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Medication Summary:

Appropriate medication for managing bipolar affective disorder, or manic-depressive illness (MDI), depends on the
stage the patient is experiencing. The choice of agent depends on the presence of symptoms such as psychotic symptoms, agitation, aggression, and sleep disturbance. Drug categories include mood stabilizers, anticonvulsants, and antipsychotics

Anxiolytics, Benzodiazepines
Class Summary
By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and the action of other inhibitory transmitters.

Lorazepam (Ativan)

Lorazepam is an anxiolytic hypnotic with an intermediate onset of effects and a relatively intermediate half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the central nervous system (CNS), including the limbic and reticular formation.

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

Mood stabilizers

Class Summary
Lithium is the drug commonly used for prophylaxis and treatment of manic episodes. A 2012 study suggested that lithium may also have a neuroprotective role.[80] However, this agent is also associated with an increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment.

Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[83] Lithium therapy may serve to protect and preserve the hippocampal volumes, in contrast to patients with major depression (ie, unipolar), who show diminished hippocampal volumes.[84]

Furthermore, recognizing that patients with bipolar affective disorder are at risk for suicide, lithium may also have some anti-suicidal action. A report from Lewitka and Bauer suggest that lithium may be an option for patients with affective disorders who are at risk for suicide. However, they caution that lithium is still a medication that requires careful assessment and monitoring. Patient adherence is essential.[43]

Lithium carbonate (Lithobid)

Lithium is considered a first-line agent for long-term prophylaxis in bipolar illness, especially for classic bipolar disorder with euphoric mania. It also can be used to treat acute mania, although it cannot be titrated up to an effective level as quickly as valproate can. Evidence suggests that lithium, unlike any other mood stabilizer, may have a specific antisuicide effect.

Monitoring blood levels is critical with this medication. Serum levels should be determined twice weekly during the acute phase, and until the serum level and clinical condition of the patient has been stabilized.

Anticonvulsants

Class Summary
Anticonvulsants have been effective in preventing mood swings associated with bipolar disorder, especially in those patients known as rapid cyclers. For the depressed phase, mood stabilizers, such as lithium and lamotrigine, are preferred, because antidepressants may propel a patient into a manic episode or exacerbate irritability in mixed-symptom mania. Gabapentin, although not a mood stabilizer, also may have anxiolytic properties.The most widely used anticonvulsants have been carbamazepine, valproate, and lamotrigine. More recently, topiramate and oxcarbazepine also are being tried.

Note that the Department of Veterans Affairs/Department of Defense (VA/DoD) do not recommend lamotrigine, topiramate, and gabapentin in patients with mania or mixed episodes.[3]

Carbamazepine (Equetro)

Carbamazepine is effective in patients who have not had a clinical response to lithium therapy and who have rapid-cycling bipolar disorder. Its efficacy is not well established for long-term use; therefore, periodically reevaluate the long-term risks and benefits of carbamazepine for individual patients. This drug can also act to inhibit seizures induced through the kindling effect, which is thought to occur by way of repeated limbic stimulation.

Valoprate sodium, valproic acid, divalproex sodium (Depakene, Depakote, Depakote ER, Depacon, Stavzor)

Valproate has proven effectiveness in treating and preventing mania. It is classified as a mood stabilizer and can be used alone or in combination with lithium. This agent is useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination of valproic acid and valproate has been effective in treating persons in manic phase, with a success rate of 49%.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is an anticonvulsant that appears to be effective in the treatment of the depressed phase in bipolar disorders. It is used for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults treated for acute mood episodes with standard therapy.

Topiramate (Topamax)

Topiramate has an off-label indication for the treatment of bipolar disease. In a small retrospective review, marked improvement occurred in 62% of patients when topiramate was added to their current regimen.[114] It is unclear if topiramate’s efficacy occurs only as adjunctive treatment. More studies are needed to examine potential benefits of this drug in treating bipolar. Unlike conventional neuroleptics, topiramate is not associated with weight gain.

Antipsychotics, 2nd Generation

Class Summary
Second-generation, or atypical, antipsychotics are increasingly being used for treatment of both acute mania and mood stabilization in patients with bipolar I disease.

Asenapine (Saphris)

Asenapine is indicated as monotherapy for the acute treatment of manic or mixed episodes that are associated with bipolar I disorder. It is also indicated as adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disease. The efficacy of asenapine is thought to be mediated through a combination of antagonist activity at dopamine 2 and serotonin (5-HT2) receptors.

Ziprasidone (Geodon)

Ziprasidone is approved for the treatment of acute or mixed episodes that are associated with bipolar disorder. It can be used as maintenance treatment or as an adjunct to lithium or valproate.

Quetiapine (Seroquel, Seroquel XR)

Quetiapine is indicated for acute treatment of manic (immediate release and extended release [XR]) or mixed (XR) episodes that are associated with bipolar I disorder. It can be used as monotherapy or adjunctively with agents such as lithium or divalproex.

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone is indicated for short-term treatment of acute manic or mixed episodes that are associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate. Risperidone can be used in adults and adolescents aged 10-17 years with bipolar I disorder.

Aripiprazole (Abilify, Abilify Discmelt)

Aripiprazole is indicated for the acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate.

Olanzapine (Zyprexa, Zyprexa Zydis)

Olanzapine is used for the acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate. Olanzapine can be used in adults and adolescents aged 13-17 years with bipolar I disorder.

Olanzapine and fluoxetine (Symbyax)

The drug combination includes olanzapine, a second-generation antipsychotic, and fluoxetine, a selective serotonin reuptake inhibitor. This drug is indicated for the acute treatment of depressive episodes associated with bipolar I disorder in adults. The clinical effects of this agent have not been studied in patients younger than 18 years.

