TYPICAL AND ATYPICAL ANTIPSYCHOTICS
DRUG THERAPY FOR SCHIZOPHRENIA: TYPICAL AND ATYPICAL ANTIPSYCHOTICS.
INTRODUCTION
The biological approach to treating schizophrenia is based on the understanding that the disorder is linked to imbalances in brain chemistry, particularly in neurotransmitter systems. Schizophrenia has long been associated with abnormalities in dopamine regulation, with the dopamine hypothesis suggesting that an overactivity of dopamine in certain brain regions contributes to the positive symptoms of schizophrenia, such as delusions and hallucinations.
The mainstay of treatment for schizophrenia has been antipsychotic drugs, which aim to modify the activity of neurotransmitters, especially dopamine. Typical antipsychotics, also known as first-generation antipsychotics, work by blocking dopamine receptors, particularly the D2 receptors, to reduce dopamine activity in the brain. While effective at reducing positive symptoms, these drugs are associated with a range of side effects, such as tardive dyskinesia and other movement disorders, due to their broad effect on the dopaminergic system.
Atypical antipsychotics, the second generation of antipsychotic drugs, were developed to address the limitations of typical antipsychotics. These drugs, such as risperidone and olanzapine, not only block dopamine receptors but also affect serotonin receptors, offering a broader approach to managing symptoms. Atypical antipsychotics are thought to reduce the risk of movement-related side effects seen with typical antipsychotics and may be more effective in treating both positive and negative symptoms of schizophrenia.
Clozapine, a particularly important atypical antipsychotic, works differently from other antipsychotic medications. It not only targets dopamine and serotonin receptors but also affects glutamate systems in the brain, particularly the NMDA receptor. This unique mechanism of action is thought to contribute to clozapine’s superior efficacy in treating treatment-resistant schizophrenia, making it a critical option for patients who do not respond to other antipsychotic medications. However, clozapine is associated with significant side effects, including agranulocytosis, which requires regular blood monitoring.
In summary, the biological approach to drug treatment in schizophrenia focuses on restoring balance in neurotransmitter systems, particularly dopamine, serotonin, and glutamate. These treatments have revolutionized the management of schizophrenia, though challenges remain in balancing efficacy with side effects
KEY TERMS
CHEMOTHERAPY: Drug therapy
NEUROTRANSMITTER: is a chemical that allows neurons in the brain to communicate, they do this by producing a bridge across the synapse between the axon terminals and dendrites; this process allows the continuation of the nerve impulse to progress.
DOPAMINE: a neurotransmitter.
DOPAMINE FUNCTION: Dopamine plays a crucial role in various brain functions, including behaviour and cognition (thinking), voluntary movement, motivation, punishment and reward, pleasure, and focus. It is key to the brain's reward system, influencing mood and decision-making
PSYCHOTROPIC DRUGS: A psychotropic drug is any substance that affects behaviour, mood, thoughts, or perception. It serves as an umbrella term for a wide range of drugs, including both prescription medications and commonly misused substances. Psychotropic drugs can alter the chemical processes in the brain, affecting the way individuals think and feel.
PHARMACEUTICAL PSYCHOTROPIC DRUGS
There are several types of legal, prescription psychotropic medications used to manage various mental health conditions. These are broadly categorised into five primary types:
Antidepressants: Medications that help alleviate symptoms of depression by influencing neurotransmitters like serotonin, dopamine, and norepinephrine. Common examples include Prozac (fluoxetine) and Sertraline.
Anti-anxiety medications: These reduce symptoms of anxiety, often by enhancing the effects of GABA (a calming neurotransmitter). Examples include Valium (diazepam) and Xanax (alprazolam).
Stimulants: These are commonly used to treat ADHD and narcolepsy, increasing dopamine and norepinephrine to improve focus and alertness. Examples include Ritalin (methylphenidate) and Adderall (amphetamine).
Antipsychotics: Used to treat disorders like schizophrenia and bipolar disorder, these medications work by blocking dopamine receptors to reduce psychotic symptoms. Examples include Risperidone and Clozapine.
Mood stabilisers: These are used to manage mood fluctuations, particularly in bipolar disorder. Common examples include Lithium and Valproate.
AGONISTS/STIMULANTS: Agonists, or stimulants, are drugs that enhance the activity of neurotransmitters in the brain by increasing their production, release, or preventing their reuptake. More neurotransmitters are available in the synapse, leading to amplified effects on brain function. Agonists work by binding to specific receptors, mimicking the action of naturally occurring neurotransmitters, and increasing the intensity of their signals.
Depending on the specific drug, agonists affect neurotransmitters, including dopamine, serotonin, norepinephrine, and acetylcholine.
ILLEGAL AGONISTS, AKA ILLEGAL PSYCHOTROPIC DRUGS, are often street drugs that stimulate neurotransmitter activity in the brain. Some examples include:
Cocaine: Increases dopamine and norepinephrine availability by blocking their reuptake, leading to heightened euphoria and energy.
Crack cocaine: A more potent form of cocaine with similar effects on dopamine levels.
Amphetamines (speed) and methamphetamine: Increase the release of dopamine and norepinephrine, resulting in enhanced alertness and euphoria.
Ecstasy (MDMA): Stimulates serotonin, dopamine, and norepinephrine activity, leading to heightened mood and emotional connectivity.
