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Substance Induced Mood Disorders

Substance Induced Mood Disorders

Article Author:
Neelambika Revadigar
Article Editor:
Vikas Gupta
11/19/2020 2:00:47 PM
For CME on this topic:
Substance Induced Mood Disorders CME
PubMed Link:
Substance Induced Mood Disorders


Per the DSM-5, the overall category of substance-induced disorders includes intoxication, withdrawal, and other substance/medication-induced mental disorders. Substance/medication-induced mental disorders encompass, for example, substance-induced psychotic disorder, substance/medication-induced bipolar and related disorder, substance-induced depressive disorder.

Both substance-induced depressive disorder and substance/medication-induced bipolar and related disorders cause a change in mood caused by taking or stopping a drug, which may last days or weeks. Substances of abuse or medications can cause people to be depressed or have euphoria, irritability, and increased goal-driven activity(hypomania/mania). Depression and bipolar disorder frequently co-occur with substance use disorders (SUDs) and are prevalent in the general population.[1][2] Both substance-induced depressive disorder and substance/medication-induced bipolar and related disorders were included in the category of substance-induced mood disorder. Substance-induced mood disorder is a DSM-IV diagnosis; however, the two are now covered under the category of substance/medication-induced mental disorders in DSM-5. This review will cover both substance-induced depressive disorder and substance/medication-induced bipolar and related disorders.

Psychiatric comorbidity among individuals with cocaine use disorder is highly indicative of depressive disorders. It was estimated that the lifetime prevalence of depressive disorders among cocaine abusers in treatment range was about 20% to 47%.[3][4] However, a significant proportion of mood disorder was imputed to alcohol-induced affective symptoms.[5] Data gathered from outpatient participants with opioid use disorder reported that around 55% of these participants had a substance-induced depression.[6] Major depressive disorder and bipolar disorders are the most common psychiatric comorbidities among patients with substance use disorders.[7]

There is a paucity of literature for empirical studies to delineate substance/medication-induced disorders from major depressive disorder or bipolar disorder.[8] Substance/medication-induced disorders refer to individuals reporting a history of use of a substance (illicit drugs or prescribed medications), which leads to symptoms of depression or mania. It does not require that the full criteria for major depression or bipolar disorder are met. Substance/medication-induced disorders disorder can cause significant impairment in social, occupational, or other important areas of functioning. It can also cause life-threatening medical complications and suicide.


Substance/medication-induced disorders may develop in the context of drug use, intoxication, or withdrawal from medications or substances of abuse. Half of the depressive episodes develop in the context of heavy drinking and alcohol use.[9][10][11] The use of cocaine and opioids, especially heroin, may also be contributory. The neurotransmitter systems whose function appears to be altered in depression are serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin-releasing factor, neuropeptide Y, and somatostatin. Substance use disorder and depression may be associated with alterations of neurotransmitter function in limbic-related brain structures.[12] Research showed that both substance use and mood disorders have genetic risk factors.[7] Besides illicit substance use, medications like interferon (IFN), corticosteroids, digoxin, and antiepileptic drugs may induce depression.[13][14] Corticosteroid use may lead to mania or affective instability. Prescribed medicines, such as levoamphetamine and dextroamphetamine, may cause mania with use or depression on withdrawal. Withdrawing from illicit drugs or prescribed medication such as alprazolam can elicit mood symptoms such as restlessness, irritability, excessive worries, and fear. Protracted withdrawal can mimic mood symptoms. A core symptom of major depressive disorder-anhedonia- may develop in individuals who had been abstinent from alcohol, opioids, and other drugs for an extended period (sometimes over a year).[15] Long term use of marijuana may lead to amotivational syndrome that mimics depression.

