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Psychotropic Drugs:
Introduction and Biopsychiatry
- Psychotropic drugs are medications used to treat mental illness.
- Biopsychiatry , also known as the biological approach, is a theoretical framework that views mental health disorders as biological malfunctions of the nervous system.
- This approach suggests that brain function is influenced by factors like genetics, neurodevelopment, drugs, infection, and psychosocial experiences, alone or in combination.
- Abnormal changes in behaviour, mental, and emotional experiences are believed to be caused by disturbances in normal brain function.
- When the brain is not working correctly, how it produces and responds to neurotransmitters changes, potentially leading to symptoms of depression, anxiety, PTSD, or other disorders.
- The primary goal of drug therapy is to restore "balance" to a malfunctioning brain.
- Understanding how psychotropic drugs improve symptoms is still an area of ongoing research. Early theories like the dopamine theory of schizophrenia and the monoamine theory of depression are now considered overly simplistic.
- Evidence suggests clinically useful drugs may work via additional pathways at the genetic level, causing long-term changes in brain structure and function. Current research focuses on refining the understanding of how drugs alter the brain's responses to neurotransmitters, hormones, and coregulators. Structure and Function of the Brain
- The brain is responsible for regulating behaviour and carrying out mental processes.
- Many brain functions, including mental health disturbances, are carried out by similar mechanisms (interactions between neurons) and often in similar locations, meaning drugs used for mental disturbances can interfere with other brain activities.
- Functions of the Brain (summarised): o Monitor changes in the external world. o Monitor the composition of body fluids. o Regulate the contractions of skeletal muscles. o Regulate the internal organs. o Initiate and regulate basic drives (hunger, thirst, sex, aggressive self-protection). o Mediate conscious sensation. o Store and retrieve memories.
o Regulate mood (affect) and emotions. o Think and perform intellectual functions. o Regulate the sleep cycle. o Produce and interpret language. o Process visual and auditory data.
- The brain acts as a coordinator and director of the body's response to internal and external changes, aiming to maintain homeostasis.
- Information from sense organs is relayed to the brain by peripheral nerves and interpreted. Major psychiatric disturbances like schizophrenia can involve alterations in sensory experience, such as auditory hallucinations (hearing voices).
- The brain controls skeletal muscles for movement and coordinated actions. Both psychiatric disease and psychotropic drug treatment can be associated with movement disturbances. Muscles essential for breathing (diaphragm) and speech (throat, tongue, mouth) are controlled by the brain, so drugs affecting brain function can impact respiration or speech.
- The brain monitors internal functions like blood pressure, body temperature, and fluid composition to maintain homeostasis by controlling internal organs, for example, directing the heart and arterioles to adjust blood pressure.
- The autonomic nervous system (sympathetic and parasympathetic divisions) and the endocrine system serve as communication links between the brain and internal organs.
- Mental health disturbances like anxiety can translate into altered internal function through this brain-organ linkage. For instance, anxiety can cause inappropriate activation of parasympathetic nerves to the digestive tract (leading to diarrhea) or sympathetic nerves to cardiac muscle and arterioles (leading to fast heart rate and hypertension).
- The brain influences internal organs by regulating hormonal secretions of the pituitary gland, which in turn regulates other glands. The hypothalamus is involved in basic drives and secretes hormones (e.g., CRH) that act on the pituitary gland.
- The relationship between the brain, pituitary gland, and adrenal glands is important in normal and abnormal mental function. The system involving CRH, corticotropin, and cortisol is activated by stress and influences nerve cells; it is overactive and improperly regulated in anxiety and depression.
- Basic drives like sex and hunger are strong influences on behaviour and can be disturbed in mental health disorders like depression (e.g., eating disorders, loss of sexual interest).
- The entire sleep and wakefulness cycle and alertness are regulated by brain regions. Sleep is essential for well-being, and sleep pattern assessment is part of diagnosing mental health disorders. Many psychotropic drugs interfere with sleep regulation and alertness, causing sedation or drowsiness, requiring caution with activities needing attention.
- Reuptake : Neurotransmitters are taken back into the presynaptic neuron via transporters in the cell membrane. Once inside, they are recycled or degraded by intracellular enzymes (e.g., monoamine oxidase (MAO) degrades monoamine neurotransmitters like norepinephrine, dopamine, serotonin). Reuptake is a target for many drugs.