Clozapine (Clozaril, FazaClo ODT)

Clozapine has an off-label indication for treatment of acute manic episodes associated with bipolar disorder and treatment of refractory bipolar mania. This agent demonstrates weak D2 receptor and D1 receptor blocking activity. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Paliperidone (Invega)

Paliperidone may be used for refractory, moderate to severe mania alone or in combination with lithium or valproate. This agent is typically reserved for patients who decline electroconvulsive therapy (ECT) and who do not respond to medication combinations involving lithium or valproate plus aripiprazole, haloperidol, or another first-generation antipsychotic.

Antipsychotics, 1st Generation
Class Summary
First-generation antipsychotics, also known as conventional or typical antipsychotics, are efficacious for treating both psychotic and nonpsychotic manic and mixed episodes, as well as hypomania. These agents are strong dopamine D2 antagonists. However, each drug in this class has various effects on other receptors, such as 5-HT2 serotonin, alpha1, histaminic, and muscarinic receptors.

Loxapine inhaled (Adasuve)

The mechanism of action for loxapine is unknown, but it is theorized to antagonize central dopamine D2 and serotonin 5-HT2a receptors. The inhaled dosage form is indicated for acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

Haloperidol (Haldol)

Haloperidol is used for the acute treatment of mania or mixed episodes in patients with bipolar disorder. It can be used alone or in combination with lithium or valproate in an adult patient. Haloperidol blocks postsynaptic dopamine receptors (D2) in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor

Antipsychotics, Phenothiazine
Class Summary
Phenothiazine antipsychotics, which are classified as first-generation antipsychotics, are efficacious for treating both psychotic and nonpsychotic manic and mixed episodes, as well as hypomania.

Chlorpromazine (Thorazine)

Chlorpromazine is used to treat manic and mixed episodes in patients with bipolar I disorder. It can be used alone or in combination with lithium or valproate. Chlorpromazine blocks postsynaptic dopamine receptors (D2) in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor

Antiparkinson Agents, Dopamine Agonists
Class Summary
Dopamine agonists are non-ergot agents that bind to D2 and D3 dopamine receptors in the striatum and substantia nigra.

Pramipexole (Mirapex, Mirapex ER)

Pramipexole is used as add-on therapy for patients whose condition is refractory to combination therapy and have bipolar depression. Pramipexole is a non-ergot, full dopamine agonist that binds to D2 and D3 dopamine receptors.

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In patients whose bipolar depression is unresponsive to monotherapy, consider the combination of lithium with lamotrigine.[3] Alternatively, consider short-term augmentation of antidepressant agents with a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), bupropion, and monoamine oxidase inhibitor (MAOI); patients using this treatment strategy must be closely monitored for triggering of manic symptoms.[3]

As in severe mania or severe mixed episodes, consider adding clozapine for augmentation, and closely monitor the patient for metabolic or other adverse effects.[3] Because of the known complications involved with clozapine, it is recommended that a psychiatric consultation be initiated.

The VA/DoD found insufficient evidence for or against the use of augmentation with aripiprazole, olanzapine, risperidone, haloperidol, oxcarbazepine, topiramate, ziprasidone, valproate, or carbamazepine in bipolar depression.[3] However, the VA/DoD advised against the use of gabapentin and tricyclic antidepressant agents (TCAs) for monotherapy or augmentation in patients with acute bipolar depression, except in cases in which there was[3] : (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

Dosing or medication adjustments

Switch to another effective treatment for patient intolerance to side effects. For patients that switch into mania or hypomania or enter a mixed manic state, follow the recommendations discussed above in Mania/hypomania or mixed episodes.

Reevaluate patients every 1-2 weeks for a minimum of 6 weeks. As noted earlier, the therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL.[3] If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached.[3]

In patients with a partial treatment response (no response 2-4 weeks after initiation of an adequate medication dose), consider augmenting the medication with additional agents as discussed under Combination therapy,discontinuing the current drug (tapered withdrawal with monitoring for antidepressant syndrome and mood destabilization) and switching to another effective agent, or electroconvulsive therapy (ECT) if multiple trials of switching medications/augmentation strategies have been unsuccessful.[3]

Other considerations
A study by Bauer et al suggested that lithium may also have a neuroprotective role.[83] However, this agent is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[84]

Atypical antipsychotics are increasingly being used for the treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (ie, major depression). However, ECT may also be considered for patients with severe mania or treatment-resistant mania, those who prefer ECT, and pregnant women with severe mania.[3] Ansari and Osser developed a very useful algorithm for the Harvard South Shore Program to treat a bipolar patient in a depressed phase through “an organized, sequential, and evidence-supported approach.”[85] Finally, another set of medications is chosen for the maintenance and preventive phases of treatment.

Diazgranados and colleagues reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of the N -methyl-D -aspartate (NMDA) antagonist ketamine was administered.[86] Increasingly, the role of glutamate in mood disorders is being researched, and experimental evidence shows that the NMDA receptor antagonist ketamine may be helpful in short-term treatment of depression, even in the context of bipolar disorder. However, it is important to note that the benefit of such treatment disappeared after 4 days.

Although antidepressant medications are most often prescribed for patients with bipolar disorder who are experiencing an acute depression, a study found that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression.[87]

Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[88] These medications not only serve to stabilize the patient’s mood, as the name implies, they can also dampen extremes of mania or depression. Kessing et al found that, in general, lithium was superior to valproate.[89]

Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, and asenapine) are also now frequently used to stabilize acute mania—or even to treat bipolar depression in some cases.

