UNIT IV - Biopsychology of Psychiatric Disorders

Anxiety Disorders

Anxiety disorders are characterized by excessive, irrational fear and anxiety, leading to
significant distress and impairment. They are among the most prevalent psychiatric
conditions globally, affecting millions .

Possible Causes

1.​ Genetic Factors

-​ Family and twin studies indicate a hereditary component, particularly for panic
disorder, generalized anxiety disorder (GAD), and social anxiety disorder .
-​ Variations in the BDNF (brain-derived neurotrophic factor) gene may contribute to
susceptibility (Pfleiderer et al., 2007).
2.​ Environmental Triggers
○​ Traumatic experiences can precipitate anxiety disorders, especially in
genetically vulnerable individuals .

Neurobiological Mechanisms

-​ The amygdala, cingulate cortex, prefrontal cortex, and insular cortex are key brain
areas involved in anxiety disorders. Among these, the amygdala plays a central role in
regulating fear and anxiety.
-​ According to some studies, individuals with anxiety disorders exhibit heightened
amygdala responses when exposed to anxiety-related cues. Brain imaging research
using PET scans has shown that during a panic attack, there is decreased activity in
the right orbitofrontal cortex and the anterior cingulate cortex, along with increased
activity in the amygdala.
-​ Other studies have found that people with social anxiety disorder experience greater
activation of the amygdala when viewing angry, disgusted, or fearful facial
expressions. This increased activation is also positively correlated with the severity of
their anxiety symptoms.
-​ Research on adolescents with generalized anxiety disorder (GAD) has revealed
increased activity in the amygdala and decreased activity in the ventrolateral
prefrontal cortex when they are exposed to angry faces. Similarly, highly anxious
 college students—though not clinically diagnosed—also show heightened activation
in both the amygdala and insular cortex, which corresponds with their anxiety levels.
-​ These findings suggest that anxiety symptoms may result from disruptions in neural
modulation within the central nervous system. Specifically, low serotonin activity and
elevated noradrenergic activity are believed to contribute to the development of
anxiety.

Major Affective Disorders

Affective disorders, also known as mood disorders, are psychological conditions

characterized by disturbances in mood and emotional state.

There are two main types of major affective disorders:

1.​ Bipolar Disorder:​

This type involves alternating episodes of mania and depression.
2.​ Major Depressive Disorder (MDD):​
This form is marked by episodes of depression without mania.

Possible Causes

Genetic Factors (Heritability)

-​ People with close relatives affected by mood disorders are about 10 times more likely
to develop these conditions themselves.
-​ Twin studies show a 69% concordance rate in monozygotic twins, compared to
only 13% in dizygotic twins, indicating a strong genetic component.

Genetic Research Findings

-​ The RORA gene, which helps regulate circadian rhythms, has been strongly linked
to major depressive disorder.
-​ Another gene, GRM8, which encodes a metabotropic glutamate receptor, is also
suspected to play a role in depression.
 -​ The RORB gene, another circadian rhythm-related gene, has been associated with
rapid-cycling bipolar disorder, particularly in children.

Role of the Frontal Cortex in Depression

-​ The frontal cortex plays a critical role in the development and regulation of mood
disorders, especially depression. According to some studies, a key region involved is
the subgenual anterior cingulate cortex (ACC), which acts as a central hub within a
network of brain areas responsible for mood regulation. In individuals with
depression, neuroimaging has revealed hyperactivity in the subgenual ACC and
reduced activity in other regions of the frontal cortex such as: Dorsolateral Prefrontal
Cortex (dlPFC), Ventrolateral Prefrontal Cortex (vlPFC) , Ventromedial Prefrontal
Cortex (vmPFC), Orbitofrontal Cortex (OFC)
-​ Successful antidepressant treatments have been shown to reduce the activity in the
subgenual ACC and increase activity in other frontal areas. The subgenual ACC also
has strong connections with the amygdala, hippocampus, and nucleus accumbens,
which are all crucial to emotional regulation The prefrontal cortex is known to
inhibit the amygdala, which is associated with generating negative emotional
responses like fear. Therefore, reducing subgenual ACC activity through treatment
may help calm the overactive amygdala, both directly and indirectly, via prefrontal
modulation.

