or direct this process

• in adulthood: neurodegenerative → brain loses function over time

• therapeutic strategies: targeted blocking (of harmful gene products) and replacement therapy (neurons through transplantations)

excitotoxicity (how do mental illnesses modify synaptic neurotranmission?)

• homeostasis of the brain’s neurotransmission is disrupted → imbalances manifest as clinical symptoms

• glutamate release → glutamate receptors open calcium channels → massive Ca++ influx → accumulation of free radicals → neuronal death

• the process is necessary up to certain level to remove unnecessary connections so new ones can grow

• control of symptoms and use of glutamate antagonists or neutralization of free radicals

neurotransmission (how do mental illnesses modify synaptic neurotranmission?)

absence

• degenerated neurons, deficit or lack of functionality

• e.g. Parkinson, Huntington, ALS

• tr: replace neurotransmitters/transplants

excess

• neuronal hyperactivation and excitability

• e.g. epilepsy, psychosis, panic attacks

• tr: antagonists to curb transmission (and prevent neuron death)

neuroinflammation (how do mental illnesses modify synaptic neurotranmission?)

• a normal communication process between nervous and immune systems that can become destructive

• pathology depends on the duration and intensity of the inflammatory response

• resident cells/sources: microglia, astrocytes, endothelial cells, immune cells

• mediators/agents: cytokines, reactive oxygen species (ROS/RNS)

other alterations that modify synaptic neurotranmission

• neurotransmitter imbalance (e.g. imbalance between dopamine and acetylcholine systems causes movement disorders)

• rhythmic disruption: incorrect rates of synaptic transmission leading to sleep disturbances

• wiring errors: misdirected synapses and poor connectivity (common in autism)

depressive disorders

• major depressive depression (MDD): characterized by one or major depressive episode; unipolar

• persistent depressive disorder (dysthymia): chronic

• destructive mood dysregulation disorder: primarily diagnosed in children with chronic, severe irritability

• premenstrual dysphoric disorder: severe mood changes related to the menstrual cycle

• susbtance/medication/induced depressive disorder

• depressive disorder due to another medical condition

bipolar and related disorders

• bipolar 1 disorder: at least one manic episode

• bipolar 2 disorder: at least one current or past hypomanic episode and one current or past major depressive episode

• cyclothymic disorder: chronic state (at least 2 years, 1 for kids and adolescents) featuring numerous periods of hypomanic and depressive symptoms that do not completely meet episode criteria

persistent sadness (symptoms clusters in clinical depression - motivational symptoms, vegetative and cognitive alterations)

• general state of inhibition

• significant weight gain or loss

• decreased recent memory

pessimistic thoughts (symptoms clusters in clinical depression - motivational symptoms, vegetative and cognitive alterations)

• apathy and indifference

• psychomotor retardation or agitation

• impaired attention

emotional discomfort (symptoms clusters in clinical depression - motivational symptoms, vegetative and cognitive alterations)

• anhedonia (inability to enjoy)

• insomnia or hypersomnia

• reduced concentration

negative appraisals (symptoms clusters in clinical depression - motivational symptoms, vegetative and cognitive alterations)

• chronic fatigue

• somatic complaints

• negative bias in experience

the five R’s of clinical management (evaluation of treatment)

1. response: reduction of at least 50% in baseline symptoms (I’m better)

2. remission: virtually all symptoms dissapear (I feel fine)

3. recovery: state of remission sustained for 6-12 months

4. relapse: worsening of symptoms occurring before remission turns into recovery

5. recurrence: appearance of new episode after full recovery

foundational evidence for the biological risk factors of mood disorders

• family studies: 1st degree relatives of affected individuals are 10x more likely to develop a mood disorder

• twin studies: concordance rates are way higher in monozygotic twins

• adoption studies

receptor upregulation hypothesis

• explain therapeutic latency (temporal gap)

• suggests that neurotransmitters deficiency causes an upregulation (increased number or sensitivity) of postsynaptic receptors

• chronic antidepressants will eventually induc desensitization (downregulation) of certain noradrenergic receptors → delay in recovery

which interconnected systems are involved in depression?