- Neurotransmitters and Receptors (Table 11.1 summarises key types and their associations with mental health disorders): o Monoamines : ▪ Dopamine (DA) : Involved in movement, emotions, thoughts, decision making, hypothalamic hormone release. Decreased in Parkinson's disease, depression; increased in schizophrenia, mania. Receptors: D1, D2, D3, D4, D5. ▪ Norepinephrine (NE) (noradrenaline): Affects mood, attention, arousal; stimulates sympathetic nervous system (fight or flight). Decreased in depression; increased in mania, anxiety states, schizophrenia. Receptors: α1, α2, β1, β2. ▪ Serotonin (5-hydroxytryptophan [5-HT]) : Plays roles in sleep, hunger, mood, pain perception, hormonal activity, aggression, sexual behaviour. Decreased in depression; increased in anxiety states. Receptors: 5-HT1, 5- HT2, 5-HT3, 5-HT4. ▪ Histamine : Involved in alertness, inflammatory response, gastric secretion. Decreased is associated with sedation, weight gain. Receptors: H1, H2. o Amino Acids : ▪ Gamma-aminobutyric acid (GABA) : Major inhibitory neurotransmitter; reduces aggression, excitation, anxiety; has anticonvulsant and muscle- relaxing properties; may impair cognition/psychomotor function. Decreased in anxiety disorders, schizophrenia, mania, Huntington's disease; increased results in reduction of anxiety. Receptors: GABAA, GABAB. ▪ Glutamate : Excitatory; AMPA plays a role in learning and memory. Decreased (NMDA) in psychosis; increased (NMDA) prolonged state can be neurotoxic (neurodegeneration in Alzheimer's); increased (AMPA) improves cognitive performance. Receptors: NMDA, AMPA. o Cholinergics : ▪ Acetylcholine (ACh) : Plays roles in learning, memory; regulates mood, mania, sexual aggression; stimulates parasympathetic nervous system. Decreased in Alzheimer's, Huntington's, Parkinson's; increased in depression. Receptors: Nicotinic, muscarinic (M1, M2, M3). o Peptides (Neuromodulators) :
▪ Substance P (SP) : Has antidepressant/anti-anxiety effects in depression; promotes memory; enhances pain receptor sensitivity; involved in mood/anxiety regulation, pain management. Receptor: Neurokinin 1 (NK1). ▪ Somatostatin (SST) : Alters cognition, memory, mood. Decreased in Alzheimer's, spinal fluid of some depressed patients; increased in Huntington's disease. Receptors: SST1, SST2, SST3, SST4, SST5. ▪ Neurotensin (NT) : Has endogenous antipsychotic-like properties. Decreased levels in spinal fluid of schizophrenic patients. Receptors: NTSR1, NTSR2.
- Neurotransmitter release can be regulated by presynaptic receptors ; autoreceptors bind to the neuron's own neurotransmitter, typically inhibiting release. Other presynaptic receptors respond to neurotransmitters from adjacent neurons, stimulating or inhibiting release.
- Neurons can release more than one chemical simultaneously, including larger molecules like neuropeptides , which may cause long-term changes in postsynaptic neurons (e.g., genetic expression, cell shape, responsiveness).
- Communication between neurons is not unidirectional; neurotrophic factors (proteins, gases) are released by postsynaptic cells and influence the growth, shape, and activity of presynaptic cells. These are important in fetal brain development and contribute to brain plasticity throughout life. Organization of the Brain
- Brainstem : Responsible for vital functions (internal organs, blood gases, blood pressure). Acts as a psychosomatic link between higher brain activities (thought, emotion) and internal organ function. Initial processing centre for sensory information. Projections of the reticular activating system (RAS) regulate sleep-wake cycles and conscious mental activity. Mesolimbic and mesocortical pathways project to the limbic system and modulate the emotional value of sensory material, using neurotransmitters like norepinephrine, serotonin, and dopamine. The hypothalamus is in the brainstem and plays a vital role in basic drives.
- Cerebellum : Located posteriorly to the brainstem. Primarily involved in regulating skeletal muscle coordination, contraction, and maintaining equilibrium. Crucial for smooth, directed movement.
- Cerebrum : Situated on top of the brainstem, distinguishing humans from other mammals. Responsible for mental activities, conscious sense of being (perception, emotional status, memory), and control of skeletal muscles. Also responsible for language. o Consists of the cerebral cortex (outer layer, grey matter) and basal ganglia (deep within grey matter).