Cannabis (THC): Mimics the action of natural cannabinoids, impacting memory, coordination, and pleasure.
Heroin: Acts as an opioid agonist, stimulating endorphin receptors and producing intense pleasure and pain relief.
LEGAL AGONISTS/ PSYCHOTROPICS ( see above). Several agonists used in medical settings enhance neurotransmitter availability to treat various conditions. Some examples include:
L-dopa: Prescribed to Parkinson’s disease patients to increase dopamine levels in the brain, helping to improve motor function.
Methadone: An opioid agonist used in pain management and addiction treatment, acting on endorphin receptors to relieve pain and reduce withdrawal symptoms.
Prozac (fluoxetine): A selective serotonin reuptake inhibitor (SSRI), it increases serotonin availability in the brain to treat depression and anxiety.
Valium (diazepam): A GABA agonist that enhances the effects of GABA, an inhibitory neurotransmitter, to reduce anxiety, muscle spasms, and seizures.
ANTAGONIST/BLOCKERS Antagonists are drugs that block the availability or action of neurotransmitters in the brain by preventing their binding to receptors. They are typically used to treat conditions like psychosis, as they reduce excessive brain activity caused by neurotransmitters such as dopamine.
ILLEGAL DRUGS THAT FUNCTION AS BLOCKERS (ANTAGONISTS):
PCP (Phencyclidine) – NMDA receptor antagonist
Ketamine – NMDA receptor antagonist
Scopolamine (Datura, Devil’s Breath) – Acetylcholine receptor antagonist
Diphenhydramine (DPH, Benadryl abuse) – Histamine (H1) and acetylcholine receptor antagonist
LEGAL ANTAGONISTS: Antipsychotics/Neuroleptics: These are dopamine antagonists that block dopamine receptors, reducing excessive dopamine activity associated with conditions like schizophrenia and psychosis.
Chlorpromazine (Thorazine): A typical antipsychotic used to reduce hallucinations and delusions.
Risperidone: An atypical antipsychotic used to treat schizophrenia and bipolar disorder.
Clozapine: Another atypical antipsychotic, often used for treatment-resistant schizophrenia.
Naloxone: An opioid antagonist that reverses the effects of opioid overdose by blocking opioid receptors.
Beta-blockers (e.g., Propranolol): These block adrenaline receptors used for treating anxiety and heart conditions
ANTIPSYCHOTICS: Antipsychotic drugs are antagonists that block neurotransmitter availability in the brain, particularly dopamine. These are primarily used to manage symptoms of psychosis and schizophrenia by reducing excessive neurotransmitter activity.
Typical Antipsychotics Block dopamine receptors (D2) and are effective in treating positive symptoms of schizophrenia (e.g., hallucinations and delusions). Example: Chlorpromazine (Thorazine).
Atypical Antipsychotics: Block both dopamine and serotonin receptors, making them more effective for treating both positive and negative symptoms of schizophrenia (e.g., avolition, anhedonia). Examples: Risperidone, Clozapine, Olanzapine.
NEUROLEPTICS: NEUROLEPTICS: Another term for antipsychotics. Neuroleptics and antipsychotics are often used interchangeably, but there are subtle differences between them, primarily related to the dopamine receptors they target (e.g., D1, D2, D3 receptors).
Neuroleptics are typically older, typical antipsychotics, like Hariperidol, which primarily target D2 receptors.
FIRST-GENERATION ANTIPSYCHOTIC DRUGS are referred to as "typical" or "conventional antipsychotics" and were introduced in the 1950s. These drugs primarily work by reducing dopamine activity in the brain, explicitly targeting D2 receptors. They are effective at reducing the positive symptoms of schizophrenia, such as hallucinations and delusions, but are less effective in addressing negative symptoms.
SECOND-GENERATION ANTIPSYCHOTIC DRUGS are referred to as atypical antipsychotics. These are newer antipsychotics, developed in the 1990s, that target both dopamine and serotonin receptors. Unlike typical antipsychotics, they are effective at reducing both the positive symptoms (such as hallucinations and delusions) and the negative symptoms.
HYPO AND HYPER-: These two prefixes are easily confused as they sound similar, but they have, in fact, more or fewer opposite meanings. Hyper- means over, excessive, more than usual, as in such words as hyperbole (extravagant and obvious exaggeration) and hyperactive (abnormally or pathologically active). Hypo means low, under, beneath, down, or below normal, as in hypoglycaemia (low blood sugar) and hyposensitivity (under sensitivity). Regarding neurotransmitters, a hyper neurotransmitter system means too much neurotransmitter is being secreted into the synapses within a specific neural circuit. Because of this, it produces over-stimulation of the cells and causes an exaggeration of functions.
TARDIVE DYSKINESIA: is a difficult-to-treat form of Dyskinesia (disorder resulting in involuntary, repetitive body movements) that can be Tardive (having a slow or belated onset). It frequently appears after long-term or high-dose use of typical antipsychotic drugs. Tardive Dyskinesia is characterized by repetitive, involuntary, purposeless movements, such as grimacing, tongue protrusion, lip-smacking, puckering and pursing lips, and rapid eye blinking. Fast movements of the extremities may also occur. Impaired movements of the fingers may also appear. For comparison, patients with Parkinson's disease have difficulty moving, while patients with Tardive Dyskinesia have difficulty not moving.