Overall, substance use, such as opioids, alcohol, methamphetamine, marijuana, and cocaine, can cause mood symptoms. The mood symptoms can develop in acute intoxication, continuous use, withdrawal, or protracted withdrawal. Specific medications class are particularly notorious for causing mood disorder during taper or discontinuation. Benzodiazepines mimic depression, generalized anxiety, and panic disorder.[16]


The lifetime prevalence of substance/medication-induced disorders is yet to be elucidated. While the lifetime prevalence of substance/medication-induced depressive disorder was 0.26% in the U.S.[17], another study reported that less than 1% of the general population had a substance-induced major depressive episode.[1] Other investigations noted higher lifetime rates of substance/medication-induced disorders( depression and bipolar), especially depression (40% and 60%) among individuals with alcohol use disorder.[11][18][19] Both substance-induced depression (60% of attempters) and independent depression (13% of attempters) confer a risk factor that may precipitate suicide attempts.[20] Of the individuals with major depression, 16.5% had an alcohol use disorder, and 18% had a drug use disorder. Additionally, 56.1% of individuals with bipolar disorder had a substance use disorder. Data indicate that the lifetime prevalence of substance use disorders in bipolar I patients is 61%.[21] The literature on epidemiological studies of substance/medication-induced mania or bipolar disorder is lacking. About 50% of patients with bipolar disorder also have a substance use disorder. Bipolar type I has shown to have higher rates of co-occurring substance use disorder than bipolar type II and cyclothymic disorder.[22][23]


The pathophysiology of substance/medication-induced disorders is still a topic of ongoing growing research. Drug-induced mood symptoms produce changes in limbic structures, such as the frontal cortex, the nucleus accumbens, the olfactory tubercle, the hippocampus, the amygdala, and the hypothalamus.[24] Also, drug-induced mood symptoms involve complex alterations of serotonergic, dopaminergic, corticotropin-releasing factor (CRF), and neuropeptide Y (NPY) neurotransmitter circuitries.[25][26] Neuroimaging studies using positron-emission tomography(PET) demonstrated a marked reduction in dopamine D2 receptor binding. In contrast, single-photon emission computed tomography (SPECT) analyses showed an increase in the dopamine transporter that persisted for weeks after cessation of a stimulant like cocaine.[27][26] It appears that neurobiological alterations that are expressed into neuropsychiatric symptoms involve mostly serotonin and dopamine.

History and Physical

The symptomatology of drug abuse can mimic depression or mania. Both alcohol and stimulant intoxication can produce symptoms of mania or hypomania, and substance withdrawal often manifests as symptoms of dysphoria and depression. Alcohol use may lead to euphoria, decreased impulse control, or mood lability, often followed with hang-over symptoms and dysphoria. Cocaine and amphetamines may mimic bipolar spectrum disorders causing symptoms such as euphoria, increased energy, decreased appetite, grandiosity, and paranoia. Cocaine withdrawal can cause anhedonia, apathy, depressed mood, and suicidal ideation. Also, benzodiazepines, opiates, and barbiturates can lead to depressive symptoms, including poor concentration, anhedonia, and difficulty sleeping, while withdrawal from these medications can result in anxiety and agitation.[7] Opioid intoxication may cause intense euphoria, while withdrawal leads to dysphoria and withdrawal symptoms like severe body aches and gastrointestinal symptoms. A protracted withdrawal syndrome from opioids may last weeks with depression and dysphoria.

However, subtle affective disorders such as dysthymia and cyclothymia are particularly challenging to differentiate from symptoms of substance use disorder.[7] Substance-induced depressive disorder is mostly encountered among individuals with excessive alcohol use. These individuals have a lower average number of months of abstinence since the onset of alcohol use disorder and involvement with more categories of drugs.[5] Depressive symptoms among individuals with cocaine use disorder are apparent in the first 3 to 5 days after cessation of cocaine use (the “crash”). Crash or withdrawal-induced elevations in depressive symptoms can make it challenging to be able to diagnose current or lifetime depressive disorders among substance abusers during this time. 