In the treatment of depression associated with bipolar disorder type II, Swartz and associates reported that 95% of relevant trials were published later than 2005.[90] They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. However, mixed support was noted for lamotrigine.[90]

Maintenance
The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,[91] as is the use of long-acting antipsychotics to help with the maintenance phase. The APA’s 2005 guideline watch for the treatment of patients with bipolar disorder considered both lamotrigine and lithium to have substantial utility in the maintenance treatment of patients with bipolar disorder.[52]

Popovic et al suggested the use of a Polarity Index to guide the choice of maintenance therapy in bipolar patients.[92] Based on results from randomized, placebo-controlled trials, the investigators indicated that this index may provide a measure of the relative preventive antimanic versus antidepressive efficacy of drugs that are used to treat bipolar disorder.[92] They defined a Polarity Index value greater than 1.0 as having a relative greater antimanic prophylactic efficacy, whereas a value less than 1.0 would have a relative greater antidepressive efficacy. The following are this study’s polarity indices results for maintenance drugs in bipolar disorder[92] :

Risperidone: 12.09
Aripiprazole: 4.38
Ziprasidone: 3.91
Olanzapine: 2.98
Lithium: 1.39
Quetiapine: 1.14
Lamotrigine: 0.40
Note that Popovic et al indicated the respective polarity indices for valproate and oxcarbazepine were potentially unreliable owing to the failure of their maintenance trials.[92]

There have been concerns that ziprasidone may have adverse effects on body weight, fasting lipids, and fasting glucose. When Pappadopulos et al looked at a comprehensive set of analyses of metabolic alternations in patients on this medication, they found no significant differences between the ziprasidone and placebo groups in levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies.[93]

According to a multiple treatments meta-analysis of treatments for acute mania, the most efficacious treatments are haloperidol, risperidone, and olanzapine, significantly outperforming primary mood stabilizers and other antipsychotic medications.[94] In several randomized, double-blind, controlled studies, olanzapine monotherapy was significantly more effective in treating manic or mixed episodes than haloperidol[95] or divalproex monotherapy.[96] The adjunctive use of olanzapine with divalproex or lithium,[97] or of risperidone with divalproex or lithium, was also significantly more effective than divalproex or lithium alone.[98, 99]

As outlined in the APA’s 2002 clinical practice guideline,[100] benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. Additionally, the guideline stated that manic symptoms may be treated with chlorpromazine, which was deemed superior to placebo in a randomized trial and was deemed comparable to lithium (for controlling manic and psychotic symptoms) in acute treatment comparison trials.

Children and adolescents who have bipolar disorder are particularly challenging to treat, and their discussion is beyond the scope of this article (see the Medscape Reference article Pediatric Bipolar Affective Disorder). However, Hamrin and Iennaco developed guidelines and recommendations for medications and management approaches after an extensive literature review using research findings on medication effectiveness in this population.[101]

There is evidence that risperidone may be the best first-line treatment for childhood mania, as shown in a randomized controlled trial with patients aged 6 to 15 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) diagnosis of BPI (manic or mixed phase).[102] Specifically, risperidone was significantly more effective than lithium or divalproex sodium for the initial treatment of childhood mania; however, use of risperidone had the potential for serious metabolic side effects.[102]

Caution in polyantipsychotic therapy in bipolar disorder
In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis.[103]

In a study that sought to evaluate the safety and tolerability of second-generation antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar disorder receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), Brooks et al concluded that although polytherapy was fairly common in bipolar disorder, it was also associated with increased side effects (eg, dry mouth, sexual dysfunction, and constipation) and increased health service use (almost threefold) but not with improved clinical status or function.[104] Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.[104]

Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is useful in a number of instances in patients with bipolar affective disorder, or manic-depressive illness (MDI), such as the following[3] :

When rapid, definitive medical/psychiatric treatment is needed
When the risks of ECT are less than that of other treatments
When the bipolar disorder is refractory to an adequate trial with other treatment strategies
When the patient prefers this treatment modality
Often, the severity of the patient’s symptoms, the lack of response to medications, or the presence of contraindications to certain medications necessitates the use of ECT. This treatment modality has proven to be highly effective in the treatment of acute mania.

The 2010 Department of Veterans Affairs/Department of Defense (VA/DoD) clinical practice guideline for management of bipolar disorder indicates ECT is the primary therapy in bipolar disorder patients that present with psychotic symptoms, catatonia, severe suicidality, food refusal leading to nutritional compromise, or who have a history of previous positive response to ECT.[3] Indeed, in a review of 50 years’ experience with ECT for acute manic episodes, data from early literature revealed that 313 of 400 patients with acute mania who received ECT showed significant clinical improvement.[105]

Dietary and Activity Measures
Unless the patient with bipolar affective disorder, or manic-depressive illness (MDI), is on monoamine oxidase inhibitors (MAOIs), no special diet is required. Patients should be advised not to make significant changes in their salt intake, because increased salt intake may lead to reduced serum lithium levels and reduced efficacy, and reduced intake may lead to increased levels and toxicity.

Although a meta-analysis by Starris et al found strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3, omega-3 does not improve bipolar mania.[106]

Patients in the depressed phase are encouraged to exercise. These individuals should try to develop a regular daily schedule of major activities, especially times of going to bed and waking up. Propose a regular exercise schedule for all patients, especially those with bipolar disorder. Both the exercise and the regular schedule are keys to surviving this illness. However, increases in exercise level, with increased perspiration, can lead to increased serum lithium levels and lithium toxicity.

Complications
The main complications of bipolar affective disorder, or manic-depressive illness (MDI), are suicide, homicide, and addictions.