Disturbances of Mental Function
- The origin of most mental health dysfunction is unknown.
- Known biological causes include drugs (LSD, high-dose prednisone), unusually high hormone levels (thyroxine, cortisol), infections (encephalitis, AIDS), and physical trauma.
- The mechanistic link between causative factors (biological and psychosocial) and dysfunction is not fully understood.
- Many psychiatric disorders may have a genetic predisposition; incidence is higher in relatives and concordance is strong in identical twins.
- Psychosocial stress (family, society) increases the likelihood of mental health problems, including biological changes. Genetics and environment interact.
- Research aims to understand dysfunction in terms of altered neuronal activity in specific brain areas.
- Current interest focuses on neurotransmitters and their receptors, especially in the limbic system: norepinephrine, dopamine, serotonin, GABA, and glutamate.
- Dysfunction can be due to decreased neurotransmitter release or inability of postsynaptic receptors to respond. This can be a cause or consequence of disease.
- Schizophrenia is associated with excess dopamine transmission (excess release or increased receptor responsiveness), among other changes.
- Abnormalities in GABA-related neurotransmission are linked to anxiety; anti-anxiety drugs often increase GABA effectiveness (primarily by increasing receptor responsiveness).
- Brain areas are interconnected; a limited number of neurotransmitters are used by different circuits for varied activities. Alterations in one neurotransmitter's activity due to disease or drugs can cause multiple seemingly unrelated effects (e.g., changes in drives, sleep, movement, autonomic functions). Use of Psychotropic Drugs
- Pharmacodynamics : Biochemical and physiological effects of drugs on the body, including mechanisms of action. o Agonist : Binds to and activates a target, producing a response. o Antagonist : Binds to but does not activate a target; typically prevents other molecules (neurotransmitters) from binding; produces no effect by itself.
- Pharmacokinetics : Actions of the body on the drug. Involves:
- Absorption : How much drug enters circulation.
- Distribution : Drug spread to body tissues.
- Metabolism : Chemical change of the drug by the body (major organ: liver).
- Excretion : Removal of the drug or its metabolites (major route: urine via kidneys).
- Pharmacokinetics determines blood levels over time and guides dosage. It is crucial for dosing in patients with liver and kidney disease.
- Pharmacogenetics : Study of how genetic factors cause variations in drug response among individuals and ethnic groups. o Variations in genes coding for cytochrome P450 (CYP450) liver enzymes lead to differences in drug metabolism rates (e.g., CYP2D6 metabolizes 25-30% of prescribed drugs). o Individuals can be "poor metabolizers" (higher drug levels, increased adverse effects) or "ultra-metabolizers" (lower drug levels, reduced therapeutic benefit). o Pharmacogenetics is key to personalized medicine , tailoring drugs/doses to individual genetic makeup for maximum benefit.
- Cultural and ethnic beliefs, attitudes toward mental health systems, and cultural practices affect adherence to medication regimens.
- An ideal psychiatric drug would relieve symptoms without causing additional mental or physical effects. Current drugs are not fully effective or free of unwanted effects.
- Developing drugs/treatment protocols with fewer adverse effects is a goal, as adverse effects are a frequent reason for non-adherence.
- Non-adherence (non-persistence, lack of consistency) is a significant barrier to treatment success. Rates vary (e.g., 47-95% for antipsychotics in schizophrenia). Poor adherence to antidepressants increases relapse/hospitalisation risk. Non-adherence is typically due to adverse effects and lack of efficacy.
- Psychotropic drugs target neurons, neurotransmitters, and receptors, usually by increasing or decreasing activity of specific neurotransmitter-receptor systems. Dysfunctional systems are believed to differ depending on the mental health condition.