Symptoms of depression may include sadness, lack of energy, anhedonia, lack of motivation, loss of interest, weight loss, insomnia or hypersomnia, feelings of guilt, lack of appetite, or suicidal ideation. Symptoms of hypomania/mania would include grandiosity, increased goal-directed activity, insomnia, distractibility, racing thoughts, impulsivity, risky behaviors, irritability, and pressured speech.


Substance-induced psychiatric symptoms may be differentiated from a primary psychiatric illness through observation during a period of abstinence. For alcohol, cocaine, and alprazolam, the intoxication and withdrawal duration are likely to be of shorter duration. Thus, valid diagnoses with shorter periods of abstinence may be possible. An important clue is that a primary psychiatric disorder may be more likely if there is a family history of psychiatric disorders, the onset of psychiatric symptoms is before the onset of substance use, and there are sustained psychiatric symptoms during lengthy periods of abstinence.[21] For substance-induced depressive disorder, the clinical picture is characterized by a depressed mood or a markedly diminished interest or pleasure in all spheres of life, and the symptomatology is corroborated with the history, physical examination, or laboratory findings. For the substance/medication-induced bipolar, the clinical picture is delineated by an elevated, expansive, or irritable mood, with or without depressed mood, or markedly diminished interest or pleasure in all spheres of life. Clinical evidence is corroborated with the history, physical examination, or laboratory findings.

Screening tools have been found useful, such as the Alcohol Use Identification Test, the Michigan Alcohol Screening Test, and the Drug Abuse Screening Test in screening for alcohol and drug abuse problems. The Symptom Checklist (SCL-90) is a widely used instrument for psychiatric screening. Other screening tools include a modified version of the SCID, such as the Psychiatric Research Interview for Substance and Mental Disorders (PRISM). Urine drug screens and urine/serum biomarkers can help establish the appropriate diagnosis. Lastly, sound clinical judgment is essential to determine whether a drug or medication indeed induce the symptomatology of mood symptoms. 

Treatment / Management

Due to the temporary nature of substance-induced depressive symptoms, there is no sound evidence to support a specific pharmacological strategy. Some studies support the use of SSRIs for the treatment of comorbid alcohol use disorder and major depression.[21] A study suggested that imipramine could significantly decrease depression in a group of depressed patients receiving methadone maintenance.[28] Selective serotonin reuptake inhibitors (SSRIs), in general, can be used for depressive symptoms, and symptoms of mania may respond to valproic acid, lithium, or olanzapine.

The main focus of the use of tricyclic antidepressants (TCAs) for cocaine use disorder seems to be on the treatment of the disorder rather than on the treatment of depressive symptoms. Studies have shown improvement of anhedonia and cocaine craving and increased initial abstinence in nondepressed patients with desipramine. There is a paucity of published data on the treatment of bipolar disorder complicated by substance use disorder. Note that substance abuse may be a predictor of inadequate response to lithium.[29] Participants with bipolar type I with co-occurring alcohol and cocaine dependence who received valproate had significantly lower numbers of heavy drinking days and a significant increase in the number of days abstinent from cocaine.[30][31] Participants with bipolar type I and bipolar type II with co-occurring cocaine dependence who received quetiapine had a significant improvement in scores on the Hamilton Depressive Rating Scale.[32] The effectiveness of psychotherapy as an adjunct to medications for bipolar and depression with co-occurring substance use disorder was also studied and seems to be promising.[33][23] There is no evidence that the success of these medications can be extrapolated to imply that they will benefit patients with substance/medication-induced disorders (depression and bipolar) though they are frequently used in this condition.

Differential Diagnosis

Transient substance/medication-induced disorders may be differentiated from a primary psychiatric illness through observation during a period of abstinence with a temporal association of the intake of a substance. A family history of a primary psychiatric illness may also facilitate a diagnosis differential. For substance-induced symptoms of mania, the differentiation may be more complex because of a high probability of temporal association or causality of mood symptoms after substance use(cocaine, amphetamine).