Previously or currently suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. The risk of self-destructive behavior and death is lifelong. Hong et al’s study demonstrated a genetic link between bipolar disorder and suicidal behavior, especially in white individuals.[107] According to a more recent study, men with bipolar disorder are at higher risk for suicide.[108]

The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study, a 2-year prospective, observational study, suggested the following characteristics found in patients with bipolar disorder who are suicidal may help identify subjects at risk for suicidal behavior[109]:

Female sex
A history of alcohol abuse
A history of substance abuse
Young age at first treatment for a mood episode
Longer disease duration
Greater depressive symptom severity (5-item Hamilton Depression Rating Scale [HAMD-5] total score)
Current benzodiazepine use
Higher overall symptom severity (Clinical Global Impression-Bipolar Disorder [CGI-BP]: mania and overall score)
Poor compliance.

Quality of life (QOL) has been an important way to look at the effects of mental illness. Bipolar disorder type I (BPI) results in diminished quality of life as measured by health utility and QOL and utility-based health-related quality of life. The QOL losses in patients with BPI were less than those in persons with schizophrenia. The patients with depression sustained the greatest loss in QOL.[111]

In a study by Fiedorowicz et al, hypomania symptoms were frequently associated with progression to bipolar disorder, even when symptoms were low intensity; however, most patients did not have hypomania symptoms at baseline.[112] The study concluded that monitoring for progression to bipolar disorder is necessary in patients with long-term major depressive disorder.

Some of the most challenging situations involve children and adolescents with severe emotional lability. Often, psychiatrists have applied the bipolar diagnosis to this group. Leibenluft reviewed this situation and concluded that children have increasingly been diagnosed with bipolar disorder.[113] In some cases, the criteria were clearly met, whereas other cases were less clear.

Severe mood dysregulation is a syndrome formulated to describe the symptoms of children who do not clearly meet the criteria for bipolar disorder. Leibenluft’s findings revealed that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders (not bipolar disorders) in adulthood. In fact, data suggest that children and adolescents with severe mood dysregulation have lower familiar rates of bipolar disorder than children and adolescents with bipolar disorder.

Prevention and Long-Term Monitoring
Prevention is the key to the long-term treatment of bipolar affective disorders, , or manic-depressive illness (MDI), as follows:

First, use medications such as lithium serve as mood stabilizers
Second, psychoeducation is instituted for the patient and the patient’s family; it is critical that the patient and the patient’s family understand and recognize the importance of medication compliance and the early signs of mania and depression
Regardless of the pharmacologic regimen chosen in individual patients with acute bipolar mania, hypomania, or mixed episodes, and those with bipolar depression, reevaluate for treatment response every 1-2 weeks for a minimum of 6 weeks.[3] Continue to monitor these individuals for the following situations[3] :

Depressive symptoms (or changes in), suicidal/homicide ideation
Neurovegetative symptoms
New-onset/change in psychotic symptoms or manic/hypomanic symptoms
Illicit substance use
Medication side effects and compliance
Medical stability
Significant psychosocial changes
Reevaluate all patients for treatment response at 4-8 weeks, after each change in treatment, and periodically until full remission is achieved.[3] Full remission is defined in patients with mania as the absence of significant mania symptoms for 2 months; in patients with mixed episode, it is the absence of significant mania or depression symptoms for 2 months; and in those with bipolar depression, it is the absence of significant depressive symptoms for 2 months.

Treat adult patients who have had an acute manic episode for a minimum of 6 months after the initial episode is controlled; encourage these individuals—as well as those who have had more than 1 manic episode or with 1 manic and 1 depressive episode, or 3 or more depressive episodes—to continue on lifelong prophylactic pharmacotherapy.[3] Following full remission of the depressive episode, consider withdrawing antidepressant treatment after 4-6 months. Discontinuation should consist of a gradual taper over a minimum 2-4–week period, unless medically contraindicated.[3]

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History:

Correct diagnosis of a disorder leads to proper effective treatment. Nowhere is that more relevant than in diagnosing a patient with bipolar affective disorder, or manic-depressive illness (MDI).

Perform a thorough clinical assessment for patients with a manic, hypomanic, or mixed episode, or those with a bipolar depression episode, including information about the patient’s clinical and psychosocial status, medical and psychiatric comorbidities, current and past medications as well as medication compliance, and substance use.[3] Obtain a detailed review of symptoms, symptom severity, and their effects on daily functioning in combination with the use of a standard tool.[3]

The diagnosis of bipolar disorder type I (BPI) requires the presence of a manic episode of at least 1 week’s duration or that leads to hospitalization or other significant impairment in occupational or social functioning. The episode of mania cannot be caused by another medical illness or by substance abuse. These criteria are based on the specifications of the DSM-V.[2] The Department of Veterans Affairs and Department of Defense (VA/DOD) recommend using a standardized rating scale such as the Young Mania Rating Scale to assess the severity of a manic episode.[3]

Manic episodes are feature at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness (referred to as gateway criteria). At least 3 of the following symptoms must also be present[2] :

Grandiosity
Diminished need for sleep
Excessive talking or pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Excessive pleasurable activities, often with painful consequences
The mood disturbance is sufficient to cause impairment at work or danger to the patient or others. The mood is not the result of substance abuse or a medical condition.

Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 consecutive days’ duration. At least 3 of the following symptoms are also present[2] :

Grandiosity or inflated self-esteem
Diminished need for sleep
Pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Engaging in activities with a high potential for painful consequences
The mood disturbance is observable to others. The mood is not the result of substance abuse or a medical condition. The episode is not severe enough to cause social or occupational impairment.