AGRANULOCYTOSIS: A lowered number of white blood cells (remember these are vital for fighting infection and made in the bone marrow. Agranulocytosis may be asymptomatic or clinically present with sudden fever, rigours and sore throat. Infection of any organ may be rapidly progressive (e.g., pneumonia, urinary tract infection). Septicaemia may also progress rapidly. Neutrogena and Agranulocytosis are associated with gum diseases, such as gingival bleeding, saliva increase, halitosis, osteoporosis, and destruction of periodontal ligament. Causes: Many drugs have been associated with Agranulocytosis, including some antipsychotics (the atypical antipsychotic Clozapine. Clozapine users in the US must be nationally registered to monitor low white blood cell counts.
NEUROLEPTIC MALIGNANT SYNDROME (NMS) is a life-threatening neurological disorder most often caused by an adverse reaction to Neuroleptic or Antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability, and cognitive changes such as delirium, and is associated with elevated Creatine Phosphokinase (CPK). The incidence of the disease has declined since its discovery (due to proactive prescription habits), but it is still dangerous to patients being treated with antipsychotics. Because of its unpredictability, there is no one set course of action to treat the syndrome. Still, generally, removal of the antipsychotic drug treatment, along with medical management, leads to a positive outcome.
PHENOTHIAZINE, ANTIHISTAMINES AND SURGICAL SHOCK (1940s)
Before the 1950s, psychiatric treatments for schizophrenia were harsh and ineffective. Patients were often subjected to lobotomies, electroconvulsive therapy (ECT), insulin shock therapy, and lifelong institutionalisation, reflecting the grim outlook for the treatment of this condition. Schizophrenia was regarded as a chronic, irreversible illness, and the focus was primarily on managing agitation and controlling distressing behaviors rather than addressing the psychotic symptoms of the disorder itself.
This situation began to change with the introduction of phenothiazine-based compounds in the 1950s, which marked the first real pharmacological approach to managing schizophrenia. Phenothiazine compounds, originally created for use in dyes, were found to have therapeutic effects when modified chemically. Phenothiazine itself was not a drug but served as a chemical scaffold to create a new class of drugs with therapeutic effects, such as antihistamines.
In the 1940s, French surgeon Henri Laborit was experimenting with antihistamines to prevent surgical shock, a serious drop in blood pressure that could occur during operations. Laborit found that the sedative properties of certain antihistamines not only stabilised the patients physically but also made them calmer, less anxious, and more emotionally detached—even in those that were psychotic This emotional detachment was noted, prompting scientists to consider whether these drugs could also alleviate agitation in psychiatric patients, particularly those with schizophrenia.
PSYCHIATRIC TESTING OF CHLORPROMAZINE (1951-1952)
Laborit’s findings attracted the attention of psychiatrists Jean Delay and Pierre Deniker, who began investigating the potential of chlorpromazine, a derivative of promethazine, for treating psychiatric agitation. In 1951, they began testing the drug on agitated psychiatric patients, and by 1952, the drug was trialed on patients with schizophrenia at Sainte-Anne Hospital in Paris. The results were unexpected: chlorpromazine did not just calm patients as sedatives did, but it actively reduced psychotic symptoms like hallucinations, delusions, and disorganized thinking.
Unlike traditional sedatives, which induced sleep or reduced general behavior, chlorpromazine seemed to specifically target psychotic symptoms, indicating that the mechanism of action was different from what was understood about sedatives. The phenothiazine nucleus in chlorpromazine was identified as responsible for its tranquilizing and antipsychotic effects, offering a new approach to treating schizophrenia that was not merely sedative.
TYPICAL ANTI PSYCHOTICS
Due to its effectiveness in treating psychosis in trials, chlorpromazine (later marketed as Thorazine) was officially introduced as the first neuroleptic in 1952. This drug was part of the first generation of antipsychotics, later termed typical antipsychotics, marking the beginning of modern pharmacological treatment for schizophrenia.
At the time of its introduction, the mechanism of action behind chlorpromazine was unknown. Early hypotheses suggested that it might be acting on noradrenaline or serotonin, but it wasn’t until later studies that a clear link to dopamine began to emerge.
LINKING CHLORPROMAZINE TO DOPAMINE AND SCHIZOPHRENIA
In the 1950s, Arvid Carlsson, a Swedish neuroscientist, made groundbreaking discoveries about dopamine and its role in the brain. Carlsson's research focused on reserpine, a drug known to deplete dopamine levels. His findings showed that depleting dopamine caused significant motor impairments and led to Parkinsonian-like symptoms in animals. This was pivotal because it demonstrated that dopamine was not just a precursor to other neurotransmitters but an essential neurotransmitter in its own right, crucial for movement and potentially for cognitive processes.
Around the same time, amphetamine psychosis was gaining attention. Amphetamines, which increase dopamine activity in the brain, could induce symptoms such as hallucinations, paranoia, and delusions. These symptoms were strikingly similar to those observed in patients with schizophrenia, leading researchers to hypothesize that dopamine overactivity in certain brain regions might be a contributing factor to psychotic symptoms.
