Comprehensive Study Guide on Antipsychotics, Antidepressants, and Mood Stabilizers

Dopaminergic Pathways and the Pathology of Schizophrenia

In the study of Schizophrenia without pharmacological intervention, the dopaminergic system exhibits distinct patterns of activity across four primary pathways. The Mesolimbic pathway is characterized by hyperactivity, which is directly responsible for the positive symptoms of the disorder, such as hallucinations and delusions. Conversely, the Mesocortical pathway is marked by hypoactivity, leading to the negative, cognitive, and affective symptoms associated with the disease. The Nigrostriatal and Tuberoinfundibular pathways typically maintain a normal basal functioning level, as they are not inherently affected by the pathophysiology of Schizophrenia itself.

When treating Schizophrenia with first-generation or typical antipsychotics, a global and massive blockade of $D_2$ receptors occurs. In the Mesolimbic pathway, this decrease in dopamine improves positive symptoms. However, the blockade in the Nigrostriatal pathway drastically reduces dopamine levels, acutely triggering extrapyramidal symptoms ($\text{SEP}$). In the Tuberoinfundibular pathway, the blockade leads to a drop in dopamine that triggers hyperprolactinemia. Furthermore, the treatment worsens the existing hypodopaminergia in the Mesocortical pathway, resulting in a state of neurolepsis and the exacerbation of negative symptoms.

Second-generation or atypical antipsychotics utilize a mechanism that combines $D_2$ antagonism with $5HT_{2A}$ antagonism. The blockade of cortical and striatal $5HT_{2A}$ receptors halts the inhibition mediated by $\text{GABA}$ and glutamate. This results in a selective increase in dopamine release within the Nigrostriatal, Tuberoinfundibular, and Mesocortical pathways. This balanced approach helps to reverse and stabilize adverse effects such as $\text{SEP}$, neurolepsis, and hyperprolactinemia, all while maintaining effective antipsychotic action within the Mesolimbic pathway.

Typical Antipsycotics: Mechanism and Clinical Scope

Typical antipsychotics are primarily defined by their mechanism of action involving the pure and potent blockade of postsynaptic dopaminergic $D_2$ receptors, known as $D_2$ antagonism. Historically, the first antipsychotic discovered was Clorpromazina during the 1950s. Among the most potent and traditionally utilized agents in clinical practice is Haloperidol. These medications are indicated for the treatment of Schizophrenia, acute and chronic psychotic disorders, manic episodes featuring psychotic symptoms, and cases of acute psychomotor agitation.

The side effect profile for typical antipsychotics is extensive. Rare but grave complications include Neuroleptic Malignant Syndrome, which presents with hyperthermia, severe muscle rigidity, autonomic instability, and altered consciousness. Dermatological reactions may include photosensitivity, skin eruptions, and hyperpigmentation. Psychical effects often manifest as neurolepsis, affective flattening, apathy, psychomotor slowing, and pseudodepression. Reversible neurological side effects include acute extrapyramidal symptoms such as acute dystonias, akathisia, and pharmacological parkinsonism involving tremors and rigidity. Irreversible neurological effects include Tardive Dyskinesia, characterized by involuntary choreoathetoid movements of the tongue, mouth, and face following chronic treatment.

Vegetative side effects are categorized by the receptors they affect. Alpha-blocking actions can cause orthostatic hypotension, dizziness, and nasal congestion. Anticholinergic actions lead to dry mouth, blurred vision due to accommodation disorders, constipation, and urinary retention. Endocrine effects are largely driven by hyperprolactinemia, resulting in galactorrhea, amenorrhea, and gynecomastia, alongside sexual dysfunction symptoms such as decreased libido and erectile dysfunction.

Atypical Antipsychotics and Specific Pharmacological Profiles

Atypical antipsychotics differ from their predecessors by adding $5HT_{2A}$ receptor antagonism or partial $D_2$ agonism to the classic dopaminergic blockade. Clinically, they maintain antipsychotic efficacy while drastically reducing $\text{SEP}$, neurolepsis, and hyperprolactinemia. These agents possess diverse actions, including antidepressant, antimanic, anxiolytic, and hypnotic-sedative properties. They are often categorized into groups such as the "Pinas" and "Donas."

Among the "Pinas," Clozapina is recognized for high efficacy in refractory schizophrenia, though it is not a first-line option. It is particularly useful for patients exhibiting violence or aggressiveness and reduces suicidal risk. It carries almost no risk of $\text{SEP}$, tardive dyskinesia, or hyperprolactinemia, but it can cause agranulocytosis, necessitating periodic blood monitoring, and significant weight gain. Quetiapina does not generate $\text{SEP}$ or hyperprolactinemia and serves as an effective antipsychotic, antidepressant, and sedative-hypnotic. Olanzapina carries a high cardiometabolic risk with substantial weight gain, though it does not produce $\text{SEP}$ or elevate prolactin levels, even at high doses.