Major depressive episodes are characterized as, for the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of the symptoms being either a depressed mood or characterized by a loss of pleasure or interest[2] :

Depressed mood
Markedly diminished pleasure or interest in nearly all activities
Significant weight loss or gain or significant loss or increase in appetite
Hypersomnia or insomnia
Psychomotor retardation or agitation
Loss of energy or fatigue
Feelings of worthlessness or excessive guilt
Decreased concentration ability or marked indecisiveness
Preoccupation with death or suicide; patient has a plan or has attempted suicide
Symptoms cause significant impairment and distress and are not the result of substance abuse or a medical condition

The mixed symptomatology is quite common in patients presenting with bipolar symptomatology. This often causes a diagnostic dilemma[61] and has prompted a revision to the definition of bipolar disorder in DSM-5. With the aim of capturing mixed symptoms more effectively, the “mixed episode” diagnosis has been eliminated in favor of a “mixed features specifier” that could be added to any mood bipolar disorder diagnosis.[62] Other specifiers include anxious distress, rapid cycling, mood-congruent psychotic features, catatonia, peripartum onset and seasonal pattern.

Of interest, when investigating bipolar mixed states, Swann and colleagues concluded that although controversy exists regarding the definitions and properties of mixed states, the concept of mixed states and their characteristics over a range of clinical definitions and diagnostic methods has remained consistent.[63] Moreover, “distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.”[63]

In addition to the well-known differences between manic and hypomanic episodes, other key differences exist between BPI and BPII that may be used to help distinguish between the 2 types of conditions. Data from 1429 bipolar patients included in the National Epidemiological Survey on Alcohol and Related Conditions showed significant differences between BPI and BPII patients in unemployment, a history of a suicide attempt, depressive symptoms (eg, weight gain, feelings of worthlessness), and the presence of specific phobias.[64]

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Bipolar Affective disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge.[1]

Signs and symptoms
Bipolar affective disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania.

Manic episodes are feature at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness (referred to as gateway criteria). At least 3 of the following symptoms must also be present[2] :

Grandiosity
Diminished need for sleep
Excessive talking or pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Excessive pleasurable activities, often with painful consequences
Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 consecutive days’ duration. At least 3 of the following symptoms are also present[2] :

Grandiosity or inflated self-esteem
Diminished need for sleep
Pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Engaging in activities with a high potential for painful consequences
Major depressive episodes are characterized as, for the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of the symptoms being either a depressed mood or characterized by a loss of pleasure or interest[2] :

Depressed mood
Markedly diminished pleasure or interest in nearly all activities
Significant weight loss or gain or significant loss or increase in appetite
Hypersomnia or insomnia
Psychomotor retardation or agitation
Loss of energy or fatigue
Feelings of worthlessness or excessive guilt
Decreased concentration ability or marked indecisiveness
Preoccupation with death or suicide; patient has a plan or has attempted suicide

Diagnosis
Examination of patients with suspected bipolar Affective disorder includes evaluation using the Mental Status Examination as well as assessment of the following:

Appearance
Affect/mood
Thought content
Perception
Suicide/self-destruction
Homicide/violence/aggression
Judgment/insight
Cognition
Physical health
Testing

Although bipolar disorder is diagnosed based on the patient’s history and clinical course, laboratory studies may be necessary to rule out other potential causes of the patient’s signs and symptoms as well as to have baseline results before administering certain medications.

Laboratory tests that may be helpful include the following:

CBC count
ESR levels
Fasting glucose levels
Electrolyte levels
Protein levels
Thyroid hormone levels
Creatinine and blood urea nitrogen levels
Liver and lipid panel
Substance and alcohol screening
Depending on the patient’s presentation, other laboratory tests may be indicated, which may include the following:

Urinary copper levels
Antinuclear antibody testing
HIV testing
VDRL testing
Electrocardiography is important in elderly patients and before antidepressant therapy. Electroencephalography and/or MRI may be appropriate for selected patients.

Management
The treatment of bipolar affective disorder is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase, and it may involve a combination of psychotherapy and medication. Always evaluate patients with mania, hypomania, or mixed episode, and those with bipolar depression, for suicidality, acute or chronic psychosis, or other unstable or dangerous conditions.[3]

Pharmacotherapy

Medications used to manage patients with bipolar disorder include the following:

Benzodiazepines (eg, lorazepam, clonazepam)
Antimanic agents (eg, lithium)
Anticonvulsants (eg, carbamazepine, valproate sodium, valproic acid, divalproex sodium, lamotrigine, topiramate)
First-generation antipsychotics (eg, inhaled loxapine, haloperidol)
Second-generation antipsychotics (eg, asenapine, ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, olanzapine and fluoxetine, clozapine, paliperidone)
Phenothiazine antipsychotics (eg, chlorpromazine)
Dopamine agonists (eg, pramipexole)
Nonpharmacotherapy

Psychotherapy may help to decrease relapse rates, improve quality of life, and/or increase functioning, or more favorable symptom improvement.[4]

Electroconvulsive therapy may be useful in selected patients with bipolar disorder.

SOURCE MEDSCAPE;

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Types of Mental Illness

There are many different conditions that are recognized as mental illnesses. The more common types include:

Anxiety disorders: People with anxiety disorders respond to certain objects or situations with fear and dread, as well as with physical signs of anxiety or panic, such as a rapid heartbeat and sweating. An anxiety disorder is diagnosed if the person’s response is not appropriate for the situation, if the person cannot control the response, or if the anxiety interferes with normal functioning. Anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias.