By the early 1960s, research into the pharmacological action of chlorpromazine and other neuroleptics, including haloperidol, demonstrated that these drugs were successful in treating delusions and hallucinations. While the precise mechanisms were still not fully understood, these findings laid the groundwork for Jacques van Rossum (1967) dopamine hypothesis of schizophrenia. His theory proposed that schizophrenia is caused by excessive dopamine activity.
WHY DOES EXCESS DOPAMINE CAUSE POSTIVE SYMPTOMS
Dopamine is a neurotransmitter that helps relay signals between neurons by crossing the synapse, allowing communication between brain cells. In schizophrenia, excess dopamine in the synapses leads to overstimulation of neurons, which manifests as the hallucinations, delusions, and disordered thinking seen in psychosis. Chlorpromazine and other typical antipsychotics work by reducing this overstimulation, thereby managing the psychotic symptoms.
Kapur expanded this further by explaining that dopamine acts as a “fuel” for the cognitive distortions that people with schizophrenia often exhibit. According to Kapur, individuals with schizophrenia are prone to jumping to conclusions or adopting extreme interpretations of reality, and the excess dopamine in their brains further inflames these tendencies. By blocking dopamine receptors, drugs like Chlorpromazine effectively "douse the flames" of these psychotic tendencies, though they do not change the underlying cognitive patterns.
Dopamine plays a central role in processes like motivation, attention, and reward. It helps the brain prioritize relevant stimuli over irrelevant ones, enabling focus on important information. In schizophrenia, however, dopamine dysfunction leads to a breakdown in this filtering mechanism, causing irrelevant stimuli to become overemphasized, which can result in delusions and disorganized thinking.
Research by Shitij Kapur in the 1990s suggested that dopamine not only drives psychotic symptoms but also amplifiesexisting cognitive patterns. People with schizophrenia tend to jump to conclusions or interpret events in extreme ways, and dopamine dysregulation fuels this tendency, leading to increased cognitive distortions. Kapur explained that excess dopamine acts as a biochemical fuel, intensifying these cognitive tendencies into full-blown psychosis.
ANALYSIS SPECIFIC TO TYPICAL ANTIPSYCHOTICS
The mechanism behind chlorpromazine’s effectiveness is linked to its ability to block dopamine receptors in the brain, specifically D2 receptors. This was the first significant step towards using drug treatments as a primary intervention for schizophrenia, providing a biological basis for controlling the symptoms of the disorder. The introduction of chlorpromazine, the foundation for further research into dopamine's role in mental health, paving the way for the development of atypical antipsychotics that would target not only dopamine but also other neurotransmitter systems involved in schizophrenia.
RESEARCH FOR TYPICAL ANTIPSYCHOTICS
Research that supports the dopamine hypothesis has shown that drugs such as cocaine, amphetamine, and methamphetamine—which increase dopamine activity—can induce psychosis in people who do not have schizophrenia. This reinforces the idea that excess dopamine is a critical factor in psychotic episodes, and it underscores why drugs like Chlorpromazine are so effective in managing these symptoms.
FOR EXAMPLE:
If a dopamine imbalance causes schizophrenia, there should be evidence of unusual dopamine activity in the brains of individuals with the disorder. Early studies provide both support and critique for this hypothesis. Below is a summary of the key research evidence, from historical methods to modern imaging techniques.
The primary evidence used to support the dopamine hypothesis is the theory behind the success of typical and atypical antipsychotic drugs such as Thorazine (chlorpromazine), e.g., as they reduce dopamine firing, schizophrenia must be caused by excess dopamine. Activity. Moreover, not only do anti-psychotic drugs (dopamine antagonists) reduce positive symptoms (hallucinations, delusions) in type one schizophrenics, but when the same individuals are given drugs with a dopamine agonist, e.g., medications such as L-dopa that increase dopamine availability, then their symptoms became much worse.
RESEARCH ANALYSIS: ANTI-PSYCHOTICS
Also adding support to the theory is research on Parkinson’s sufferers and dopamine agonists. A lack of dopamine causes Parkinson's disease. As a result, Parkinson’s patients are treated with synthetic legal agonists to increase their dopamine availability (e.g., L-Dopa). However, if Parkinson’s patients are given high levels of L-dopa, they can suffer from positive symptoms, e.g., they can experience psychotic side effects which mimic the symptoms of schizophrenia. Conversely, Type 1 schizophrenics can suffer from Parkinson’s symptoms when on antipsychotic drugs.
RESEARCH ILEGAL STREET DRUGS
This conclusion is further supported by the research of drug addicts who use street drugs with dopamine agonist properties, such as LSD, cocaine, amphetamine, cannabis methamphetamine and other similar substances, as all illegal drugs dramatically increase the levels of dopamine in the brain. Indeed, drug addicts often have symptoms that resemble those present in psychosis, particularly after large doses or prolonged use. This type of addiction is usually referred to as "amphetamine psychosis" or "cocaine psychosis," which may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. In the early 1970s, several studies experimentally induced amphetamine psychosis in ordinary participants to better document the clinical pattern of schizophrenia.
It is also worth noting that when schizophrenics abuse street drugs (schizophrenia is comorbid with drug addiction), positive symptoms become much worse. For example, up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis when given moderate doses of amphetamine or other dopamine-like compounds/drugs, all given at doses that neuro-typical volunteers do not have any psychologically disturbing effects. Lastly, repeated exposure to high doses of antipsychotics (dopamine antagonists gradually reduced paranoid psychosis in these neurotypical participants. There are ethical issues with the above studies.