- Understanding the relationship between specific neurotransmitters and disorders often comes from the pharmacology of drugs used to treat them (e.g., drugs blocking D dopamine receptors reduce delusions/hallucinations, suggesting overactivity of dopamine pathways in schizophrenia). Drug Classes
- Drugs Used to Treat Anxiety and Insomnia o GABA is the major inhibitory neurotransmitter in the CNS. Drugs enhancing GABA actions at GABAA receptors exert sedative-hypnotic effects. o Benzodiazepines : Enhance GABA actions by binding to a specific site on the GABAA receptor complex. They only have an effect if GABA is also bound. This interaction decreases neuronal excitability. Examples: diazepam (Valium),
o Understanding neurophysiological basis is incomplete. o Monoamine theory : Depression results from a deficit in monoamine neurotransmitters (serotonin, norepinephrine). Supported by findings that drugs altering monoamine levels affected mood. Decreasing monoamine levels depressed mood, elevating them improved mood. Led to drugs elevating serotonin or norepinephrine. o Antidepressants are more effective than placebo. However, a significant proportion of depressed people are resistant to current drugs. o Drug Targets : Antidepressants interact with targets responsible for therapeutic and non-therapeutic effects. Normal release, reuptake, and degradation of monoamines are key processes. o Tricyclic Anti-depressants (TCAs) : Widely used before SSRIs. No longer first-line due to more adverse effects, slower dose optimisation, and higher lethality in overdose. Used for neuropathic pain. ▪ Mechanism: Primarily block reuptake of serotonin and norepinephrine, increasing neurotransmitter accumulation in the synapse. Secondary amines (nortriptyline) block norepinephrine reuptake; tertiary amines (amitriptyline, imipramine) block both. ▪ Adverse effects: Many by acting as antagonists at muscarinic acetylcholine receptors (parasympathetic effects). Predictable effects: blurred vision, dry mouth, constipation, urinary hesitancy, sinus tachycardia. Can cause memory/cognitive deficits due to acetylcholine's role. Can lead to adherence issues. ▪ Can act as antagonists at histamine (H1) receptors, causing sedation/drowsiness. ▪ Overdose can be fatal due to cardiac conduction disturbances. o Selective Serotonin Reuptake Inhibitors (SSRIs) : Introduced for fewer adverse effects than TCAs. Preferentially block serotonin reuptake from the synapse. Examples: fluoxetine (Prozac), paroxetine (Paxil), citalopram (Celexa), escitalopram (Cipralex), fluvoxamine (Luvox). Sertraline (Zoloft) inhibits serotonin reuptake most, less so norepinephrine and dopamine. ▪ Bind poorly to acetylcholine muscarinic and H1 receptors compared to TCAs, resulting in fewer anti-cholinergic and sedating effects, potentially improving adherence. ▪ Other adverse effects: insomnia, low libido, failure of orgasm, nausea/vomiting (due to inappropriate stimulation of serotonin receptors). ▪ Less likely to cause cardiotoxicity than TCAs in overdose, but high doses can cause fatal ventricular arrhythmias.
o Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) : Increase both serotonin and norepinephrine levels. Examples: venlafaxine (Effexor XR), desvenlafaxine (Pristiq), duloxetine (Cymbalta). Also weak dopamine reuptake inhibitors. ▪ Venlafaxine: SSRI action at lower doses, SNRI action at higher doses. Duloxetine: affects norepinephrine and serotonin reuptake equally, greater noradrenergic effect than venlafaxine at lower doses. ▪ Indications: Major depressive disorder, GAD, SAD, PD, fibromyalgia, neuropathic pain (e.g., diabetic peripheral neuropathy). Mechanism for neuropathic pain: activation of descending norepinephrine and serotonin pathways to the spinal cord, limiting pain signals. o Serotonin Modulator and Stimulator : Vortioxetine (Trintellix). Affects multiple serotonin receptors: inhibits serotonin reuptake (like SSRIs), activates 5-HT1A, partial agonist at 5-HT1B, blocks 5-HT3, 5-HT1D, 5-HT7. ▪ May improve cognitive deficits in geriatric patients independently of antidepressant effect. ▪ Adverse effects: constipation, nausea, vomiting, hyponatremia, rarely hypomania/mania. o Serotonin and Norepinephrine Disinhibitors (SNDIs) : Mirtazapine (Remeron) is the only drug in this class. ▪ Mechanism: Increases norepinephrine, dopamine, and serotonin transmission by acting as an antagonist at central presynaptic α2-adrenergic receptors. Blocking these autoreceptors prevents the inhibition of neurotransmitter release, thus potentiating release (disinhibitor). ▪ May have faster onset than single-neurotransmitter drugs due to affecting multiple systems. ▪ Potent antagonist of 5-HT2C receptors (anti-anxiety, anti-depressant effects, as activation typically inhibits NE/DA release). Antagonist at 5-HT2A and 5- HT3 receptors (less likely to cause sexual dysfunction and nausea compared to other drugs). ▪ Potent H1-receptor antagonist, causing drowsiness and increased appetite/weight gain. ▪ May cause orthostatic hypotension and occasional anti-cholinergic effects. o Monoamine Oxidase Inhibitors (MAOIs) : Prevent the destruction of monoamines by inhibiting MAO. ▪ MAO degrades monoamine neurotransmitters (norepinephrine, epinephrine, dopamine, serotonin) and monoamine food/drug substances. MAO is in nerve endings and the liver.