Mood disorders: These disorders, also called affective disorders, involve persistent feelings of sadness or periods of feeling overly happy, or fluctuations from extreme happiness to extreme sadness. The most common mood disorders are depression, bipolar disorder, and cyclothymic disorder.

Psychotic disorders: Psychotic disorders involve distorted awareness and thinking. Two of the most common symptoms of psychotic disorders are hallucinations — the experience of images or sounds that are not real, such as hearing voices — and delusions, which are false fixed beliefs that the ill person accepts as true, despite evidence to the contrary. Schizophrenia is an example of a psychotic disorder.

Eating disorders: Eating disorders involve extreme emotions, attitudes, and behaviors involving weight and food. Anorexia nervosa, bulimia nervosa, and binge eating disorder are the most common eating disorders.
Impulse control and addiction disorders: People with impulse control disorders are unable to resist urges, or impulses, to perform acts that could be harmful to themselves or others. Pyromania (starting fires), kleptomania (stealing), and compulsive gambling are examples of impulse control disorders. Alcohol and drugs are common objects of addictions. Often, people with these disorders become so involved with the objects of their addiction that they begin to ignore responsibilities and relationships.

Personality disorders: People with personality disorders have extreme and inflexible personality traits that are distressing to the person and/or cause problems in work, school, or social relationships. In addition, the person’s patterns of thinking and behavior significantly differ from the expectations of society and are so rigid that they interfere with the person’s normal functioning. Examples include antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder.

Obsessive-compulsive disorder (OCD): People with OCD are plagued by constant thoughts or fears that cause them to perform certain rituals or routines. The disturbing thoughts are called obsessions, and the rituals are called compulsions. An example is a person with an unreasonable fear of germs who constantly washes his or her hands.

Post-traumatic stress disorder (PTSD): PTSD is a condition that can develop following a traumatic and/or terrifying event, such as a sexual or physical assault, the unexpected death of a loved one, or a natural disaster. People with PTSD often have lasting and frightening thoughts and memories of the event, and tend to be emotionally numb.

http://www.bipolar4lifesupport.co

Even though expressing your anger can be good for you, flying into a rage at every suspected slight isn’t the answer. For instance, blowing off steam by hurling hardware at your hubby or breaking plates over the boss’s head aren’t great solutions. But it is possible — even desirable — to use anger in a positive rather than negative way.

Forget the pop notion of channeling anger into more productive pursuits. “Relationship enhancement is the most productive outlet possible for anger,” says Deborah Cox, PhD, a psychologist at Southwest Missouri State University in Springfield — and this can happen when you let the other person see you’re upset. So what concrete tips might help when you’re mad as hell and not going to take it any more? Read on.

Seek out a safe place to seethe. Before confronting the object of your wrath, talk with a trusted friend, co-worker, or counselor who can help get to the root of what’s pressing your buttons. Mulling it over with someone safe may help you figure out less hostile, more instructive ways to express your feelings with a loved one, colleague, or boss.

Approach the person who sent your blood boiling in the first place. As a general guideline, the more significant the relationship, the more important it is to articulate feelings in a constructive way, says Dana Crowley Jack, EdD, a psychologist at Fairhaven College at Western Washington University in Bellingham. She suggests trying something like, “This is bothering me. Something has to change. How can we deal with it?”

Identify the reason behind the rage. There’s always something underlying an angry reaction. The trick here is to find the trigger. If it’s not obvious, keeping a log of anger experiences may help you uncover patterns. For some people, professional help may be needed to delve through deep-rooted feelings of shame and anger that started in childhood.

Find a physical release. Though jogging and other physical activities can be helpful, Cox advocates an anger workout: hitting a mattress with a tennis racket or slapping the sofa with a bat when you really start to see red. The key, says Cox, is to talk as you thwack the furniture. Engaging large muscle groups along with your voice should help you work through some of your fury. Kickboxing or Tae-Bo may give the same results. You’ll feel less likely to lose it if you have a physical release first, explains Cox. “When a client tells me: ‘If I really let it out, we’d all burst into flames,’ then I might suggest an anger workout,” she says.

Take several deep breaths. If you find yourself blinded by heat-of-the-moment anger, try to buy some time to cool off a bit, especially if you think you’re at risk of harming someone physically or emotionally. You may even need to walk away from the situation for a while. Remember, though, that in the long run, fleeing the scene won’t help you express yourself. So ask for a few moments to collect your thoughts and then say what needs to be said.

Look for like-minded souls. All fired up about a societal injustice? Sick of suffering? Then hook up with people who share your passion or problem through a support group or organization. Consider working with an organization for change, like Mothers Against Drunk Driving (MADD). “Joining other people who care about what you do can transform anger into a positive expression,” says Jack.

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Web MD

Everyone has memory blips from time to time — the word that’s on the very tip of your tongue, or the house keys that aren’t where you swear you left them. As you get older, these kinds of slip-ups may become even more common and frequent.

Yet you don’t have to resign yourself to memory loss. Try 9 simple steps that can help keep your brain sharp as you age.

1. Step It Up

A 30-minute daily walk is one of the best things you can do for your body, including your brain.

“Physical exercise has the best evidence for preserving memory and mental function with aging,” says R. Scott Turner, MD, PhD, director of the Memory Disorders Program at Georgetown University Medical Center.

Exercise can help prevent conditions that can lead to memory loss, such as:

High blood pressure
Diabetes
High cholesterol
Obesity
Stroke
Some studies suggest that physical activity also triggers the release of a protein called BDNF, which promotes healthy nerve cells in the brain. That could give your memory a boost.

2. Go Mediterranean

A healthy diet is always good for your brain, but one eating style in particular may be best for preserving memory. “There’s good evidence for the Mediterranean-style diet,” says Argye Hillis, MD, professor of neurology at Johns Hopkins Medicine.