RESEARCH ANALYSIS ILEGAL DRUGS
However, this type of research has also fallen out of favour with the scientific research community, as drug-induced psychosis is now thought to be qualitatively different from schizophrenia psychosis. Differences between the drug-induced states and the typical presentation of schizophrenia have now become more apparent, e.g., euphoria, alertness, and over-confidence. Some researchers believe these symptoms are more reminiscent of mania (manic side of bipolar depression) than schizophrenia.
SIDE EFFECTS ARE DEBILITATING
A major drawback of typical antipsychotics is their high dropout rate. Research shows that the majority of patients who take antipsychotics stop their medication after a short period. Lieberman et al. 2005 Questionnaire survey reveals that the reason many patients with schizophrenia discontinue typical antipsychotic treatments is due to the severe side effects, particularly tardive dyskinesia. This is because typical antipsychotics block all types of dopamine activity (in other parts of the brain as well), and this contributes to harmful side effects.
One of the worse side effects is a neurological condition callesd Tardive dyskinesia. that is characterised by repetitive, involuntary, and purposeless movements such as grimacing, tongue protrusion, lip-smacking, puckering, and rapid eye blinking. This syndrome affects around 20-30% of patients treated with typical antipsychotics (Correll & Schenk, 2008; Jeste et al., 1995). The longer patients are prescribed typical antipsychotics, the greater the likelihood that they will develop tardive dyskinesia, and in many cases, the condition becomes permanent. Some patients have reported that tardive dyskinesia is more distressing than schizophrenia itself (Kane et al., 1988).
As a result of these side effects, patients often stop taking their medications when their symptoms improve, which leads to relapse. This pattern is usually referred to as revolving door syndrome, where patients briefly improve, only to relapse and be readmitted to care.
Because of such severe side effects, some clinicians believe it is unwise to prescribe high doses of typical antipsychotics for extended periods. As a result, many patients with schizophrenia are given tiny doses of these drugs (Goff et al., 2017). However, this creates a dilemma for clinicians: lowering the dosage increases the chance of relapse, while higher dosages increase the risk of severe and sometimes irreversible side effects (Whitaker, 2010).
DRUG RESISTANCE IN TYPICAL ANTIPSYCHOTICS
A significant disadvantage of typical antipsychotics is that approximately 30% of schizophrenics exhibit negative symptoms. Typical antipsychotics do not address these negative symptoms and, in some cases, may even exacerbate them (Kirkpatrick et al., 2006). This failure to treat negative symptoms effectively reveals a limitation not only in the medications themselves but also in the original dopamine hypothesis, which focused on hyperactive dopamine transmission as the sole cause of schizophrenia.
Furthermore, a significant number of patients with schizophrenia do not respond to these drugs, even when they exhibit positive symptoms such as hallucinations and delusions (Leucht et al., 2003). These patients are considered drug-resistant, meaning that despite having symptoms typically associated with excess dopamine activity, they do not experience improvement when treated with typical antipsychotics. This highlights a significant limitation of typical antipsychotics, as they fail to provide relief for a substantial portion of patients who present with positive symptoms.
ATYPICAL ANTIPSYCHOTICS
The limitations of typical antipsychotics, particularly their failure to effectively treat negative symptoms or typical drug-resistant positive symptom schizophrenia, as well as their tendency to cause severe side effects such as tardive dyskinesia, led to the development of atypical antipsychotics in the 1990s (Kane et al., 1988).
The new class of antipsychotics was called atypical antipsychotics. This new class of drugs targeted both dopamine and serotonin receptors, giving them a broader efficacy in treating both positive and negative symptoms.
Atypical antipsychotics receptors, specifically block:
Dopamine D2 receptors
Serotonin 5-HT₂A receptors
This dual action is a key feature of atypical (second-generation) antipsychotics, which distinguish themselves from typical antipsychotics by:
Reducing positive symptoms (via D2 antagonism in the mesolimbic pathway)
Improving negative/cognitive symptoms and reducing side effects (via 5-HT₂A antagonism, especially in the prefrontal cortex)
At first glance, it seems illogical that blocking serotonin receptors could help with negative symptoms of schizophrenia that are thought to be caused by low availanbility of dopamine. If negative symptoms are linked to hypodopaminergia in the mesocortical pathway, and drugs like risperidone and clozapine are not only dopamine antagonists but serotonin antagonosts , how do they avoid worsening this deficiency?
The answer lies in the dual mechanism of certain atypical antipsychotics. These drugs block D2 dopamine receptors (to a lesser extent) particularly in the mesolimbic pathway to reduce positive symptoms such as hallucinations and delusions. However, they also block 5-HT₂A serotonin receptors, especially in the prefrontal cortex. This is not because serotonin itself causes schizophrenia symptoms, but because 5-HT₂A activation normally inhibits dopamine release. By blocking serotonin receptors, atypical antipsychotics remove that inhibition, enhancing dopamine release in mesocortical areas where it is abnormally low.