o Validity of Monoamine Theory : While useful and led to effective drugs, the several- week delay in symptom relief questions if initial monoamine elevation is the sole mechanism. ▪ Alternative explanations for delayed effect: Increased levels of BDNF (essential for neuron survival/growth), which are low in depression and increase with antidepressants. BDNF supports neurogenesis in the hippocampus, which has lower levels in depressed people. Animal models show antidepressants promote neurogenesis and reduce depressive behaviours. The timeline of BDNF increase fits symptom relief better. ▪ Another explanation: Clinical efficacy is due to initial monoamine increase causing receptor desensitization over time (e.g., desensitization of 5-HT1A autoreceptors leads to less inhibition on serotonin release, increasing levels). This timeline also correlates better with symptom relief. ▪ Pathways involving glutamate and its receptors are likely involved in depression pathophysiology, suggested by ketamine's rapid effects. o Suicide Risk : Concern about increased risk with antidepressant use. Studies results are contradictory/inconclusive, partly due to rare events and inconsistent reporting. Evidence suggests likely not increased in adults, but data are most consistent for increased risk in children and adolescents, although this is questioned. Health Canada requires warnings on labels, especially for SSRIs/SNRIs, advising awareness of potentially dangerous behavioural changes.
- Drug Treatment for Bipolar Disorders o Lithium Carbonate : Established mood stabilizer for many years, still a first-line option. Mechanism not fully understood. ▪ May enhance neuroprotective pathways and decrease neuronal injury/death. One target: inhibiting glycogen synthase kinase 3ß (GSK3ß), which affects neuroprotective pathways. Also appears to increase BDNF levels. ▪ Inhibits inositol monophosphatase 1 (in phosphatidylinositol pathway), disrupting signalling and potentially lessening neuronal cell death by improving mitochondrial health. ▪ Decreases excitatory neurotransmission by decreasing glutamate release and acting as antagonist at certain glutamate receptors, potentially preventing neuronal harm from excessive glutamatergic activity. ▪ Adverse effects: Many arise from mimicking sodium, altering electrical properties of neuronal membranes. Potential threat to functions regulated by electrical currents (e.g., cardiac contraction, can induce sinus bradycardia). Overdose causes extreme cerebral conductivity alteration (convulsions). Changes in nerve/muscle conduction commonly cause
tremor at therapeutic doses, more extreme motor dysfunction with overdose. ▪ Commonly induces polyuria (decreased vasopressin effectiveness on renal function). Long-term use can cause goiter and potentially hypothyroidism. Hyponatremia increases lithium toxicity risk due to increased kidney reabsorption of lithium with sodium. ▪ Has a low therapeutic index (ratio of lethal dose to effective dose). Dose causing death is not much greater than effective dose. Blood level monitoring required regularly to avoid dangerous levels. o Other Drugs for Bipolar Disorders (Anti-seizure drugs): Used to treat seizures but also effective for bipolar disorder (mood stabilizers). Mechanism: Decrease neuronal excitability. ▪ Modes of action: (1) inhibit sodium channel activity, (2) inhibit calcium channel activity, (3) enhance GABAergic transmission, (4) inhibit glutamatergic transmission. Some use a combination. ▪ Three key anti-seizure drugs used as mood stabilizers: valproate , carbamazepine , and lamotrigine. Thought to re-establish balance between excitatory and inhibitory pathways. May also inhibit GSK3ß activity, similar to lithium. ▪ Carbamazepine (Tegretol) : Primary mechanism: inhibit neuronal sodium channels during depolarization, reducing excitability. Greater effect on frequently firing neurons. ▪ Common adverse effects: anti-cholinergic effects (dry mouth, constipation, urinary retention, blurred vision), orthostatic hypotension, sedation, ataxia. Rash may occur. ▪ Baseline lab work: liver function, CBC, ECG, electrolytes. Blood levels monitored for toxicity, but no established therapeutic levels for bipolar disorder. ▪ Valproate (Depakene) : Blocks sodium and calcium channels, may elevate GABA by inhibiting its degrading enzyme. ▪ Common adverse effects: tremor, weight gain, sedation. Rare but serious: thrombocytopenia, pancreatitis, hepatic failure. Potent teratogen. ▪ Baseline liver function/CBC required; repeated periodically. Blood levels monitored within recommended therapeutic range. ▪ Lamotrigine (Lamictal) : Most effective for maintenance therapy, less effective in acute mania. Best for depressive phase of bipolar disorder, lower risk of causing switch to mania compared to antidepressants. Inhibits