• BDNF (synapse maintenance) and neuronal viability → otherwise loss of dendritic trees and neuronal death

• HHA axis (hypothalamic-hypophysial-adrenal) is disregulated, leading to elevated glucocorticoids; chronic stress leads to failure of hippocampus and amygdala to inhibit axis → atrophy, damage

• neuroinflammation

• cycle → neuronal damage → vulnerable relapse

norepinephrine

main precursor tyrosine → steps

dopa dopamine norepinephrine

general characteristics of antidepressants

• delay in the onset of therapeutic action (latency): after increase of neurotransmitter, there won’t be an instant clinical effect → takes time → over time, clinical effect will increase and receptor sensitivity will decrease

• anxiety-inducing

• similar therapeutic effects, difference in tolerability and side-effects

• increase monoamines in CNS

• downregulation in certain receptors

paradigm current neuropharmacology

• monoaminergic systems regulate the efficiency of information processing in specific brain regions

• deficient processing in these circuits produces symptoms

structure lithium

• John Cade

• simplest psychotropic drug (pure ion) → fundamentally different from synthetic mood stabilizers

clinical profile lithium

• rapid absorption by all routes → treats (hypo)mania acute; often combined with neuroleptics for severe agitation/hallucinations

• true anti-euphoriant (unique strength

• within 2-3 days early therapeutic effects are observed (latency)

• after 7-10 days, maximum therapeutic effects are achieved

• prophylactic use: prevents recurrent bipolar episodes and major depression without developing tolerance

• protective use: preventive action against suicide and self-harm (unique strength)

• limitations: effective in only 40-50% of cases

toxicity lithium

• narrow therapeutic window

• monitoring every 4-5 days, for long-term treatment every 1-2 months

• acute intoxication: loss of consciousness and coma, coarse tremors, fasciculations, rigidity, muscle hypertonia, convulsions, respiratory depression and death

• chronic intoxication: intense nausea and vomiting, diarrhea, coarse tremors, drowsiness, dizziness and difficulty speaking

adverse effects lithium

• nausea

• dizziness

• fine tremors in the hands

• polyuria with polydipsia (more thirst)

• muscle weakness

• drowsiness

• lethargy (sedation)

• weight gain

• memory problems

• hypothyroidism (10-20% of patients)

dangerous interactions lithium

lithium: mechanism of action

the seizure parallel

theory suggests mania ‘triggers’ subsequent mania, structurally parallel to seizure disorders, leading to the use of anticonvulsants

carbamazepine

• anticonvulsant

• acute mania, bipolar disorder, rapid cycling prophylaxis (unique strength)

• secondary uses: neuropathic pain, fibromyalgia, migraine, anxiety

• severe warning: bone marrow suppression (blood cell monitoring)

carbamazepine: mechanism of action

• inhibits voltage-dependent Na+ channels, at a site inside the channel called the alpha subunit

• also acts on Ca++ and K+ ion channels

• modulates GABA to reduce hyperexcitability

valproic acid

• anticonvulsant

• acute mania, bipolar affective disorder, prophylaxis, neuropathic pain, migraine, anxiety

• unique strenghts: migraine treatmen, high efficacy in acute mania

• side effects: hair loss, weight gain, sedation

• side effects from chronic use: hepatic toxicity, metabolic alterations, amenorrhea and polycystic ovary syndrome (PCOS), severe teratogen (fetal malformation)

valproic acid: mechanism of action

• inhibits voltage-gated Na+ channels: may reduce excess of neurotransmitters by decreasing ion flow through Na+ channels, which reduces glutamate release

• enhances GABA activity: increases its release, decreases its reuptake and slows its metabolic inactivation

• regulates intracellular signal transduction cascade: inhibits GSK-3, blocks protein kinase C → this promotes neuroprotection and long-term plasticity

cariprazine: mechanism of action (mood stabilizers)

• targeted dopaminergic activation

• partial agonist of D3 (in ventral tegmental area), D2 and 5-HT1A receptors → increased dopamine release in the PFC

• result: stimulation of D1 receptors in the PFC directly improves depressive symptomatology

lamotrogine - mood stabilizers

• sodium (Na+) channel blockage → glutamate inhibition

• specifically for bipolar depression

recent research regarding mood stabilizers: NMDA receptor antagonists

medication combos for bipolar disorder

evidence-based combos for mania

• 5HT/DA blocker + lithium

• 5HT/DA blocker + valproate

practice based combos for depression

• 5HT/DA blocker + lamictal/lamotrigine

be careful with this combo

• 5HT/DA blocker + lamictal/lamotrigine + monoamine reuptake blocker: gives a lot of effects we do not want

dependence vs addiction

dependence is physiological and temporary, addiction is structural and chronic (and a disease)

• dependence: development of tolerance and withdrawal syndrome upon cessation; temporary and self-limiting (physical withdrawal will end by itself)

• addiction: compulsive use, profound long-lasting structural neuroadaptations and a loss of control; enduring and characterized by multiple relapses over a lifespan

types of psychoactive substances

• CNS depressants: alcohol, hypnotics, benzodiazepines

• psychostimulants: (meth)amphetamine, cocaine, synthetic drugs

• opioids: heroin, morphine, methadone

• cannabinoids: hashish, marijuana

• hallucinogens: LSD, mescaline

what is the final common pathway of reward

the mesolimbic dopamine pathway

barbiturates

• important historical stage before safer anxiolytic agents appeared

• produces general CNS depression (by enhancing GABA activity at the GABAa receptor complex)