So it's not that serotonin is causing negative symptoms it's that blocking serotonin allows dopamine to be restored in underactive regions. This selective enhancement is the reason second-generation antipsychotics are often better at treating negative and cognitive symptoms compared to earlier drugs, which simply suppressed dopamine across the board
These medications are associated with a 5% risk of tardive dyskinesia, significantly lower than the 20-30% risk posed by typical antipsychotics (Jeste et al., 1995). These newer drugs were designed to alleviate both positive symptoms and negative symptoms, which typical antipsychotics often worsened or failed to address (Leucht et al., 2009).
Other widely used atypical antipsychotics include Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), and Ziprasidone (Geodon).
Among these drugs, Clozapine has been particularly effective in treating treatment-resistant positive schizophrenia, offering relief to patients who do not respond to at least two other typical and atypical antipsychotics (Kane et al., 1988). Clozapine is widely regarded as the most effective antipsychotic for treatment-resistant schizophrenia, yet its mechanism of action differs significantly from other atypicals. Like risperidone, it blocks D2 dopamine and 5-HT₂A serotonin receptors, but it does so less potently at D2, which may reduce motor side effects. Crucially, clozapine also acts on a wide range of other receptors, including D4, 5-HT1A, muscarinic, histaminergic, and adrenergic targets. However, what truly sets clozapine apart is its effect on glutamate transmission.
Emerging evidence suggests that clozapine may enhance NMDA receptor activity, either directly or via modulation of glycine and glutamate pathways. Since NMDA receptor hypofunction has been implicated in both positive and negative symptoms of schizophrenia, clozapine’s influence here may explain its broader efficacy — especially for negative and cognitive symptoms that other drugs often fail to treat.
This glutamatergic modulation places clozapine at the intersection of the dopamine, serotonin, and glutamate models of schizophrenia, and may account for its status as the gold-standard antipsychotic when others prove ineffectiHowever, Clozapine carries a significant risk of agranulocytosis, a potentially fatal reduction in white blood cells, which occurs in approximately 1% of patients and requires regular blood monitoring (Kane et al., 1988).
For other patients who are unwilling or unable to take medication regularly, long-acting depot preparations of antipsychotics may be given every two weeks to achieve control.
EVALUATION SPECIFIC TO ATYPICAL ANTIPSYCHOTICS
SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
Atypical antipsychotics are less likely to cause Tardive dyskinesia (5% compared to 20-30%, but there are many new side effects that may be seen as equally debilitating. For example, one of the most common is massive weight gain, which can be as much as a stone (14 pounds) per year and is consistent throughout treatment. This often leads to diabetes in patients.
Other serious side effects include extrapyramidal symptoms, which resemble Parkinson’s disease. These symptoms include tremors, shuffling gait, and drooling. Patients may also experience dystonia, causing muscle rigidity and involuntary movements like chewing or twisting of the body, as well as akathisia. In this condition, individuals cannot stay still and constantly feel the need to move.
Additional effects can include a sense of being in an emotional straightjacket, with sexual dysfunction being a frequent complaint among patients. Though rarer, a serious condition known as neuroleptic malignant syndrome affects around 1% of patients and is characterized by severe muscle rigidity, fever, and in extreme cases, coma.
RESEARCH STUDIES FOR ATYPICAL DRUGS
Many clinicians view antipsychotic drugs as highly effective because they are relatively cheap to produce and easy to administer, and they initially seem to have a positive effect on many sufferers. For example, Kahn et al. (2008) found that antipsychotics are generally effective for at least one year but that second-generation drugs were no more effective than first-generation ones. This finding was also replicated in a meta-analysis by Crossley et al. (2010), who suggested that atypical antipsychotics are no more effective but do have fewer side effects.
However, a large-scale, randomised clinical trial by Lieberman et al. (2005) compared four atypical antipsychotics with one typical antipsychotic. This study involved nearly 1,500 patients across the USA and challenged the belief that atypicals were more effective or produced fewer side effects than typical antipsychotics. The study revealed that:
Atypical drugs were not significantly more effective than typical drugs.
Atypical drugs did not lead to fewer side effects than typical antipsychotics.
Nearly three-quarters of the patients stopped taking their medication before the 18-month study period ended.
Further data from the study showed that:
50% of patients stopped their medication within the first year.
75% discontinued medication by the second year.
Even among patients who continued taking their medication, the relapse rate was high:
40% relapsed in the first year.
15% relapsed in each subsequent year.
These findings suggest that antipsychotic medications, whether typical or atypical, are not particularly effective over the long term, as many patients discontinue treatment due to side effects, disorganised thinking, or the perception that the medication is no longer effective. Additionally, a significant proportion of patients are not symptom-free even while on medication.