The "Donas" group includes Risperidona, which is associated with $\text{SEP}$ at high doses and increases prolactin even at low dosages; it carries a moderate risk of weight gain and is used at low doses for psychosis and agitation in dementia. Ziprasidona is notable for causing little to no weight gain and having a low association with dyslipidemia. However, it prolongs the $QTc$ interval in a non-dose-dependent manner. Switching a patient to Ziprasidona often results in weight loss and reduced triglyceride levels. Other atypical agents include Aripiprazol, a partial $D_2$ agonist indicated for mania, schizophrenia, and resistant depression, which has a low propensity for weight gain and does not cause sedation or prolactin elevation. Amisulpiride improves negative symptoms at low doses with a procognitive and antidepressant profile, though it prolongs the $QTc$ interval in a dose-dependent manner.

General side effects for atypical antipsychotics include orthostatic hypotension, lipothymia, constipation, nausea, vomiting, double vision, urinary retention, and headaches, though these occur less frequently than with typicals. The cardiometabolic risks are a significant concern, encompassing weight gain, diabetes, dyslipidemia, and cardiovascular disease. Clozapina and Olanzapina represent high risk; Risperidona, Quetiapina, and Amisulpiride represent moderate risk; while Aripiprazol and Ziprasidona represent low risk.

Theories of Depression and the Role of Neurotrophic Factors

The classical or monoaminergic hypothesis of depression suggests the disorder results from a depletion of the monoamine neurotransmitters serotonin ($5HT$), noradrenaline ($NE$), and dopamine ($DA$). A variant of this, the receptor hypothesis, suggests that this deficiency causes a compensatory upregulation of synaptic receptors. Alternatively, the neurotrophic hypothesis focuses on the decrease of $\text{BDNF}$ (Brain-Derived Neurotrophic Factor), a protein essential for neuronal growth and viability. Chronic stress is believed to deactive the genes responsible for $\text{BDNF}$ production, leading to cellular atrophy or apoptosis in the hippocampus and prefrontal cortex.

Selective Serotonin Reuptake Inhibitors (SSRIs)

In cases where SSRI treatment does not achieve full remission, symptoms like insomnia, fatigue, physical pain complaints, concentration problems, and lack of motivation often persist. Antidepressants generally function best against depressed mood, psychomotor retardation, and suicidal ideation. The primary mechanism of SSRIs is the selective blockade of the serotonin transporter ($\text{SERT}$), which prevents the reuptake of $5HT$ and increases its availability in the synaptic cleft.

Specific SSRIs have unique profiles. Fluoxetina acts as a $5HT_{2C}$ antagonist, which disinhibits $DA$ and $NE$. It is an activating agent ideal for fatigue and hypersomnia but contraindicated for anxiety; it is also approved for bulimia. Sertralina weakly inhibits the dopamine transporter ($\text{DAT}$) and binds to $\sigma_1$ receptors, providing anxiolytic effects useful in psychotic or atypical depressions. Paroxetina provides mild anticholinergic $M_1$ effects for sedation and inhibits nitric oxide synthetase, which can induce male sexual dysfunction. Fluvoxamina is a potent $\sigma_1$ agonist with strong anxiolytic properties, making it highly effective for Obsessive-Compulsive Disorder ($\text{TOC}$). Citalopram is a mixture of $R$ and $S$ enantiomers, where the $R$ form interferes with the $S$ form, sometimes requiring higher doses that risk $QTc$ prolongation. Escitalopram contains only the pure $S$ enantiomer, lacks antihistamine effects, and is the best-tolerated SSRI with the fewest drug interactions.

General indications for SSRIs include major depression and various depressive symptoms. Specific indications include $TOC$ (Paroxetina, Citalopram, Fluvoxamina, Sertralina, Escitalopram), Generalized Anxiety Disorder (Paroxetina, Escitalopram), Post-Traumatic Stress Disorder (Paroxetina, Sertralina), Panic Disorder (all), Bulimia (Fluoxetina), Psychotic Depression (Sertralina, Fluvoxamina), and Social Anxiety (Paroxetina, Sertralina, Fluvoxamina, Escitalopram). Side effects include headache, gastrointestinal distress, initial anorexia, sexual dysfunction, weight gain, somnolence, and the risk of triggering a manic episode.