The Monoamine Hypothesis

One popular theory for the biological basis of depression is the monoamine hypothesis,
which suggests that the condition results from a deficiency of certain
neurotransmitters—primarily serotonin, norepinephrine, and dopamine—within the
brain. While serotonin and norepinephrine have been the main focus of research, dopamine
may also play a role. Studies have shown that depletion of tryptophan (a precursor to
serotonin) does not affect mood in healthy individuals, but does trigger depressive symptoms
in those with a personal or family history of mood disorders—implying underlying
biological vulnerability.

Role of the 5-HT Transporter

Research has pointed to the serotonin transporter gene (5-HTT) as a potential contributor
to depression. The promoter region of this gene exists in two forms: short and long
Longitudinal studies have suggested that individuals with one or two short alleles are more
likely to develop major depressive disorder following stressful life events. This supports
the idea of an interaction between genetic vulnerability and environmental stress.
However, several meta-analyses have found inconsistent results, and the overall scientific
consensus is that the exact role of the 5-HTT promoter in depression remains unproven and
requires further investigation.

Neurogenesis and Depression

Research in animals has shown that chronic stress, which can trigger depressive symptoms,
inhibits hippocampal neurogenesis. Although direct evidence in humans is limited, these
findings suggest that reduced neurogenesis may contribute to the development of depression
and that restoring it could be a therapeutic target.

Circadian Rhythms and Depression

Disruptions in circadian rhythms, especially sleep patterns, are commonly observed in

individuals with depression. These alterations suggest that circadian dysregulation may be
a significant factor in the onset and maintenance of depressive symptoms.

Treatment of Depression

Pharmacological Treatments: Antidepressants, including SSRIs, SNRIs, ketamine, and

lithium, have shown effectiveness in treating depressive symptoms.

Non-Pharmacological Treatments:

●​ Electroconvulsive Therapy (ECT)

●​ Vagus Nerve Stimulation (VNS)
●​ Transcranial Magnetic Stimulation (TMS)
●​ Deep Brain Stimulation (DBS)
-​
 Schizophrenia

Schizophrenia is a severe and chronic psychiatric disorder characterized by a profound

disconnection from reality and the self. It involves disorganized thought processes, emotional
incongruity, and a withdrawal from social interactions. The condition affects approximately
1% of the global population, with an estimated 3.5 million individuals diagnosed in India as
of 2017. Schizophrenia tends to appear earlier in males (typically before age 40) and later in
females (after age 40).

Symptoms of Schizophrenia

Schizophrenic symptoms are broadly categorized into three groups: positive, negative, and
cognitive.

Positive Symptoms (Excess or distortion of normal functions):

●​ Delusions
●​ Hallucinations
●​ Thought Disorders

Negative Symptoms (Deficit or loss of normal functions):

●​ Flat affect – Diminished emotional expression.

●​ Anhedonia – Inability to feel pleasure.
●​ Avolition – Lack of motivation or initiative.
●​ Alogia – Reduced speech output.
●​ Social withdrawal – Limited interpersonal engagement.

Cognitive Symptoms:

●​ Impaired attention and concentration.

●​ Slow psychomotor responses.
●​ Deficits in learning, memory, and executive functioning.
●​ Poor problem-solving abilities

Causes and Risk Factors

Genetic Contributions Schizophrenia has a strong hereditary component, as supported by
twin and adoption studies. Although no single “schizophrenia gene” has been identified,
numerous genes across nearly all chromosome pairs have been implicated. One rare but
significant mutation affects the DISC1 gene, which plays roles in neurogenesis, neuronal
migration, and synaptic function. Although rare, DISC1 mutations can increase schizophrenia
risk by 50%.

Developmental and Structural Anomalies

Behavioral Indicators in Childhood

Early signs of schizophrenia may be present long before diagnosis. Retrospective studies
using childhood home videos reveal that affected individuals often showed:

●​ More negative facial expressions.

●​ Unusual motor behavior.
●​ Reduced sociability and psychomotor development.

Physical Anomalies

Minor physical anomalies, such as high-arched palates and unusual eye spacing, have been
observed more frequently in individuals with schizophrenia.

Brain Abnormalities

-​ CT and MRI studies show that patients with schizophrenia have enlarged ventricles,
suggesting a loss of brain tissue
-​ Accelerated gray matter reduction, particularly in the frontal and temporal lobes, is
common in patients and some unaffected relatives, implying a genetic predisposition
-​ Many experts suggest that prenatal disturbances in brain development contribute to
schizophrenia, with environmental and genetic vulnerabilities interacting.