▪ Muscarinic cholinergic blockade : Typical anti-cholinergic effects: blurred vision, dry mouth, tachycardia, urinary retention, constipation. ▪ α1-adrenergic blockade : Receptors on smooth muscle cells responding to norepinephrine. In blood vessels, causes vasodilation, drop in blood pressure, orthostatic hypotension. On vas deferens, can cause failure to ejaculate. ▪ H1 blockade : Causes sedation and substantial weight gain. Sedation may be beneficial for agitated patients. ▪ Patient adherence negatively affected by numerous/severe adverse effects. Quest for drugs with fewer adverse effects led to second generation. o Second-Generation (Atypicals) Antipsychotic Drugs : Introduced in the 1990s. Target positive and possibly negative symptoms of schizophrenia. May produce fewer EPS. ▪ Pharmacological profile difference: Act as D2 receptor antagonists AND antagonists at certain serotonin receptors (regulate neurotransmitter release). Serotonin receptor interaction may alleviate negative symptoms, cognitive/memory effects, and result in fewer EPS. Often first-line due to lower EPS risk. ▪ Can increase risk for metabolic syndrome (increased weight, elevated blood glucose/triglycerides). Due to simultaneous blockade of muscarinic, 5 - HT, and H1 receptors (increased appetite, weight gain). Anti-muscarinic properties on pancreatic cells may cause insulin resistance/hyperglycemia. Mechanism for elevated triglycerides unknown. ▪ Clozapine and olanzapine have high metabolic syndrome risk; aripiprazole and ziprasidone have lower risk. ▪ Clozapine (Clozaril) : First second-generation drug. Relatively free of EPS. Thought to block dopamine receptors preferentially in mesolimbic system over nigrostriatal area (minimises EPS while maintaining antipsychotic action). Antagonist at serotonin 5-HT2A receptors. ▪ Higher adherence rates. Potential to suppress bone marrow, induce agranulocytosis (deficiency in white blood cells, infection risk). Requires regular weekly/bi-weekly/monthly white blood cell count monitoring. ▪ Risk of seizure (5%). Limited to patients with treatment-resistant schizophrenia, non-responsive/intolerant to others. ▪ Caution with drugs increasing clozapine concentration. Potential for myocarditis, fever. Most common adverse effects:
drowsiness/sedation, hypersalivation, reflex tachycardia, constipation, dizziness/vertigo. ▪ Risperidone (Risperdal) : Acts at D2 and potent antagonist at 5-HT2A receptors. Low risk of agranulocytosis/convulsions. High therapeutic doses (>6 mg/day) may cause motor complications. ▪ Highest EPS risk among second-generation drugs. May increase prolactin release (sexual dysfunction). Can cause orthostatic hypotension (fall risk in older persons). Weight gain, sedation, sexual dysfunction may affect adherence. ▪ First second-generation drug available as long-acting depot injection (Risperdal Consta, every 2 weeks). ▪ Rare but serious adverse effect: increased stroke/TIA risk in older persons with dementia treated for agitation. ▪ Quetiapine (Seroquel) : Broad receptor-binding profile. Antagonist at D2, potent antagonist at 5-HT1A and 5-HT2A. Strong H1 antagonism causes sedation. ▪ Combination of H1 and serotonin antagonism leads to weight gain and moderate metabolic syndrome risk. ▪ α1-adrenergic antagonism can cause orthostatic hypotension, dizziness, syncope. ▪ Low risk for EPS or prolactin elevation. Rapid dissociation from D receptors thought to cause fewer EPS/prolactin effects. ▪ Other second-generation drugs : ▪ Olanzapine (Zyprexa): Similar structure to clozapine. Adverse effects: sedation, weight gain, hyperglycemia (new-onset type 2 diabetes), higher risk for metabolic syndrome. ▪ Ziprasidone (Zeldox): Binds to various dopamine/5-HT receptors, also an SNRI. Main adverse effects: dizziness, moderate sedation. Contraindicated in patients with QT interval prolongation history, recent acute myocardial infarction, or uncompensated heart failure. ▪ Aripiprazole (Abilify): Unique as a dopamine system stabilizer , a partial agonist at D2 receptors. Partially activates D2 at low dopamine levels; prevents excess dopamine from activating receptor at high levels while still providing some activation. Prevents extreme D2 fluctuations. Induces little sedation or weight gain. Adverse effects: insomnia, akathisia.