Tricyclic Antidepressants (TCAs) and Catecholamine Inhibitors

Bupropión acts as a catecholamine inhibitor by blocking the reuptake of dopamine and noradrenaline through the inhibition of $\text{DAT}$ and $\text{NET}$. It is used for smoking cessation, depression, and improving positive affect and sexual dysfunction. Side effects include insomnia, irritability, hypertension, and tremors. Tricyclic antidepressants ($\text{ADT}$) utilize a mixed blockade of $\text{SERT}$ and $\text{NET}$. Amitriptilina is highly sedating due to potent histamine $H_1$ blockade and is effective for pain management. Clomipramina is the "gold standard" for $TOC$ due to its high serotonergic potency. Nortriptilina prefers $\text{NET}$ blockade, improving physical energy with fewer anticholinergic effects. Maprotilina is a pure selective $\text{NET}$ blocker with no effect on serotonin.

The primary problem with $ADT$ is their broad side effect profile and high lethality in overdose. Central anticholinergic effects include memory failure and delirium, while peripheral effects include dry mouth and urinary retention. Histaminergic effects involve sedation and weight gain. Adrenergic effects include orthostatic hypotension and tremors. Crucially, the blockade of sodium ($Na^+$) channels can cause severe arrhythmias and seizures.

Clinical indications for $ADT$ are varied. Amitriptilina is used for major depression, panic disorder, neuropathic pain, and fibromyalgia. Imipramina targets major depression and anxiety. Clomipramina is indicated for $TOC$, $TGA$, social phobia, and chronic pain. Maprotilina is used for depression with insomnia. Nortriptilina is often preferred for elderly patients due to a lower adverse profile and is used for depression and neuropathic pain, though it is ineffective for migraines because it lacks activity on $5HT$.

Mood Stabilizers and Lithium Therapy

Lithium is a primary mood stabilizer that works by inhibiting enzymes such as Inositol monophosphatase ($\text{IMPasa}$), which reduces excitatory signaling and calcium excitotoxicity, and Glycogen synthase kinase 3 ($\text{GSK-3}$), which prevents apoptosis. It is indicated for acute manic episodes, preventing recurrences of affective phases, and active suicide prevention. Side effects are multi-systemic. Neurological effects include fine tremors, cognitive fog, and affective flattening. Cardiac effects include arrhythmias and bradycardia. Endocrine and renal effects include weight gain, hypothyroidism, and Nephrogenic Diabetes Insipidus. Dermatological issues like acne and psoriasis exacerbation may occur, along with gastrointestinal distress. Toxicity signs include dysarthria, ataxia, severe confusion, and nystagmus. It is contraindicated in cases of renal failure, severe cardiovascular disease, and pregnancy due to first-trimester teratogenicity.

Other stabilizers include anticonvulsants such as Valproic Acid, which enhances $GABA$ transmission and blocks $Na^+$ and $Ca^{2+}$ channels; it is used for epilepsy and mania but can cause liver toxicity and weight gain. Carbamazepina acts on sodium channels and enhances $GABA$, used for mania, bipolar prophylaxis, and trigeminal neuralgia. Lamotrigina acts by decreasing glutamate release and is a first-line treatment for the depressive phase of bipolar disorder. A critical warning in bipolar treatment is that antidepressants used in monotherapy can precipitate a manic switch or accelerate disease cycling; therefore, they must be used with a mood stabilizer.

Definitions and Classifications in Substance Use

In the study of drugs of abuse, several neurobiological terms are essential. Abstinence refers to the physiological and psychological reactions to the abrupt cessation of a substance. Abuse is the self-administration of non-culturally approved substances leading to adverse consequences. Addiction is a pattern of extreme dependence and compulsive use with a high tendency for relapse. Compulsion involves repetitive actions independent of goals, linked to the dorsal striatum, while Impulsivity is the tendency to act without foresight, linked to the ventral striatum.

Dependence occurs when a physiological adaptation requires continued consumption to avoid withdrawal. Habit refers to responses triggered automatically by environmental stimuli. Rebate (rebound) is the exaggerated expression of original symptoms after stopping medication. Relapse is the recurrence of the original clinical condition after interrupting treatment. Reinforcement is the intrinsic capacity of a substance to motivate repeated administration. Tolerance is the phenomenon where a fixed dose produces less effect over time, requiring an increase in dosage.

To summarize pharmacological classifications: Antidepressants include $ISRS$ (Fluoxetina, Sertralina, etc.), catecholamine inhibitors (Bupropión), Agomelatina, and Tricyclics (Amitriptilina, etc.). Antipsychotics are divided into Atypicals (Clozapina, Risperidona, etc.) and Typicals (Haloperidol, Clorpromazina). Mood Stabilizers include Lithium and anticonvulsants (Ácido valproico, Carbamazepina, Lamotrigina). Anxiolytics may include benzodiazepines as adjuvants, though they lack intrinsic efficacy for treating the core bipolar disorder.