Substance/medication-induced disorders sometimes carry a poor prognosis in case there is a delay in detection, treatment, and frequent relapses on substances of abuse. Patients with substance use history often have personality factors (antisocial, narcissism), and symptoms like grandiosity in bipolar disorder and lack of motivation in depression that may make engagement with mental health professionals and patient compliance with treatment difficult. Treatment delay of the disorder, as well as continuous use of alcohol and other drugs, can cause medical and neuropsychiatric complications and higher utilization of emergency services with phenomenal medical costs. Suicide ideation, mania, or paranoia may hamper recovery and may lead to treatment dropout. When substance use or medication use leads to mood disorder, abstinence, and stopping the medication usually results in complete resolution of symptoms.


There is no sound evidence of complications involving substance/medication-induced disorders. However, one can suggest that the same complications involving substance use disorder and comorbid psychiatric illness may apply for substance/medication-induced disorders. Around 14% to 16% of individuals with bipolar disorder and co-occurring substance use disorder complete suicide.[34] Medical complications include the gastrointestinal system, physical trauma, and contracting human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Legal complications, such as driving under the influence (DUI), assault, and domestic violence, are common.[2]

Deterrence and Patient Education

  • Refrain from the use of alcohol or illicit drugs.
  • Avoid people or milieu that most likely trigger the use of alcohol or illicit drugs.
  • Consider psychosocial interventions like AA and NA to promote recovery from alcohol and substance abuse.
  • Discuss with a physician about any new medication prescribed by another physician because some medications can cause mania or depression.
  • Contact a physician if having concerns regarding over the counter medicines because some OTCs can augment the effects of other medications and may cause mania or depression.
  • Eat a healthy diet, limit caffeine, and quit smoking. 
  • Be aware of depression or mania that result after the initiation of substance use or use of medication and discuss them with your primary care physician or psychiatrist.

Pearls and Other Issues

  • Substance-induced disorders encompass intoxication, withdrawal, and other substance/medication-induced mental disorders.
  • Substance/medication-induced mental disorders may include substance-induced psychotic disorder, substance-induced depressive disorder, substance-induced bipolar disorder, and related disorder.
  • Substance-induced mood disorder is no longer a diagnosis in the DSM-5. Disorders of substance-induced mood disorder are described in the DSM-5 into substance-induced depressive disorder, substance/medication-induced anxiety disorder, and substance-induced bipolar disorder and related disorder.
  • The academic literature on substance/medication-induced mental disorders is sparse and scant.
  • Further research on substance/medication-induced mental disorders is warranted due to elevated risks of medical and psychiatric complications and the clinical complexity of the disorders.

Enhancing Healthcare Team Outcomes

Managing substance/medication-induced disorders disorder requires a multidisciplinary approach involving the patient, the patient’s family, physician, nurse, and therapist. Although substance/medication-induced disorders (depression and bipolar) subside after the biological effects of the drug fade, vulnerable individuals can develop a full-blown major depressive disorder or bipolar disorder, without proper management, psychiatric and medical complications can be fatal. 

In the emergency department, physicians and assigned nurses are responsible for coordinating the care, which includes the following:

  • Drug levels in the blood and or urine
  • Monitor the patient for signs and symptoms of respiratory depression and cardiac arrhythmias.
  • Administer benzodiazepines or antipsychotics for acute mania.
  • Creatine phosphokinase (CPK) to rule out rhabdomyolysis 
  • Provide rehydration with normal saline
  • Provide 1:1 for safety (suicide and injury to others)
  • Consider involuntary status for imminent threats to self and others
  • Physical restraints as the last result
  • Consult an addiction specialist

In the outpatient clinic physician and assigned nurse are responsible for:

  • Assure the patient’s safety and others in case of acute mania or severe depression.
  • Transport the patient to the emergency department.
  • Consider an involuntary commitment to a psychiatric hospital for imminent threats to self and others.

Physicians, nurses, and therapists should discuss and involve the family in the treatment plan. An interprofessional team that provides a holistic and integrated approach can help achieve the best possible outcomes. 


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