ANTIPSYCHOTIC DRUG GROUPS AND NAME ENDINGS (PORTRAIT FORMAT)
A guide to recognising and understanding common antipsychotic types by their suffixes
GROUP: TYPICAL ANTIPSYCHOTICS
COMMON NAME ENDING: -zine
CHARACTERISTICS:
First-generation (typical) drugs
Strong D2 dopamine receptor blockers
Treat positive symptoms (e.g. delusions, hallucinations)
Higher risk of extrapyramidal side effects (e.g. tremors, stiffness)
EXAMPLES:Chlorpromazine
Thioridazine
Perphenazine
GROUP: ATYPICAL ANTIPSYCHOTICS – “THE PINES”
COMMON NAME ENDING: -pine
CHARACTERISTICS:
Second-generation (atypical) drugs
Block dopamine D2 and serotonin 5-HT2A receptors
Often sedating
Associated with weight gain and metabolic issues
EXAMPLES:Olanzapine
Clozapine
Quetiapine
Asenapine
GROUP: ATYPICAL ANTIPSYCHOTICS – “THE DONES”
COMMON NAME ENDING: -done
CHARACTERISTICS:
Block dopamine and serotonin receptors
Less sedating than the pines
Can increase prolactin
Some risk of agitation or insomnia
EXAMPLES:Risperidone
Paliperidone
Ziprasidone
Lurasidone
Iloperidone
GROUP: ATYPICAL ANTIPSYCHOTICS – “TWO PIPS”
COMMON NAME ENDING: -piprazole
CHARACTERISTICS:
Dopamine partial agonists
Regulate dopamine rather than fully blocking it
Lower risk of weight gain, sedation, and movement problems
May improve mood and motivation
EXAMPLES:Aripiprazole
Brexpiprazole
GROUP: ATYPICAL ANTIPSYCHOTICS – “THE RIP”
COMMON NAME ENDING: -prazine
CHARACTERISTICS:
Acts on dopamine D3 receptors as well as D2
Can help with negative symptoms (e.g. apathy, flat affect)
Useful for improving energy and motivation
EXAMPLE:Cariprazine
EVALUATION OF ANTIPSYCHOTICS: TYPICAL AND ATYPICAL
BEFORE ANTIPSYCHOTICS
Before the introduction of antipsychotic drugs, around 50% of patients admitted to psychiatric hospitals, often referred to as lunatic asylums, stayed there for life. The treatment of these individuals was usually brutal or non-existent. Standard practices included electric convulsive therapy (ECT), frontal lobotomies, and insulin shock therapy, all of which were invasive and distressing. Living conditions were equally inhumane, with many patients subjected to straitjackets and housed in padded cells. These methods primarily focused on control and containment rather than treatment, and hospital staff were often poorly educated, resorting to harsh methods rather than providing care.
In stark contrast, today, only about 3% of individuals with schizophrenia are in hospitals, and typically only for a few weeks. This dramatic shift reflects significant improvements in the treatment of mental illness, particularly in Western and individualistic societies. However, while antipsychotic drugs played a role in allowing patients to live more independently, it is essential to acknowledge that improvements in social awareness and human rights likely would have led to better treatment of individuals with mental health conditions, even without the advent of these drugs.
WHO DO ANTIPSYCHOTIC DRUGS BENEFIT?
For many individuals, antipsychotics have significantly improved their ability to function in daily life, allowing them to maintain jobs, relationships, and a degree of independence. Moreover, as patients become more able to manage their symptoms, there is a positive impact on society as well, as fewer people require long-term institutional care, reducing healthcare costs and enabling some patients to return to work and contribute economically.
However, many patients report feeling emotionally numb or “zombified” while on antipsychotic medication, a feeling that can disconnect them from their emotions, thoughts, and sense of self (Moncrieff, 2009). This emotional blunting, often described as a "pharmacological straitjacket," suggests that the medications may benefit institutions and families more than the patients themselves. For example, caregivers, while well-intentioned, may also push for medication to ease their caregiving burden rather than addressing the patient’s deeper needs for psychological treatment or rehabilitation. This raises ethical concerns, as the drugs may be used as tools of control rather than as a means of supporting the patient's long-term recovery and autonomy. In extreme cases, this can lead to violations of patient rights, with the Human Rights Act ensuring no one is subjected to degrading treatment.
Thomas Szasz and Joanna Moncrieff (Szasz, 1974; Moncrieff, 2009) argue that psychotropic drugs are frequently prescribed to keep patients sedated and compliant, making them easier to handle in institutional settings rather than focusing on their well-being and psychological growth.
In summary, while antipsychotics can certainly improve symptoms and offer patients a chance at a more stable life, there are concerns that their use is sometimes more aligned with institutional convenience and societal expectations than with the best interests of the patient. This raises important questions about the balance between controlling symptoms and promoting long-term recovery and personal autonomy.
UP REGULATION IN SCHIZOPHRENIA AND ANTIPSYCHOTIC USE
A significant criticism of antipsychotics is the risk of upregulation and its long-term impact. Upregulation is a compensatory process in which the brain increases the number or sensitivity of receptors in response to antagonists, such as antipsychotics, which block neurotransmitter activity. In the case of schizophrenia, typical antipsychotics work by blocking dopamine D2 receptors to reduce the overactivity of dopamine (Abi-Dargham et al., 2000). However, long-term use of these medications may lead to dopamine receptor upregulation, whereby the brain compensates for the blocked dopamine receptors by increasing dopamine synthesis and receptor density (Seeman, 2009).
This compensatory mechanism can paradoxically lead to worsened psychosis when the medication is discontinued, as the brain’s elevated sensitivity to dopamine exacerbates symptoms of schizophrenia. Moncrieff (2006) describes this phenomenon as "supersensitivity psychosis," where patients who stop taking antipsychotics experience rebound psychosis that is often more severe than the original condition. This occurs because the brain, having adapted to dopamine blockade by upregulating dopamine receptors, suddenly becomes hyper-responsive to dopamine when the drug is removed.