o Anti-cholinesterase drugs (cholinesterase inhibitors): Interfere with acetylcholinesterase (enzyme degrading acetylcholine). Inhibiting the enzyme leads to less acetylcholine breakdown, higher synaptic concentration. Show some efficacy in slowing memory loss, sometimes improve memory. Three approved in Canada for mild to moderate Alzheimer's: donepezil (Aricept), galantamine, rivastigmine (Exelon). o Memantine (Ebixa) : NMDA receptor antagonist. Glutamatergic system important for memory. Amyloid plaques can cause glutamatergic dysfunction. Excessive NMDA receptor stimulation by high glutamate can cause excitotoxicity (too much calcium entering neuron, damage/death). Memantine prevents glutamate binding to NMDA receptor and activating calcium channel. Used for moderate to severe Alzheimer's. Natural Health Products (NHPs)
- Interest driven by belief NHPs are safer ("natural"), have fewer adverse effects.
- Examples studied: kava kava, St. John’s wort. Some lack efficacy, others potentially deadly with long-term use or combined with other substances/prescription drugs.
- Increased bleeding risk with ginkgo biloba + warfarin. Kava kava alone may increase hepatotoxicity risk at doses >240 mg/day.
- Major concerns: potential long-term effects (nerve, kidney, liver damage), adverse chemical reactions with conventional medications.
- St. John’s wort has serious interactions. With other serotonergic drugs (SSRIs, triptans), can cause serotonin syndrome. o Serotonin syndrome : Potentially life-threatening reaction from excessive 5-HT neurotransmission in CNS. Symptoms: agitation, hyperreflexia, tremors, excessive sweating, racing heart, rapid blood pressure changes, nausea, ataxia. o May reduce effectiveness of other medications by increasing metabolism. St. John’s wort is a CYP3A4 enzyme inducer. Can drop levels of drugs metabolised by CYP3A (hormonal contraceptives, HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, immunosuppressants cyclosporine/tacrolimus, antineoplastics irinotecan/imatinib) to subtherapeutic levels. Monitor drugs with narrow therapeutic index more closely.
- Regulation of NHPs: Health Canada provides information via Licensed Natural Health Products Database; authorized products have an eight-digit number. Recalls/warnings available at MedEffect Canada.
- Often little scientific evidence of NHP efficacy.
- Healthcare providers should explore patient NHP use non-judgementally. Patients should be aware of drug/substance interactions and product safety. Discussion of NHP use should be part of initial and ongoing patient interviews.
- Safety Tip : All medications (including herbals, vitamins, minerals) have potential effects/interactions. Pursuing complementary/integrative therapy risks delaying well- established treatments. Key Points to Remember
- Brain actions (sensory, motor, intellectual) involve interactions of neurons: impulse conduction, neurotransmitter release, receptor activation. Alterations in these processes can lead to mental and physical manifestations.
- Overactivity of dopamine pathways may underlie thought disturbances in schizophrenia. Deficiencies in norepinephrine, serotonin, or both may underlie depression and anxiety. Insufficient GABA signalling may play a role in anxiety.
- Pharmacological treatment targets suspected neurotransmitter-receptor problems. Antipsychotics alter dopamine signalling; antidepressants alter norepinephrine/serotonin; anti-anxiety drugs enhance GABA, 5-HT, or norepinephrine.
- Drugs with different chemical actions may be effective for the same condition due to downstream alterations in neuronal activity. Newer drugs with novel mechanisms are being used.
- Psychotropic drugs can cause undesired effects: sedation/excitement, motor disturbances, anti-cholinergic effects, α1-adrenergic antagonism, sexual dysfunction, weight gain. Effort continues to develop effective, safe, well-tolerated drugs.