Neurochemical Mechanisms

Mesolimbic Dopamine Pathway and Positive Symptoms

This pathway, extending from the ventral tegmental area (VTA) to the nucleus accumbens
and amygdala, is central to reward processing. Hyperactivity in this pathway is believed to
underlie the positive symptoms of schizophrenia. Agonists of dopamine (like amphetamines)
can mimic these symptoms, while antipsychotic medications help mitigate them by reducing
dopaminergic transmission.

-​ Paranoid Delusions may result from excess dopamine in the amygdala

-​ Aberrant Salience: Elevated dopamine may cause undue importance to be attributed
to irrelevant stimuli, leading to delusions or hallucinations

Dopamine Transmission Abnormalities

Studies show that individuals with schizophrenia may release more dopamine in response to
stimulants and exhibit modest increases in D2 receptor density. However, these differences
are not conclusively the primary cause of the disorder.

Long-Term Treatment and Its Consequences

Antipsychotic drugs, though effective for many, often cause serious side effects due to
dopamine blockade:

●​ Extrapyramidal symptoms: Parkinson-like motor issues.

●​ Tardive Dyskinesia: Involuntary movements, often irreversible.

These effects are likely due to dopamine receptor supersensitivity, where chronic D2 receptor
blockade leads to receptor upregulation, causing overcompensation in dopaminergic
signaling.

Mesocortical Dopamine Pathway and Negative/Cognitive Symptoms

The mesocortical pathway, which projects to the dorsolateral prefrontal cortex (dlPFC), is
implicated in negative and cognitive symptoms of schizophrenia.

Hypofrontality

Coined by Weinberger (1988), hypofrontality refers to reduced activity in the dlPFC. This is
associated with poor performance on executive function tasks and is believed to result from
decreased dopamine release in this region.

Glutamatergic Dysfunction
Evidence suggests reduced glutamate levels in cerebrospinal fluid of patients with
schizophrenia. NMDA receptor antagonists like PCP and ketamine can induce
schizophrenia-like symptoms in healthy individuals, reinforcing the idea that decreased
glutamate activity contributes to negative and cognitive symptoms.

Developmental Perspective and Experimental Models

Abnormal development of pyramidal neurons in the prefrontal cortex may play a primary role
in schizophrenia. In a study by Li et al. (2011), mice genetically modified to overexpress D2
receptors in the striatum exhibited schizophrenia-like behaviors and prefrontal cortex
abnormalities, suggesting an interaction between striatal dopamine dysregulation and
GABAergic dysfunction in the cortex.

Substance Abuse

-​ Substance abuse rates are generally higher among men, but prescription drug abuse
rates may be similar between men and women.
-​ Prescription painkiller abuse increased by over 25% between 2005 and 2010.

Definition and Characteristics

Substance Use Disorders involve:

-​ Impaired control over substance use

-​ Unsuccessful efforts to reduce use
-​ Significant time spent obtaining or using the drug
-​ Cravings
-​ Neglect of responsibilities
-​ Continued use despite:
○​ Interpersonal issues
○​ Health or legal consequences
-​ Development of tolerance and withdrawal symptoms

Mechanism of Reinforcement

Positive Reinforcement
Positive reinforcement strengthens behaviors by following them with rewarding stimuli. Most
drugs (except hallucinogens) activate the brain’s reinforcement system, reinforcing
drug-taking behavior. Fast-acting routes (snorting, smoking, injecting) lead to:

-​ More rapid brain entry

-​ Stronger activation of reinforcement pathways
-​ Higher abuse potential

Neural Mechanisms of Substance Abuse

Role of Dopamine : Dopamine release is a necessary condition for positive reinforcement,

though not the only one.

Mesolimbic Dopamine Pathway: Abused drugs (e.g., amphetamine, cocaine, opiates,

nicotine, alcohol, PCP, cannabis) stimulate dopamine release in the nucleus accumbens
(NAC). The substance abuse process begins in the mesolimbic system (notably the VTA) and
then spreads to other brain regions.