Keeping to a Mediterranean diet doesn’t mean pasta and pizza, she says, “but lots of fruits and vegetables, fish rather than red meat, and olive oil.”

One study found people who closely followed this diet were nearly 20% less likely to develop thinking and memory problems than people who didn’t stick to a Mediterranean eating plan.

3. Engage Your Brain

“Just like physical exercise, mental exercise is good for you,” says Mustafa Husain, MD, director of the geriatric psychiatry division at Duke University School of Medicine.

Play cards, join a book club, watch a football game with friends and discuss the score, or play a brain-training app. Any mentally challenging activity will keep your mind sharp.

4. Stay Social

Card games and book clubs also keep you socially active — another plus for your brain.

“The more social connections someone has, the better they are at preserving mental function and memory,” Turner says.

Social interaction also enhances memory through its effects on mood. “We see a lot more depression in people who are socially isolated,” Husain says. “Depression itself can cause dementia.”

5. Sleep Right

Try to get a good night’s sleep. “Attention and concentration go down when sleep is restless, and mental function is not as sharp as it is in those who have normal, restful sleep,” Husain says.

Try these tips to get better sleep:

Avoid big meals before bed.
Go to bed at the same time each night and get up at the same time each morning.
Don’t drink caffeine or alcohol close to your bedtime.
Avoid smoking or other forms of nicotine.
6. Stop Stress

“Being under stress is very bad for your brain,” Turner says. High levels of the stress hormone, cortisol, make it harder to pull out information from your brain’s memory.

To relieve stress, try different ways to relax, like meditation, yoga, or massage.

7. Stub Out Cigarettes

If you smoke, quit. Smoking speeds up memory loss as you age.

Smoking’s effect on memory is probably due to small strokes it can cause in the brain, Turner says. Try nicotine replacement, medicine, or counseling to help you kick the habit for good.

8. Get Checked

Sometimes, medical conditions like thyroid disease, diabetes, depression, or a vitamin deficiency can trigger memory loss.

Certain medicines, such as sleep and anxiety drugs, can also affect your ability to remember. See your doctor to get checked and treated for these problems, and to go over all your medicines.

9. Use Memory Tricks

When you have trouble with everyday memory, it helps to have a few tricks up your sleeve. Every time you learn a new name or word, say it out loud to seal it into your brain. Mentally connect each new name with an image. If you meet a girl named April, picture a tree in bloom to represent the month of April.

To help with recall, post sticky notes around the home and office, or set reminders on your phone so you’ll know when it’s time to take your medicine or head to an important meeting.

http://www.bipolar4lifesupport.co

WEB MD

Despite its huge impact on health and society, depression is still stigmatized and neglected worldwide, and it should receive more attention, argues an editorial in CMAJ (Canadian Medical Association Journal).

“On a global scale, [the burden of depression] is greater than that of diabetes or tuberculosis,” writes Dr. Kirsten Patrick, Deputy Editor, CMAJ. “TB and malaria, with lesser global burden, get official WHO [World Health Organization] global public health ‘days.’ Not depression. In high-income countries, only ischemic heart disease and stroke cause more disability than unipolar depression.”

Despite high-profile cases like the recent death of Robin Williams, depression does not seem to be a priority, although it affects people of all socioeconomic levels in rich and poor countries.

“We are not alone in asking why mental illness is such a low priority worldwide, in spite of coordinated efforts to destigmatize mental illness in recent years,” writes Dr. Patrick.

Depression, a disease that primarily affects people in their working years, can affect ability to function, can result in missed work days and is linked to increased risk of long-term physical conditions. The substantial negative social and health impact should not be ignored.

Dr. Patrick urges that we need greater awareness overall of the devastating impact of depression on society and should make concerted investments to make it easier for people to be treated for depression. We also need to dedicate resources to finding better treatments because many currently available treatments are ineffective.

“In Canada, we need to stop treating depression as a Cinderella disease. We need to fund research that can make a difference to people with depression. The federal government must make a commitment to improving mental-health infrastructure nationwide. Health practitioners ought to be able to connect patients identified as depressed with adequate support and appropriate treatment without delay.”

“Although substantial resources are needed, the high cost of depression to individuals, families and society justifies the expense. But such resources will only receive priority if we all decide to pay more positive attention to depression,” Dr. Patrick concludes.

In a new study published in JAMA Psychiatry, scientists claim to have identified and measured the responses to rewards during nicotine withdrawal across humans and rats.

woman snapping a cigarette
Cigarette smoking is a leading cause of preventable death worldwide.

About 20% of the US population smoke cigarettes, although more than half of this group try to quit each year. However, less than 10% of smokers attempting to quit are able to remain smoke-free, with most relapses occurring within 48 hours of cessation.

Cigarette smoking is a leading cause of preventable death worldwide.

Researchers want to understand more about the process of withdrawal and why people have difficulty quitting smoking. A greater understanding of the mechanisms at work should lead to more effective treatments to help smokers quit for good.

The researchers behind the new study say that “response to reward” is the brain’s ability to derive pleasure “from natural things such as food, money and sex.” Depression is associated with a reduced ability to respond to reward.

The scientists, from Florida Atlantic University in Boca Raton, University of California San Diego, Harvard Medical School in Boston, MA, and Washington University School of Medicine in St. Louis, MO, used what they call a “translational behavioral approach” to take different behavioral measurements from the rats and humans.

Analyzing the behaviors, the researchers found that nicotine withdrawal had a similar effect on reducing reward responsiveness in both human smokers and nicotine-treated rats. This reduced responsiveness was particularly strong in smokers with a history of depression.