Research conducted on healthy volunteers and schizophrenia patients shows that acute antipsychotic treatment can initially reduce dopamine synthesis. Still, long-term antipsychotic use leads to an increase in presynaptic dopamine synthesis capacity (Howes & Kapur, 2009). This suggests that while antipsychotics may provide temporary relief, they might worsen the underlying dopamine dysregulation over time, contributing to relapse when patients stop treatment.
Moreover, a study by Seeman (2009) highlights the long-term effects of dopamine receptor upregulation, showing that after prolonged antipsychotic use, the brain compensates by increasing dopamine D2 receptors in certain regions. This upregulation persists for years, and patients may relapse more severely upon drug withdrawal, which is one explanation for the high relapse rates observed after discontinuation of antipsychotic treatment.
In addition, upregulation contributes to the cycle of dependency on antipsychotics. Once the brain has adapted to the presence of these medications, stopping them without tapering can provoke an intense rebound psychosis, making it challenging for patients to discontinue the drugs safely. This cycle raises concerns about the long-term strategy of using dopamine-blocking agents as the primary treatment for schizophrenia.
AKATHISIA, SUICIDE IDEATION, AND VIOLENT BEHAVIOUR
Akathisia is a movement disorder marked by extreme restlessness and an inability to stay still, often caused by antipsychotics, especially typical ones, and some antidepressants like SSRIs (Healy et al., 2006). It leads to severe discomfort, anxiety, and agitation, which can result in suicidal thoughts or even violent behaviour. This inner turmoil is linked to impulsive actions, including self-harm or homicidal tendencies.
Research by Healy (2006) and Whitaker (2010) suggests a possible connection between akathisia and extreme violence, including school shootings. Whitaker (2010) raised concerns about psychiatric drugs triggering violent outbursts, particularly in adolescents. While the link is debated, numerous case reports show a disturbing pattern where individuals, after starting or stopping medication, may become prone to suicide or violence.
Healy (2006) documented several cases where patients experienced suicidal urges or aggressive behaviour shortly after adjusting their medication. Since akathisia symptoms can be mistaken for psychotic agitation, increasing the dose may worsen the problem.
More research is needed to understand the connection between akathisia and violent ideation fully, but current evidence suggests that careful monitoring is essential, particularly for young patients. Whitaker (2010) and other researchers emphasise recognising akathisia early to prevent severe outcomes, such as suicide or violence.
PSYCHOSOCIAL FACTORS AND THE LIMITATIONS OF A PURELY BIOLOGICAL APPROACH
The focus on biological treatments such as antipsychotics overlooks the importance of psychological and environmental factors. Schizophrenia is not entirely genetic, as Gottesman’s twin studies demonstrate. Monozygotic (MZ) twins have a 48% concordance rate for schizophrenia. This indicates that environmental and psychological factors play a significant role in the development of schizophrenia, and as such, treatment should not be entirely biological.
A World Health Organization (WHO) study found that patients in developing countries, where antipsychotics are less commonly used, had better long-term recovery outcomes than those in developed countries (Leff, 1992). This suggests that psychosocial factors, such as assertive community support and reduced stigma, play a significant role in recovery. Focusing solely on biological treatments like antipsychotics neglects these critical contributors to the well-being and recovery of schizophrenia patients.
ETHICAL ISSUES AND DETERMINISM
The use of antipsychotics also raises ethical concerns, particularly around issues of determinism. Biological treatments assume that schizophrenia is entirely the result of brain chemistry, leaving little room for patient autonomy or personal agency. Ross et al. argue that antipsychotic drugs merely reduce the effects of schizophrenia without addressing its underlying cause. In other words, they do not “cure” schizophrenia somewhat. They dampen symptoms so patients can live relatively “normal” lives in the community. This, they argue, diminishes patients' motivation to explore other treatments or to understand the root causes of their illness, leading to an over-reliance on pharmacological interventions. The deterministic view presented by antipsychotic treatments can disempower patients, suggesting they have no control over their condition.
In contrast, psychological therapies, such as Cognitive Behavioural Therapy (CBT), aim to empower patients by helping them challenge distorted thoughts and take control of their symptoms.
ALTERNATIVE TREATMENTS AND HOLISTIC APPROACHES
Psychological treatments such as CBT and family interventions have been shown to reduce relapse rates and improve patient outcomes. CBT helps patients recognise and challenge their distorted thinking patterns, reducing the severity of delusions and hallucinations. Family interventions, particularly those that address expressed emotion, have been shown to reduce relapse rates by creating a more supportive home environment (Davis et al., 1997).
Combining biological and psychological treatments makes patients more likely to achieve long-term stability. This holistic approach acknowledges the complexity of schizophrenia. It provides a more personalised treatment plan that addresses not only the biological aspects of the disorder but also the cognitive, social, and environmental factors that influence recovery.
CONCLUSION
Biological treatments, particularly antipsychotic medications, have revolutionised the management of schizophrenia. However, these treatments are not without limitations, including severe side effects, high dropout rates, and their inability to fully address the psychological and social factors contributing to the disorder. A more holistic approach, incorporating both biological and psychological interventions, may offer better long-term outcomes for patients, addressing the full complexity of schizophrenia while empowering patients to take an active role in their recovery.
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