Synaptic Changes in VTA - A single exposure to many drugs increases the strength of
excitatory synapses on dopaminergic neurons in the VTA. This occurs through:

-​ Insertion of AMPA receptors in the postsynaptic membrane

-​ Mediated by NMDA glutamate receptors
-​ Reflects neural mechanisms of learning and memory

Role of the Striatum

Ventral and Dorsal Striatum Activation: Changes in the ventral tegmental area (VTA) lead
to increased activation in brain areas receiving dopaminergic input, including the ventral
striatum (which includes the nucleus accumbens, NAC) and dorsal striatum(including the
caudate nucleus and putamen).

Progression from Pleasure to Habit: Initially, pleasurable drug effects reinforce behaviors
via the ventral striatum (NAC). With continued use, behaviors become habitual, driven by the
dorsal striatum. Monkey studies show that with long-term cocaine use, neural activity shifts
from the NAC to the dorsal striatum, mirroring the transition from voluntary use to
compulsive, automatic behavior

Mesolimbic-Striatal Circuitry

-​ Dorsally Cascading Connections: There is a loop of reciprocal connections between

the striatum and the VTA. Neurons in the ventral NAC project to the VTA, which
sends dopaminergic input back to more dorsal regions, moving up to the caudate
nucleus and putamen. These circuits support the progression of addiction from
goal-directed to habitual drug use.
-​ Cue-Triggered Craving: In addicted individuals, dopamine release in the dorsal
striatum is triggered not by the drug itself, but by drug-related cues (e.g., locations,
people). Over time, the motivation to use comes not from pleasure, but from
cue-induced compulsions.
-​ Dopamine Receptors: Medium spiny neurons in both striatal regions undergo
receptor changes:
■​ D1 receptors (excitatory): Increased.
■​ D2 receptors (inhibitory): Decreased.

Role of the Prefrontal Cortex

-​ Adolescent Vulnerability: 50% of substance abuse cases begin between ages 15–18.
Prefrontal cortex immaturity during adolescence leads to: Poor judgment, Risk-taking,
Impulsivity. This makes teens more prone to experiment with drugs and develop
long-term addiction.
●​ Inhibitory Control & Risk: Some prefrontal regions inhibit the striatum. More
activity in these regions correlates with resistance to substance use. Substance abusers
often show similar impairments to individuals with prefrontal cortex damage.
●​ Structural Changes in Addicts:- Cocaine abusers show a 5–11% decrease in gray
matter in the prefrontal cortex. Methamphetamine users show reduced gray matter
in the cingulate and limbic cortex.

Neuropeptides and Drug Reinforcement

 -​ Orexin (Hypocretin): Made in the lateral hypothalamus, regulates sleep and feeding.
Released in the VTA, NAC, and dorsal striatum Activated by drug use or drug cues;
injecting orexin into the VTA restores drug-seeking in animals.
-​ MCH (Melanin-Concentrating Hormone): Also made in the lateral hypothalamus.
Stimulates hunger, lowers metabolic rate. MCH receptors are present in the NAC and
interact with dopamine receptors. Stimulating both DA and MCH receptors increases
NAC neuron activity; blocking MCH reduces cocaine effects.

Negative Reinforcement and Physical Dependence

-​ Negative Reinforcement: Drug use is reinforced if it removes unpleasant feelings

(e.g., stress, anxiety).
-​ Physical Dependence: Involves tolerance and withdrawal.

Tolerance: Requires larger doses to achieve the same effect. Caused by the
body’s compensatory mechanisms fighting the drug's effects.

Withdrawal: Symptoms are the opposite of drug effects (e.g., heroin

withdrawal = dysphoria, diarrhea, agitation). These symptoms are unpleasant
and reinforce continued use (negative reinforcement).

Craving, Relapse, and Stress

-​ Craving: Can occur months or years after stopping drug use. Indicates long-lasting
brain changes that increase risk of relapse.
-​ Relapse: Known as reinstatement of previously extinguished behavior.
-​ Extinction is not forgetting, but learning to suppress the [Link] ventromedial
prefrontal cortex (vmPFC) is key to this suppression.
-​ Stress and Relapse: Stress is a major trigger for relapse. Early life stress has
long-term effects on drug-taking behavior. The hormone CRH (corticotropin-releasing
hormone) plays a central role:
a.​ Administration of CRH reinstates drug-seeking.
b.​ Blocking CRH receptors can reduce relapse.