The researchers explain that their study breaks new ground as it is the first study of its kind to replicate experimental results across species. They say this cross-species analysis allows for greater generalizability and provides a more reliable way to identify neurobiological mechanisms.

Research could lead to therapies targeting reward dysfunction

Lead author Michele Pergadia, PhD, associate professor of clinical biomedical science in the Charles E. Schmidt College of Medicine at Florida Atlantic University, says:

“The fact that the effect was similar across species using this translational task not only provides us with a ready framework to proceed with additional research to better understand the mechanisms underlying withdrawal of nicotine, and potentially new treatment development, but it also makes us feel more confident that we are actually studying the same behavior in humans and rats as the studies move forward.”

Pergadia says that future studies will look more closely at how depression vulnerability relates to reward sensitivity, as well as mapping the full course of withdrawal-related reward deficits in an effort to develop new smoking cessation aids.

“Many smokers are struggling to quit, and there is a real need to develop new strategies to aid them in this process. Therapies targeting this reward dysfunction during withdrawal may prove to be useful,” she adds.

In 2013, JAMA Psychiatry also published a study investigating whether prenatal exposure to maternal cigarette smoking had an effect on response to reward.

The researchers compared a group of 177 adolescents who had been exposed to maternal cigarette smoking prenatally with 177 peers matched by sex and maternal educational level who had not been exposed.

Analyzing activity in the ventral striatum area of the brain using functional magnetic resonance imaging, the researchers in that study reported a weaker response during reward anticipation in the prenatally exposed teens compared with the non-exposed teens.

However, the study reports no differences between the responsively of the ventral striatum in the exposed and non-exposed teens upon receipt of the reward. The authors wrote:

“The weaker responsivity of the ventral striatum to regard anticipation in prenatally exposed adolescents may represent a risk factor for substance use and development of addiction later in life. This result highlights the need for education and preventive measures to reduce smoking during pregnancy.”

Written by David McNamee

Around one-third of couples who embark upon fertility treatment are not successful in their endeavor, leaving them to adjust to an unfulfilled child-wish. Now, a new study published in the journal Human Reproduction suggests women who have difficulty accepting that they will not conceive a child after fertility treatment have worse long-term mental health than those who are able to let go of their desire to reproduce.

Woman with counselor
“It is quite striking to see that women who do have children but still wish for more children report poorer mental health than those who have no children but have come to accept it,” says Dr. Sofia Gameiro.

Researchers from the study, led by Dr. Sofia Gameiro of the School of Psychology at Cardiff University in the UK, say theirs is the first to use a large group of women to assess the different factors that could affect mental health a decade after unsuccessful fertility treatment.

“It was already known that people who have infertility treatment and remain childless have worse mental health than those who do manage to conceive with treatment,” says Dr. Gameiro. But she adds that previous research did not consider other factors for why this is.

As such, for their study, the researchers included other circumstances, such as whether or not they have children, whether they still want children, their diagnosis and medical treatment.

To conduct their research, the team – which included colleagues from the Netherlands – analyzed questionnaire answers from over 7,000 women who initiated fertility treatment at hospitals in the Netherlands between 1995-2000.

Because the questionnaires were sent to the women between January 2011-2012, their last fertility treatment would have been between 11-17 years prior to answering the questionnaire.

The questionnaire inquired about age, marital status, education, menopausal status, whether the infertility was due to them, their partners or both, and what fertility treatment they had received. They also completed a mental health questionnaire that asked how they felt during the past 4 weeks.

Women who still wanted children years later had worse mental health

In addition to the questionnaires, the researchers asked the women whether they had children, and if so, whether they were biological or adopted, as well as whether they still wished for children.

Though the majority of women had accepted the failure of their fertility treatment, the researchers found that 6% of them still wanted children at the time of the questionnaire, and this coincided with worse mental health.

In fact, Dr. Gameiro notes that the women who still wanted to have children were up to 2.8 times more likely to have mental health problems than those women who had accepted their circumstances.

She further explains:

“The strength of this association varied according to whether women had children or not. For women with no children, those with a child-wish were 2.8 times more likely to have worse mental health than women without a child-wish.

For women with children, those who sustained a child-wish were 1.5 times more likely to have worse mental health than those without a child-wish. This link between a sustained wish for children and worse mental health was irrespective of the women’s fertility diagnosis and treatment history.”

The findings also revealed that when infertility was due to male factors or had an unknown cause, women tended to have better mental health. Additionally, women who started fertility treatment at older ages had better mental health than those who started younger.

“It is quite striking to see that women who do have children but still wish for more children report poorer mental health than those who have no children but have come to accept it,” adds Dr. Gameiro.

Study has certain limitations

Though their sample size was large and nationally representative, the researchers note a limitation to their study: women without psychological data were less likely to have biological children, and nearly 16% of women who did not respond deemed the questionnaire too confronting or replied that it elicited too many emotional memories.


As such, the researchers say this could have resulted in an underestimation of the proportion of women with a continued child-wish.

The team also says their findings only show that there is a connection between an unfulfilled child-wish and worse mental health, not that the unfulfilled wish is the cause of the mental health problems.

Still, the researchers say their findings show the importance of psychological care for infertility patients and that more attention should be paid to the adjustment over longer periods of time.

Dr. Gameiro concludes:

“We live in societies that embrace determination and persistence. However, there is a moment when letting go of unachievable goals (be it parenthood or other important life goals) is a necessary and adaptive process for wellbeing. We need to consider if societies nowadays actually allow people to let go of their goals and provide them with the necessary mechanisms to realistically assess when is the right moment to let go.”